Rheumatoid arthritis lecture epidemiology rheumatoid arthritis is registered. Rheumatoid arthritis: new approaches to an old problem Diagnosis. X-ray and MRI diagnostics
. Systemic arthritis
. Oligoarthritis (persistent)
. Oligoarthritis (common)
. Polyarthritis (rheumatoid factor positive)
. Polyarthritis (rheumatoid factor negative)
. Enthesitis arthritis
. Psoriatic arthritis
. Unclassified arthritis
In this classification, homogeneous diseases are combined into groups in accordance with their clinical manifestations and course.
Epidemiology of JRA
According to the results of various studies, the prevalence of JRA ranges from 2 to 19 cases per year per 100,000 population, and the frequency of the disease varies in different ethnic groups, and therefore the etiology of this pathology is assumed to be a genetic predisposition, as well as the influence of environmental factors, such as climatic conditions and geographical conditions. Some researchers consider influenza virus as a possible cause of the development of JRA.
Clinical manifestations
Systemic arthritis
The onset of the disease is observed mainly at 2 years of age, but can also occur in one-year-old children. Boys and girls are affected with equal frequency. Systemic arthritis in adults, known as Still's disease, is rare. The main clinical manifestations are fever (up to 40°C), the peak of which occurs in the daytime, transient maculopapular rash and arthritis. Other symptoms include serositis, hepatosplenomegaly, and generalized lymphadenopathy. The diagnosis is confirmed by the following laboratory parameters (during the acute phase): increased erythrocyte sedimentation rate (ESR), increased C-reactive protein (CRP), neutrophilic leukocytosis and thrombocytosis. Over time (an average of 3-4 years), systemic manifestations decrease, and polyarthritis becomes the leading symptom.
In most cases of moderate systemic arthritis, the disease resolves spontaneously. Symptomatic therapy consists of the use of non-steroidal anti-inflammatory drugs (NSAIDs). Fever is treated with ibuprofen at a dose of 40-50 mg/kg per day (in 3-4 doses) or naproxen at a daily dose of up to 20 mg/kg. In severe cases, it is necessary to prescribe corticosteroids in high doses (1-2 mg/kg).
Untreated systemic arthritis can lead to macrophage activation syndrome(also known as hemophagocytic syndrome) with a high mortality rate. In these cases, intravenous administration of methylprednisolone and cyclosporine sequentially is recommended. With the development of amyloidosis, the use of chlorambucil is effective, but the use of this drug is limited due to severe adverse reactions.
Oligoarthritis (persistent)
With oligoarthritis, no more than 4 joints are affected (usually the wrist, knee and ankle). With this type of disease, especially in girls, antinuclear antibodies and uveitis are often detected. The general condition, as a rule, does not suffer; Due to their early age, children cannot accurately determine the location of pain. However, a more detailed survey of parents reveals lability in the child’s mood, appetite and behavior. In most cases, the ESR remains normal.
Treatment is aimed at stopping the inflammatory process with the help of NSAIDs, physiotherapy and exercise therapy. Intra-articular corticosteroids are effective and safe. The prognosis for this form of JRA is favorable, remission occurs after 4-5 years.
Oligoarthritis (common)
At the beginning of the disease, no more than 4 joints are affected, but during the first year of the disease the number of affected joints increases. In most cases, ESR increases simultaneously with the appearance of early clinical signs - joint stiffness; later swelling and a local increase in temperature in the joint area appear.
The results of the studies showed the effectiveness of oral administration of methotrexate at a dose of 15-20 mg/m 2 once a week.
Polyarthritis
JRA, which begins with polyarthritis, usually occurs in adolescents and resembles the course of rheumatoid arthritis in adults. Patients in this group predominantly experience stiffness and contractures of the joints, requiring surgical intervention. In most cases, rheumatoid factor (RF) is absent. The prevalence of RF-positive arthritis is low (3% in the UK) and the prognosis is less favourable.
In addition to NSAIDs, oral methotrexate can be used in treatment at a dose of 10 mg/m2 1 time per week. In severe cases, the dose of the drug can be increased to 1 mg/kg, and methotrexate should be administered parenterally (preferably subcutaneously).
Enthesitis arthritis
Clinical signs of this disease are unilateral (asymmetric) damage to the joints of the lower extremities, enthesitis and acute anterior uveitis, which occur in teenage boys. Typically, patients exhibit the HLA-B27 phenotype. It is believed that the clinical picture of this disease corresponds to ankylosing spondylitis in adults, with the difference that with Enthesitis arthritis only peripheral joints are affected (the sacroiliac joint is not affected).
The treatment of choice for peripheral arthritis is the use of sulfasalazine at a dose of 2-3 g/kg in addition to an NSAID (indomethacin). In severe cases, methotrexate is recommended. In general, the prognosis for this disease is favorable.
Psoriatic arthritis
In psoriatic arthritis, classic inflammation of the distal interphalangeal joints is combined with damage to large joints. Arthritis is often erosive in nature. The diagnosis can be suspected if there are changes in the skin and nails typical of psoriasis. The effectiveness of using methotrexate in patients in this group has not been definitively proven.
Treatment and prognosis of JRA
Systemic inflammation causes a general delay and cessation of growth, and local inflammation leads to accelerated growth of the epiphyses of the bones of the affected joints. In addition to general malaise, pain and joint deformation, the development of secondary amyloidosis, a fatal complication, is possible. In this regard, it is very important to achieve remission as early as possible. In most cases, this can be achieved by using methotrexate, which, however, is not effective enough for systemic arthritis. Comprehensive treatment of JRA is provided by the actions of the doctor together with physiotherapists, occupational therapists, child and family psychologists, school teachers and, possibly, employers.
Pathogenesis
The use of molecular biology methods has made it possible to identify a genetic predisposition to JRA, in which the histocompatibility system (HLA) antigens play a significant role. For example, a high prevalence of HLA-DRB1*0801 and *1401 antigens has been established in patients with polyarthritis, HLA-DRB1*0101 and 0801 in patients with the oligoarthritic form of JRA. The combination of the HLA-B27 antigen with ankylosing spondylitis and HLA-DRB1*0401 with RF-positive polyarthritis has also been proven.
Histological studies of the synovium of the affected joints demonstrate its thickening and abundant infiltration of mononuclear cells, mainly represented by activated T lymphocytes. This suggests that the interaction of T cell receptors with HLA peptides plays an important role in the pathogenesis of JRA.
It is also well known about the role of monocyte cytokines produced during JRA inside the joint and in the body as a whole. The effects of these molecules can be divided into pro-inflammatory (interleukins 1 and 12, tumor necrosis factor a, interferon g) and anti-inflammatory (interleukins 1ra, 10 and 13, soluble receptors for TNF-a and TNF-b ). An imbalance between pro-inflammatory and anti-inflammatory cytokines can lead to disease.
A detailed understanding of the mechanisms underlying JRA could lead to the development of new approaches to the treatment of this disease.
Prospects
Of great interest are studies aimed at searching and identifying genes associated with various types of JRA. It is also important to establish the “trigger” mechanisms responsible for the development of the disease and study epidemiological patterns. The effectiveness of new therapeutic drugs aimed at normalizing the balance of cytokines is currently being studied. The organization of open randomized trials is the key to achieving success in the treatment of JRA over the next decade.
Literature:
Woo P, Wedderburn LR. Juvenile chronic arthritis. Lancet 1998;351:969-73.
Rheumatoid arthritis affects millions of people around the world, but we can only offer symptomatic care to the patient as a treatment. Stopping or slowing down the destruction of joints and making the lives of patients as comfortable as possible are the challenges facing the scientific and medical community. But this requires a deep understanding of the biology of the process that constrains the movements of patients. In this article we will try to understand the medical, biological and social questions that rheumatoid arthritis poses to us.
We continue the series on autoimmune diseases - diseases in which the body begins to fight itself, producing autoantibodies and/or autoaggressive clones of lymphocytes. We talk about how the immune system works and why sometimes it starts to “shoot at its own people.” To maintain objectivity, we invited Doctor of Biological Sciences, corresponding member to become the curator of the special project. RAS, professor of the Department of Immunology of Moscow State University Dmitry Vladimirovich Kuprash. In addition, each article has its own reviewer, who delves into all the nuances in more detail.
In addition, fibroblasts begin to produce large amounts of matrix metalloproteinases and about inflammatory chemokines - cytokines that attract immune cells. Matrix metalloproteinases are special enzymes that can break down protein components of the extracellular matrix. They destroy the collagen networks that form the basis of cartilage. Tissue inhibitors of metalloproteinases, also produced by fibroblasts, are not enough to stop the avalanche-like process of joint destruction.
Immune cells, attracted by cytokines, infiltrate the synovium of the joint. This immune infiltrate contains T and B lymphocytes, macrophages, neutrophils, mast cells and other innate immune cells.
Despite the abundance of T cells in the affected joint, their functional role is still poorly understood. Attempts to treat patients by directly suppressing T-lymphocyte activity (for example, using the immunosuppressant cyclosporine) have been ineffective. This may be explained by the fact that different subpopulations of T lymphocytes are involved in the pathogenesis of rheumatoid arthritis, whose effects may be diametrically opposed. On the one hand, immunosuppressants suppress, as needed, the activity of type 1 T helper cells (Th1) and Th17 lymphocytes, which release many pro-inflammatory cytokines that increase inflammation and attract more and more immune cells to the joint. On the other hand, they similarly suppress the differentiation and functionality of regulatory T cells that could stop the inflammatory response.
At the same time, the use of abatacept, a drug based on the CTLA-4 molecule (not to be confused with therapeutic antibodies to it), which blocks the costimulatory signal between the lymphocyte and the antigen-presenting cell, turned out to be quite successful. This effect could be expected, because in the synovium there are quite a lot of dendritic cells that can activate T lymphocytes.
Disease dynamics may contribute to the confusion of the role of T lymphocytes. The fact is that T cells are important for starting the autoimmune process, but later, when more and more immune cells (for example, macrophages) are involved in the inflammatory cascade, they fade into the background. Treatment with drugs targeting T-lymphocytes begins only after the onset of symptoms, that is, already at the second stage of the disease. It is not surprising that with such a lagging strategy they are ineffective.
B cells and synovial plasma cells are also involved in the pathogenesis of rheumatoid arthritis. As a rule, B cells form spatially organized clusters with T cells in a special way, called tertiary lymphoid structures. Resembling lymph nodes in structure, they perform the same function: they facilitate the meeting of antigen-presenting cells with lymphocytes and their further maturation. The B lymphocyte itself can also act as an antigen-presenting cell. In addition, B cells synthesize proinflammatory cytokines, which further support the pathological cascade.
Autoantibodies produced by B lymphocytes have been used for many years as biomarkers in the diagnosis of rheumatoid arthritis. But they cannot be perceived only as “silent witnesses” of the disease - they contribute to its development and are even called arthritogenic. How everything happens is not yet entirely clear, but the correlation between the rate of development of the disease and the level of such antibodies in the blood has been reliably established. Antibodies (usually of the IgM class) to one's own immunoglobulins of the IgG class are called rheumatoid factor (RF). This is one of the manifestations of impaired tolerance to self-antigens, which characterizes the autoimmune process. It is believed that RF forms macroscopic immune complexes with IgG, which cause mechanical damage to the walls of blood vessels and synovial membranes, but this is not the only possible mechanism of the pathogenic action of RF.
In the blood serum of patients with rheumatoid arthritis, antibodies to cyclic citrullinated peptide (ACDC). Citrulline is one of the amino acids in the body that is not encoded in DNA by a specific codon, but is formed from arginine after protein synthesis (the reaction diagram is shown in Figure 5). Replacing arginine with citrulline affects the chemical properties of the protein and makes it more hydrophobic, which affects its spatial structure. Such unusually folded proteins can be detected by the immune system and autoantibodies are formed against them. Many synovial fluid proteins, including fibrin and fibrinogen, contain arginine residues, which, under inflammatory conditions, are modified to citrulline and cause an autoimmune response. According to the latest data, RF and ACCP enhance each other's effects.
Figure 5. Scheme of protein citrullination. Enzymes take part in the reaction deiminases, replacing the ketoimine group of arginine (=NH) with a ketone group (=O).
Macrophages are the main producers of proinflammatory cytokines responsible for the development of synovitis. In addition, they synthesize reactive oxygen and nitrogen species, as well as enzymes that destroy the intercellular matrix. This is also done by other innate immune cells present in the inflamed joint, such as neutrophils and mast cells. But still, the palm in triggering inflammation should be given to macrophages.
A cocktail of pro-inflammatory cytokines triggers the differentiation of osteoclasts that perform bone resorption, that is, simply destroy it. Under the influence of anti-inflammatory drugs, this process can be slowed down, but it is impossible to return the bone to its original appearance, since it is not able to regenerate while maintaining the same architecture.
Heads or tails: genetic and epigenetic predisposition to rheumatoid arthritis
Rheumatoid arthritis is a complex disease whose development is influenced by both genetic and environmental factors. A genome-wide search for associations has shown that certain variants of genes that regulate the functioning of the immune system have a significant impact on the occurrence and development of this disease.
The strongest influence on the predisposition to rheumatoid arthritis is major histocompatibility complex genes. As we remember from the first article in this series, it is the proteins encoded by these genes that are responsible for presenting the antigen to T lymphocytes. Some of their variants can carry out this process more effectively in relation to their own antigens, thereby contributing to the launch of the autoimmune process. One of the most interesting in this regard is the gene HLA-DRB1, whose connection with rheumatoid arthritis has long been known. It encodes components of the surface receptor HLA-DR of antigen-presenting cells that interacts with the T-cell receptor. Different alleles of this gene—for example, those encoding proteins with the QKRAA amino acid motif—are associated with the greatest susceptibility to the disease. The most “unfavorable” include options from the family DRB1*04(determining the serotype HLA-DR4) .
Allelic variants of genes for multiple proteins involved in T-lymphocyte activation are also responsible for the susceptibility of their carriers to rheumatoid arthritis. Among these proteins are molecules associated with the costimulatory signal (CD28, CTLA-4), proinflammatory cytokines and their receptors (IL2, IL2RA, IL21), necessary for the functioning of T cells, as well as various enzymes - important intracellular players in the activation of lymphocytes ( PTPN22, PRKCQ, TAGAP). The interaction of specific allelic variants of different genes (for example, HLA-DRB1 And PTPN22) increases the likelihood of disease.
In addition, during an infectious disease, immune complexes are formed, consisting of antigens and antibodies specific to them. If there are many complexes, then such antibodies themselves can become antigens. Antibodies against antibodies are the same rheumatoid factor that we talked about earlier.
Infectious agents can directly contribute to the development of rheumatoid arthritis. Recently, it has been shown that oral hygiene may influence the incidence of rheumatoid arthritis. The fact is that the bacterium that causes periodontal disease Porphyromonas gingivalis, is capable of synthesizing deiminase and, accordingly, taking part in the citrullination of host proteins, that is, humans.
Increasing evidence indicates that the composition of the gut microbiota is another important factor influencing the likelihood of developing rheumatoid arthritis. In model systems, it has been possible to convincingly show that certain types of bacteria are associated with rheumatoid arthritis. Perhaps in the near future we will have the development of a special diet that will allow us to keep them under control and thereby reduce the risk of developing autoimmunity.
It cannot be cured, but it can be alleviated. Current treatment strategies for rheumatoid arthritis
Since a clear target for the autoimmune process in rheumatoid arthritis cannot be found, it is not yet possible to develop a specific treatment. You can only reliably stop the inflammation and try to maintain the patient’s state of remission for as long as possible. The main modern treatment strategies are aimed at selecting the most effective anti-inflammatory drugs. Below we will talk about their various options.
The effect of taking DMARDs is observed in 60% of patients with rheumatoid arthritis, but it develops very slowly, so the course of taking the drug lasts at least six months. If during therapy the patient does not feel any improvement, then, as a rule, he is prescribed combination treatment with several DMARDs. However, you need to be careful with this tactic, as it significantly increases the likelihood of side effects.
Side effects of DMARDs typically affect the gastrointestinal tract and hematopoietic system. The fact is that DMARDs suppress the proliferation of the most actively dividing cells in our body, that is, immune cells (which is what their therapeutic effect is based on), but also other blood cells (for example, megakaryocytes, from which platelets are formed, and red blood cells) and cells intestinal epithelium, suffering completely undeservedly.
Biological drugs- a relatively new method of treating rheumatoid arthritis. They are antibodies or soluble receptors and can therefore specifically block certain molecules involved in the development of rheumatoid arthritis. Such “target molecules” can serve as pro-inflammatory cytokines and receptors on the surface of immune cells (Fig. 6).
Figure 6. Pattern of the immune response and the main biological drugs that can be used in the treatment of rheumatoid arthritis. To see the picture in full size, click on it.
The most common drugs that block proinflammatory cytokines are antibodies to tumor necrosis factor (TNF), interleukin-6 and interleukin-1. The first include, for example, infliximab And adalimumab- monoclonal antibodies that bind TNF. To block TNF, they also use etanercept- a drug consisting of a soluble TNF receptor and the Fc fragment of an antibody (IgG1). Therapeutic antibody tocilizumab blocks the interleukin-6 receptor, which also helps reduce inflammation. Anakinra- a genetically engineered version of the IL1-RA protein, a natural antagonist of the interleukin-1 receptor. By attaching to the receptor, anakinra blocks the transmission of a signal through it and, therefore, the launch of an inflammatory response.
As readers might have already guessed, in the treatment of rheumatoid arthritis it was simply impossible not to use agents that block the costimulatory signal to the T cell from antigen-presenting cells. This is the basis for the action of the previously mentioned abatacepta, consisting of a CTLA-4 molecule (a blocker of costimulatory molecules on the surface of antigen-presenting cells) and the Fc fragment of IgG1.
Since B cells play an important role in the pathogenesis of rheumatoid arthritis, suppression of their activity can also be a fairly effective treatment strategy. Application rituximab, an anti-CD20 monoclonal antibody drug, results in selective removal of mature B cells (antibody-producing plasma cells are not affected) and reduction in inflammation.
The use of biological drugs in combination with DMARDs mutually enhances their therapeutic effect, so these two groups of drugs have become the most significant in the treatment of rheumatoid arthritis. Alas, this is not the case in all countries. The high price of biological drugs greatly hinders their widespread use. In Russia, the cost, for example, of infliximab is about 50 thousand rubles per 100 mg. This is not enough even as a starting dose for a treatment that requires the patient to receive the drug at least every two months for a year or more.
Unfortunately, biological drugs are also not without serious side effects, primarily associated with a lack of selectivity in blocking molecules important for an effective immune response. The use of such drugs may weaken the adequate immune response to infection. Almost all biological drugs contain antibody fragments, and this can lead to the development of an autoimmune response in which they play the role of antigens. Targeted action and reduction of the immunogenicity of the drugs themselves are among the most important tasks that can be solved using new approaches to the development of biological drugs.
Constant monitoring of a patient with rheumatoid arthritis and timely change of treatment strategy in case of ineffectiveness of a particular drug can maintain a state of remission for years and even decades. Without proper treatment, inflammation and associated symptoms develop quickly enough that it can lead to surgical removal of the affected joints.
New drugs - minimum adverse reactions with maximum effectiveness
The use of biological drugs has proven to be the most effective treatment for rheumatoid arthritis, but serious side effects associated with the systemic nature of their action force scientists to develop new drugs. The next step in the evolution of rheumatoid arthritis therapy may be selective inflammatory blockers devoid of this disadvantage.
In the laboratory of Sergei Arturovich Nedospasov, located at the Institute of Molecular Biology of the Russian Academy of Sciences (Moscow), this problem has been studied for more than 10 years. Scientists believe that one of the possible ways to solve this problem is to create a drug that blocks the key pro-inflammatory cytokine, TNF, produced only by a certain type of cells, for example, macrophages. This selective neutralization will reduce inflammation associated with rheumatoid arthritis, but will not affect the body's ability to fight infections.
To solve this problem, a bispecific molecule was obtained, which consists of an antibody that blocks TNF and a second antibody that binds to the F4/80 molecule on the surface of mouse macrophages. When creating such a design, scientists used single-domain antibodies obtained from llama and camel, the bioengineering of which is described in the article by Oksana Goryaynova “ A camel will cure cancer!". Experiments on mice have shown that such antibodies actually do their job. Of course, the use of such drugs in the treatment of real patients is still very far away, but the first steps towards this have already been taken.
Patient organizations
Information support, legal assistance to patients, assistance in obtaining specialist consultations, rehabilitation, necessary medications - these are several areas of activity of patient organizations. In addition, a public organization can become a platform for communication and mutual support among patients.
In Russia, such an organization is the Russian Rheumatological Association “Nadezhda”. On its basis, schools and conferences for patients with various rheumatological diseases, including rheumatoid arthritis, are regularly held in many cities across the country. In addition, the main activity of the organization is aimed at developing patient guides and distributing them both in printed form and on the Internet.
At least one patient organization for patients with rheumatoid arthritis exists in almost every civilized country. The websites of American organizations are an excellent example of an information portal where patients can find all the necessary information about the course of the disease, methods of its treatment and diagnosis. Here are the addresses of some successful projects dedicated to rheumatoid arthritis:
- American public organization Arthritis Foundation;
- Johns Hopkins Center for Rheumatoid Arthritis.
Today, with timely diagnosis and adequate treatment, a patient with rheumatoid arthritis can lead an active lifestyle for quite a long time, and new scientific developments will help him do this even longer.
;30 Gut microbiome: the world inside us.
R. M. Balabanova, professor, doctor of medical sciences, head of the department for the study and correction of autoimmune disorders, Institute of Rheumatology, Russian Academy of Medical Sciences
E. V. Shekshina, Candidate of Medical Sciences, Junior Researcher
A chronic systemic immune-mediated inflammatory disease with predominant damage to peripheral (synovial) joints, such as symmetrical erosive-destructive polyarthritis, accompanied by the proliferation of synoviocytes and angiogenesis (which brings it closer to cancer), is called RHEUMATOID ARTHRITIS (RA).
The prevalence of RA among the adult population of various climatic and geographical zones is on average 0.6–1.3%. The annual incidence in recent years has remained at a high level - 0.02%. RA is characterized by sexual dimorphism: women are affected 3–4 times more often than men. During pregnancy, remission often develops. In women, the peak incidence of RA occurs at 35–55 years, in men – at 40–60 years.
Etiology and pathogenesis of the disease
To date, the cause of RA has not been clarified. In its development, the role of both genetic and environmental factors is equal, among which the participation of infection, immunization, nutrition, blood transfusion, smoking, UV irradiation, etc. is assumed.
A genetic predisposition to the disease is evidenced by its high aggregation in families of patients with RA. Its incidence at an early age is much more common in families where there were relatives with RA. The role of genetic predisposition to this disease is confirmed by its higher frequency among monozygotic twins (12–32%) compared to dizygotic twins (3.5–9%).
Of the endogenous factors in the development of RA, sex hormones play a certain role, which is confirmed by the high frequency of the disease among women, as well as the positive effect of pregnancy on the course of RA and its exacerbation after delivery or its interruption. Women with RA have a deficiency of androgens - testosterone and dehydroepiandrosterone; men also have low testosterone levels.
The participation of sex hormones in the development of RA confirms the influence of exogenous estrogens (oral contraceptives), which reduce the risk of developing RA.
Among the external environmental factors in the occurrence of this disease, the role of infection is primarily assumed. There is no classical epidemiological evidence of the infectious etiology of RA, but this does not exclude its involvement in a genetically predisposed organism, as evidenced by the results of animal studies.
A specific (infectious) trigger for RA has not been established, but there are many candidates: mycoplasma, parvovirus B19, cytomegalovirus (CMV), herpes simplex virus type 6, Epstein-Barr virus (EBV). One of the mechanisms for the development of so-called autoimmune diseases, which includes RA, is “molecular mimicry.” Microbes and viruses may contain protein structures (amino acid sequences) similar to those of the host. The immune response to a pathogen in order to eliminate it can “change direction,” resulting in a cross-reaction with self antigens that are structurally similar to foreign ones.
The serum of RA patients contains elevated titers of antibodies to the latent or replicative antigen of EBV. Peripheral blood T lymphocytes of RA patients are not able to control EBV-positive B-lymphoblast-like lines, and this explains the frequency of EBV-infected peripheral B lymphocytes in RA compared with controls. Long-term exposure to one or more viruses, which often occurs in RA, can play a trigger role in the initiation of immune inflammation, since viral antigens not only cross-react with host antigens, but also have an adjuvant effect.
Pathogenesis
EF RA(?) > Transformation of IgG into AutoAG > IgM, A, G-rheumatoid factors + AutoAG = CEC > synovial tissue > increased activity of inflammatory mediators, microvascular permeability, leukocyte chemotaxis, phagocytosis of CEC > damage to lysosomes of leukocytes and macrophages > release of lysosomal enzymes > damage to cellular structures > formation of new AutoAGs > chain reaction
An unknown etiological factor of rheumatoid arthritis causes a primary immune reaction in the form of the formation of antibodies in the form of IgG. For an unknown reason, they are transformed and turned into autoantigens, which, in conditions of immunodeficiency by Tsuppressors, initiate the production of antibodies of groups Ig M, A, G (rheumatoid factors) by B lymphocytes. They form circulating immune complexes (CICs) with the autoantigen, which settle mainly in the synovial membrane of the joints and cause an increase in the activity of inflammatory mediators, impaired microcirculation, and activation of leukocyte chemotaxis.
During the process of phagocytosis, the lysosomes of neutrophils and macrophages are damaged, lysosomal enzymes are released, damaging cellular structures. New autoantigens, new autoantibodies are formed, and the pathological process takes on the character of a chain reaction. It may subside for some time, but then resumes again under the influence of specific and nonspecific factors.
The outcome of the inflammatory process is characterized by a reduction and then cessation of cell migration into the inflamed tissue, followed by an increase in cell apoptosis and tissue restoration. Constant activation of monocytes and macrophages leads to their inability to block these processes, which contributes to the transition of acute inflammation to chronic.
Prostaglandins play an important role in the pathogenesis of RA.
Another mechanism involved in inflammation and cartilage destruction is increased neovascularization. This angiogenesis in the synovium is associated with the action of proinflammatory cytokines, which leads to increased penetration of inflammatory cells into the joint tissue, which provides nutrients necessary for the normal functioning of inflammatory and proliferating cells. An important role is played by neutrophils, an increase in the number of which in the synovial fluid leads to hyperproduction of chemoattractants. Degranulation of neutrophils is accompanied by the release of proteinases, reactive oxygen species, and products of arachidonic acid metabolism.
The processes occurring in the synovium in RA resemble local malignant neoplasms. The mass of newly formed cells and connective tissue is many times greater than the mass of normal synovial membrane. The pannus formed in RA has the ability to invade and destroy cartilage, subchondral bone and ligaments. Synoviocytes from RA patients have the phenotypic properties of transformed tumor cells. An increase in the level of growth factors - platelet and fibroblast - was found in the synovial fluid and tissues. The similarity between rheumatoid synovitis and localized malignancy is also evident at the molecular level. A number of cytokines have the ability to cause long-lasting phenotypic changes in cells.
The pathological process in RA primarily develops in the joints and periarticular tissues and has its own characteristics depending on the stage of the disease.
Synovitis is detected early, even in a clinically unchanged joint. Disturbances in the synovial membrane are caused by immunological processes. In the initial stages of the process, the stroma is sparsely infiltrated with lymphocytes, plasma cells, mast cells (mast cells) and macrophages. T lymphocytes have the morphological and immunological characteristics of antigen-dependent cells. B lymphocytes, as precursors of plasma cells, and plasma cells themselves synthesize immunoglobulins in situ.
At an early stage, there is a proliferation of type B covering synoviocytes, which are morphologically similar to fibroblasts. The cells form several layers with a focal “picket fence”. Capillaritis and productive vasculitis occur. At this stage, the predominance of exudative and alternative processes in the synovial membrane is revealed - edema, congestion and foci of fibrinoid changes.
The advanced stage is characterized by a picture of a chronic proliferative process. In this case, pronounced hyperplasia and hypertrophy of the villi are observed. The proliferation of covering synoviocytes with the formation of several layers and the presence of giant cells becomes more obvious.
In the morphogenesis of rheumatoid synovitis, an important place is occupied by damage to the microvasculature - vasculitis and angiomatosis. Deposits of immunoglobulins are detected in the walls of blood vessels. At this stage, rheumatoid nodules can form in the synovial membrane, and in the case of amyloidosis, amyloid masses.
A feature of the late period is pronounced angiomatosis, combined with productive vasculitis and thrombosis. The undulating course of the disease is also reflected in the morphology of the synovial membrane.
Beneath it, in the perichondral part, a synovial pannus is formed - vascular and fibrous tissue. During development, it grows into the cartilage, destroying it.
A specific morphological sign in RA is a rheumatoid nodule. It can be seen in various organs and tissues, but the most common localization is the skin and synovial membrane. The nodule is represented by a focus of fibrinoid necrosis, surrounded by palisade-shaped macrophages, lymphocytes and plasma cells. Often giant multinucleated cells are visible in it. Using monoclonal antibodies, it was possible to confirm the participation of immunopathological reactions in the development of rheumatoid nodules.
A special place in the progression of the rheumatoid process is occupied by vasculitis, which is detected in all organs, but does not have specific morphological signs. A study of skin vessels in RA patients with signs of cutaneous vasculitis showed that changes in the microvasculature are generalized.
With this disease, productive, destructive and destructive-productive vasculitis is found. Vessels are affected in a generalized and polymorphic manner - from moderate proliferation of the endothelium and infiltration of the outer membrane to necrosis of the middle membrane of the vessel wall. Lesions of small vessels predominate - skin, skeletal muscles, internal organs. The most typical are productive vasculitis and thrombovasculitis, less common is panvasculitis such as polyarteritis nodosa with focal or total necrosis of the medial membrane.
Changes in large and medium-sized vessels can be caused by damage to the vasa vasorum and ischemia of the vascular wall developing in connection with this. Sometimes a picture of aortitis is observed, followed by sclerosis and expansion of the aortic mouth.
Damage to the serous membranes most often manifests itself as dry pleurisy with slight fibrinous effusion, which leads to the formation of adhesions. In the lung tissue, the process develops according to the type of chronic interstitial pneumonia, focal or diffuse pneumosclerosis with the formation of rheumatoid nodules.
Kidney damage is caused by glomerulonephritis (membranous or membranous-proliferative), nephroangiosclerosis, chronic interstitial nephritis, angiitis. Nephropathy is often caused by the deposition of amyloid masses. In the latent stage, amyloid is found perivascularly in the tissue of the pyramids and some glomerular arterioles; in the nephrotic stage, massive amyloid deposits are found in most glomeruli, vessel walls, and pyramids.
In the gastrointestinal tract, signs of gastritis, enteritis, and colitis are detected, which are quite often caused by an immunocomplex process, which is confirmed by the detection of immunoglobulins and fibrin in the submucosa. The most severe changes in the gastrointestinal tract are associated with the deposition of amyloid masses in the mucous membrane, the wall of blood vessels with the development of lymphoid-plasmacytic infiltration, atrophy of the mucous membrane and submucosa.
In liver biopsies, changes in the portal connective tissue with productive vasculitis, lymphoid-histiocytic or plasmacytic infiltration, sclerotic changes, as well as degeneration and necrosis of hepatocytes are noted. With amyloid damage, amyloid deposits are observed in the reticular stroma of the liver lobules along the intralobular capillaries, in the wall of blood vessels. Amyloid often replaces most of the parenchyma.
In the spleen, hyperplasia and plasmatization of lymphoid tissue, proliferation of the sinus endothelium, and deposits of protein precipitates are detected.
In RA, various parts of the nervous system and its elements (vessels, connective tissue, nerve fibers) are affected. The peripheral system is mainly affected by the vasa nervorum. In the connective tissue of the nervous system, fibrinoid changes, lymphoid and plasma cell infiltrates, as well as amyloid deposits and micronecrosis are detected.
Clinical picture of RA
Articular syndrome is the leading one in the clinical picture of RA. The onset of the disease is most often subacute (55–70%), usually provoked by an acute infection or an exacerbation of a chronic infection, cooling, trauma, or a stressful situation.
The development of arthritis is preceded several weeks or months by a prodromal period, the signs of which are fatigue, weight loss, periodic pain in the joints (often in response to changes in atmospheric pressure), decreased appetite, increased sweating, low-grade fever, slight anemia, and an increase in ESR.
According to V.A. Nasonova and M.G. Astapenko (1989), in the prodromal period, 32% of patients develop morning stiffness, especially in the joints of the limbs, which goes away with active movement. Among the causes of this symptom is a disruption of the normal rhythm of hormone production by the adrenal glands with a shift to a later period of the day, as well as the accumulation of cytokines in the edematous fluid of inflamed joints during sleep.
In the initial period of RA, 1/3 of patients experience arthralgia, which worsens with movement, and 2/3 have symmetrical arthritis of small joints of the hands and feet. Pain and stiffness are greatest in the morning, gradually decreasing in the evening. The intensity and duration of these manifestations correlates with the progression of the disease, persisting with pronounced activity until lunch, and in some patients it disappears only in the evening.
In 8–15% of RA sufferers, the disease begins acutely within a few days. In this case, the patient can indicate the time and movement that provoked the pain. Arthralgia can be accompanied by the same sharp muscle pain, prolonged morning stiffness, fever, which leads the patient to immobility.
In 15–20% of cases, RA begins unnoticed with slow progression of arthritis without fever or limitation of movements.
Joint damage in the early stages of RA may be unstable and disappear spontaneously for several months or even years. Persistent polyarthritis with progression of the inflammatory process was observed in 70% of patients. As a rule, the first to be involved in RA are the second and third metacarpophalangeal, proximal interphalangeal and carpal joints, and less commonly, the metatarsophalangeal joints. Then, in terms of frequency of lesions, follow the knee, elbow, and ankle. Some authors explain the later involvement of large joints by a higher ratio of the surface of the synovial membrane to articular cartilage. According to our data, in 87% of patients it all started with damage to the small joints of the hands, in 9.7% - large ones (knees, shoulders). Persistent progressive polyarthritis occurred in 43%; in 57% of patients it had an undulating course with periods of remission. 20.4% of patients developed ischemic necrosis of the femoral heads.
Some joints at the onset of the disease remain intact (“exclusion joints”) - the distal interphalangeal joint, the first metacarpophalangeal joint of the thumb, the proximal interphalangeal joint of the little finger.
The early phase of RA is characterized by the predominance of exudative phenomena in symmetrically affected joints of the hands with the presence of effusion, determined by the symptom of fluctuation, inflammatory swelling of the periarticular tissues, severe pain on palpation, and a positive symptom of hand compression.
The skin over small joints may be slightly hyperemic, and over large joints there may be an increased temperature. Due to inflammation of the joint tissues and reflex muscle spasm, movement in the affected joints is sharply limited, which leads to the development of muscle atrophy. Arthritis is accompanied by inflammatory lesions of the tendon sheaths, most often the extensors, less often the flexors of the hand and foot.
In 15–20% of patients in the first year of the disease, spontaneous attenuation of arthritis symptoms may occur and remission of the disease may develop. But in most patients the process takes on a progressive character with a transition to the exudative-proliferative phase.
Along with general symptoms (weakness, asthenia, weight loss, deterioration of sleep, appetite, low-grade fever), articular syndrome progresses. The predominance of proliferative processes in articular tissues leads to their thickening, persistent dense or springy swelling of periarticular tissues, which causes a change in the configuration of joints, primarily small ones - hands and feet, wrists, wrists, knees, elbows. The shoulder and hip joints are rarely affected by RA, and even less often the spinal joints are involved.
RA classification
The first was proposed by A.I. Nesterov in 1961, after which it was repeatedly refined in connection with the emergence of new data on the clinic and variants of the course of RA. The latter was approved at the I All-Russian Congress of Rheumatologists in 2003.
There are 2 clinical and immunological variants: seropositive and seronegative RA. Polyarthritis, as the main manifestation of this disease, includes both options. Extra-articular manifestations are mainly classified as a seropositive variant and are presented only where rheumatoid affiliation is beyond doubt. This also includes a special form of RA – Felty’s syndrome. The seronegative variant of RA has its own clinical and laboratory characteristics, and adult Still's syndrome is also included in this category.
Characterizing the activity of the disease, 4 degrees are distinguished: 0 – remission, 1 – low, 2 – medium, 3 – high. Determination of activity is based on the most labile clinical and laboratory signs:
- severity of pain on a visual analogue scale (VAS), where its absence is equal to zero, and the maximum value is equal to 10 cm
- duration of morning stiffness in minutes
- ESR and CRP indicators
The definition of DRR in our country is not standardized, so we took the norm as the initial value, and then - its 2-3 or more fold excess.
Foreign rheumatologists have proposed using DAS (disease activity score) to assess the activity of RA.
According to ICD X, the following classification of RA is accepted: Inflammatory polyarthropathy
Rheumatoid lung disease
Classification of the disease is necessary to establish the course and activity of the process, which will allow the doctor to determine therapeutic tactics.
Currently, an indicator of inflammatory activity (PAI) has been proposed for use in practical medicine, which will be discussed at the IV Congress of Rheumatologists.
RA progression is still based on radiological criteria:
- Osteoporosis and destruction of bone cartilage (narrowing of the joint space, small isolated lesions)
- Osteoporosis, narrowing of the joint space, multiple erosions
- Signs of stage II and ankylosis
Due to the fact that a patient may have different radiographic changes in different joints, the stage of the disease is assessed by the maximum damage to the joint (mainly the hands, feet).
A division into functional classes is accepted, including the patient’s ability to serve himself, engage in non-professional activities (recreation, sports, favorite activities, etc.), as well as perform professional duties, but taking into account age and gender (study, work, housekeeping, etc.).
4 functional classes I are identified - the ability to serve oneself, engage in non-professional activities and perform professional duties is preserved
II – can serve himself and engage in non-professional activities, but is limited in his profession
III – can only serve himself
IV – needs outside help
Early diagnosis and active treatment with disease-modifying antirheumatic drugs (DMARDs) help slow down joint destruction and the development of extra-articular manifestations of the disease.
There are 7 signs, and if four of them are present, a diagnosis of rheumatoid arthritis is made.
- Morning stiffness. Its presence in the joints and periarticularly within an hour after waking up.
- Arthritis of 3 or more joints. Swelling or effusion in the joint for at least 6 weeks. These are the proximal interphalangeal, metacarpophalangeal joints, wrist, elbow, knee, ankle, metacarpophalangeal joints.
- Arthritis of the joints of the hand. Swelling of the wrist, proximal interphalangeal and metacarpophalangeal joints for at least 4 weeks.
- Symmetrical arthritis. Bilateral involvement of the joints (without absolute symmetry) indicated in point 3 for 6 weeks.
- Rheumatoid nodes. Subcutaneous on the extensor surface or periarticular area, identified by a doctor.
- Rheumatoid factor (RF).
- X-ray changes. Typical of RA in the hand and wrist, including erosions or bony decalcification.
Laboratory research
There are no specific indicators for RA. However, laboratory examination reveals a number of abnormalities, which, when compared with the clinic, can help in diagnosing this disease.
Anemia develops with an active rheumatoid process, usually normo- or hypochromic with a moderate decrease in the number of red blood cells. Its severity correlates with the activity of the process, especially with joint inflammation. Anemia increases when concomitant conditions arise - blood loss, poor nutrition, hemodilution, intercurrent infection. Anemia in RA may result from medications that cause bone marrow suppression.
The blood formula usually does not change, with the exception of special forms of RA. Thus, Felty's syndrome is characterized by leukoneutropenia, and Still's syndrome in adults is characterized by leukocytosis with a shift to the left. This can also happen in severe RA – vasculitis, pericarditis, pulmonary fibrosis, rheumatoid nodulosis.
RA is characterized by a decrease in neutrophil chemotaxis, and in severe forms, the appearance of neutrophils with unusually high peroxidase activity.
In recent years, the role of lymphocyte subpopulations in RA has been debated. Data on the ratio of T- and B-lymphocytes are quite contradictory; their functional activity and their production of cytokines and chemoreactants play a greater role.
Thrombocytosis is common in active RA, the mechanism of which is not entirely clear. It correlates with disease activity and often accompanies secondary amyloidosis. Thrombocytopenia is usually iatrogenic.
In 90% of patients, an increase in ESR is observed, clearly reflecting the activity of the process. Its short-term normalization can occur after intra-articular administration of glucocorticosteroids, and long-term normalization indicates remission of the process. A persistent increase in ESR is an unfavorable prognostic sign.
To a greater extent than ESR, the activity of the process reflects the level of acute phase proteins - CRP and amyloid. CRP has the ability to utilize nuclear debris from dead cells, bind and inactivate platelet-activating factor, a phosphocholine-containing inflammatory mediator. A correlation was found between the incidence of fractures and the level of CRP, which indicates the participation of the protein in the catabolic processes of bone tissue. Constantly elevated levels of CRP clearly correlate with joint destruction, indicating an unfavorable course of RA.
The disease is accompanied by dysproteinemia: a decrease in albumin levels and an increase in globulins. The increase in α 2 -globulin is due to an increase in the level of its constituent glycoproteins in the blood and reflects the activity of the process.
RA is accompanied by the destruction of connective tissue, the main substance of which includes glycoproteins. Their level is determined by various reactions based on indicators of sialic acid, seromucoid, etc.
The determination of RF, which can be of three types of immunoglobulins: IgG, IgM and IgA, has a high diagnostic value in RA.
In RA, it is found in 85% of patients throughout the entire period of the disease; only the titer changes depending on the activity of the process. In the early stages of the disease, RF may not be detected or may be detected in low titers. In half of RA patients, RF is detected in rare and high titers (1:128 or more). It should be remembered that elderly people may have spontaneous RF production.
With the development of a systemic process, the RF titer increases sharply and plays an unfavorable role in prognostication. The development of erosion in bone tissue correlates with high titers of RF IgA. Due to self-association, IgG RF can form immune complexes and is capable of inducing the synthesis of immunoglobulins.
The concentration of the main classes of immunoglobulins in the blood serum is, as a rule, increased and especially increases with the activation of the process and the development of systemicity.
RA is characterized by mixed type cryoglobulinemia, detected in 30–50% of patients with visceral manifestations, with Felty's syndrome, and vasculitis. Immune complexes (IC) are detected with the same frequency. It is necessary for patients with this disease with a high content of cryoglobulins and CEC, given the high prevalence of hepatitis B, C among the population and their association with RA, to be examined for the presence of markers of viral hepatitis.
To diagnose RA, especially early forms, 3 serological markers are used:
- antikeratin antibodies (AKA)
- antiperinuclear factor (ACE)
- antiRA 33 antibodies
The first two are directed against epithelial cell components and react with synthetic peptides isolated from prophyllagrin, which contains the amino acid citrulline. ACAs are specific for patients with RA - they are not found in healthy people.
To confirm the diagnosis and determine local activity, great importance is attached to the study of synovial fluid, which changes in RA, becoming more intense in color, cloudy, with reduced viscosity and a loose mucin clot. The number of leukocytes in the synovial fluid increases to 25 thousand due to neutrophils (25–90%). The protein level reaches 40–60 g/l, and the glucose level decreases to 2 mmol/l. In the cytoplasm of leukocytes, inclusions similar to a bunch of grapes are found. These are ragocytes - cells containing phagocytosed material: lipoid or protein components, IC, etc. In RA there are quite a lot of them - 30–40%. Ragocytes are also found in other diseases - psoriasis, lupus, infectious arthritis, gout, but not in such quantities. RF is often detected in synovial fluid even in its absence in the blood serum.
Treatment
The goal of RA therapy is to eliminate pain, reduce inflammation, slow down joint destruction, develop a systemic process, maintain functional ability and improve the quality and life expectancy of patients.
To accomplish these tasks, a multifactorial approach is required, including both pharmacotherapy and non-pharmacological actions - alternation of physical activity and rest, physiotherapy, diet, conservative and orthopedic surgery, education of patients and their relatives regarding the disease itself and the medications used.
In recent years, there have been significant changes in views on the timing of initiation of therapy and the choice of pharmacological agents for the treatment of RA. This is based on the reversibility of the process in the early stages of the disease, the lack of effect when using palliative therapy and significant success with aggressive treatment in the early stages at the first manifestations of articular syndrome.
Pharmacotherapy for RA includes drugs that relieve symptoms of the disease and modify the course of the disease. These are non-steroidal anti-inflammatory drugs (NSAIDs), the main mechanism of action of which is to inhibit the activity of the enzyme cyclooxygenase (COX), which has 2 isoforms - COX-1 and COX-2. COX-1 is a physiological enzyme that plays a role in maintaining normal homeostasis: protection of the gastric mucosa, kidney function, platelet aggregation, macrophage differentiation. The expression of COX-2 is induced by various physiological and pathological stimuli, providing the synthesis of prostaglandins (PG).
NSAIDs reduce pain and inflammation, but do not prevent destructive processes in joints caused by proinflammatory cytokines. Taking these drugs can mask the progression of the disease and also cause severe adverse reactions, primarily gastric bleeding, impaired renal function and cardiovascular system.
For patients with RA who are at risk (old age, history of ulcers, smoking, taking glucocorticosteroids), the drugs of choice are COX-2 inhibitors or COX-1-sparing drugs. To date, several dozen NSAIDs are known, but for the treatment of RA, preference is given to derivatives of arylalkanoic acids - arylacetic (diclofenac sodium/potassium, ortofen), arylpropionic (ibuprofen, naproxen, ketoprofen, flurbiprofen), indoleacetic (indomethacin, sulindac), enolic (piroxicam, tenoxicam).
A new class of NSAIDs - COX-2 inhibitors (nimesulide, meloxicam, celecoxib) are safer and are recommended for patients with risk factors for the gastrointestinal tract.
Highly selective COX-2 (rofecoxib, celecoxib) should be used with caution if there is a risk of myocardial infarction and stroke.
In recent years, new NSAIDs have been created that have a high analgesic effect - xefocam, aceclofenac (Aertal), valdecoxib.
Treatment of patients with RA begins with NSAIDs, especially in articular forms with minimal and moderate disease activity. The choice is made empirically, taking into account the individual sensitivity of the patient, the effectiveness of the drug, the possibility of developing side effects, and combination with other drugs taken by the patient.
Treatment begins taking into account the average daily dose:
After verifying the effectiveness and good tolerability of the drug, it is recommended for a long-term period. The dose is considered adequate if it reduces the severity of pain, the exudative component, and maintains range of motion and quality of life.
With long-term use of NSAIDs, it is necessary to monitor blood cells, the state of the coagulation system, the function of the kidneys and especially the mucous membranes of the stomach and duodenum, even if the user does not complain, since endoscopic examination reveals “silent” ulcers that require appropriate symptomatic therapy.
Rapid anti-inflammatory drugs include glucocorticosteroids (GCs), the effect of which is associated with inhibition of the expression of adhesion molecules by epithelial cells, suppression of COX-2 activity, expression of metalloproteinase genes, and transcription of proinflammatory cytokine genes. GCs are able to reduce membrane permeability, including lysosomal enzymes, which prevents the release of proteolytic enzymes. All this is aimed at suppressing immune inflammation.
For RA, GCs should be prescribed in low doses - no more than 10 mg per day (for prednisolone) as an intermediate therapy when using DMARDs.
Intra-articular (i.a.) administration of HA after evacuation of synovial fluid reduces pain and local inflammation, but this method of treatment is recommended to be used no more than a single injection every 3-6 months. Otherwise, this will lead to the development of the same side effects as when taking the drug orally, one of which is steroid osteoporosis.
Data on the dose-dependent effect of GCs confirm that at low concentrations (less than 10 mg per day) their effect is manifested due to genomic effects, when using medium doses (1 mg/kg per day) receptor-mediated ones are activated, and at high doses (1 g per day) HAs affect the physicochemical properties of target cell membranes within a few seconds. These data to some extent explain the differences in the anti-inflammatory and immunosuppressive effects of different doses of GC.
More often used to treat RA
High doses of GC are required for the treatment of rheumatoid vasculitis, Felty and Still syndrome in adults. The very next day after taking GCs, their anti-inflammatory effect appears. A sharp reduction in dose or discontinuation of use may provoke “withdrawal syndrome”. Only the absence of signs of exacerbation of the process allows the doctor to further reduce the daily dose of GC.
In case of torpid course of RA with preservation of process activity, the maintenance dose of GC is maintained for a longer period in combination with DMARDs. During GC therapy, monitoring of blood sugar, potassium, and calcium levels is necessary. Annual densitometry is necessary to detect osteopenia/osteoporosis. If such a diagnosis is confirmed, it is necessary to include calcitonins and bisphosphonates in complex treatment.
A relative contraindication for the use of GCs is gastric ulcer, duodenal ulcer in the acute stage, diabetes mellitus, hypertension, active forms of tuberculosis, angina pectoris, obesity, osteoporosis.
For aggressive current RA variants, it is necessary to use the so-called GC pulse therapy, in which 1000 mg of methylprednisolone or 32–64 mg of dexaven per 150 ml of isotonic sodium chloride solution is administered intravenously over 40–50 minutes. Course – 3 days. You can use half the dose of MP, and increase or decrease the number of infusions depending on the effect obtained.
Long-term use of GCs with a high cumulative dose leads to the development of Cushing's syndrome, adrenal insufficiency, diabetes mellitus, myopathy, and osteoporosis. GCs can provoke activation of a chronic infectious process (pyelonephritis, tuberculosis, sinusitis, cholecystitis, chronic herpetic infection).
DMARDs play a central role in the treatment of RA, given their influence on the underlying immune-mediated mechanisms of disease pathogenesis and their ability to inhibit or prevent bone destruction.
The American College of Rheumatology (ACR) has approved a list of drugs for the treatment of RA, which is also used in our country.
Table 1
| Drug, dose | Approval date | Side effects |
|---|---|---|
| Aurothioglucose, 25–50 mg per week | 1947 | Dermatitis, stomatitis, proteinuria, thrombocytopenia |
| Hydroxychloroquine, 200–400 mg per day | 1957 | Retinal change |
| D-penicillamine, 125–750 mg per day | 1977 | Myasthenia gravis, Goodpasture's syndrome |
| Azathioprine, 50–150 mg daily | 1981 | SLE-like syndrome |
| Methotrexate, 5–25 mg per week | 1987 | Hepatitis, cytopenia, pancreatitis, liver cirrhosis, pulmonary fibrosis |
| Auranofin, 3–9 mg per day | 1988 | Nephropathy, cytopenia |
| Sulfasalazine, 1–3 g per day | 1996 | Cytopenia, Steven–Johnson syndrome |
| Cyclosporine A, 2.5–4 mg/kg per day | 1997 | Dyspeptic disorders |
| Leflunomide, 20–10 mg daily | 1998 | Cytopenia, renal failure, hypertension, diarrhea, increased transaminases, infection |
| Etanercept, 25 mg 2 times a week | 1998 | Alopecia |
| Infliximab (Remicade), 500–750 mg per month | 1999 | Infection |
These drugs are recommended for the treatment of RA and by the Federal Formulary Committee. DMARDs are very similar in effectiveness, but differ in the frequency and nature of side effects. Antimalarials are somewhat weaker in effectiveness, when taking them strict contraception is necessary, as there are indications of a toxic effect on the fetus.
Methotrexate (MT) recognized as the “gold standard” DMARD due to the breadth of its spectrum of actions. The drug inhibits the infiltration and activation of B cells, macrophages, neutrophils, etc., prevents the development of angiogenesis, inhibits the proliferation of synovial fibroblast-like cells, activation of chondrocytes and osteoclasts, suppresses the production of RF, prevents the activation and release of enzymes that degrade cartilage and bone.
Tolerance to MT does not develop for 5 or more years. Its administration at the onset of articular syndrome helps prevent the development of the erosive process. The mechanism of action of MT is associated with the suppression of dehydrofolate reductase and other folate-dependent enzymes, resulting in a decrease in DNA synthesis, which occurs when megadoses of MT (100–1000 mg/m2) are prescribed for the management of cancer, where it is necessary to suppress the proliferation of mutated cells.
Low doses of MT used in rheumatology have anti-inflammatory and immunosuppressive effects due to the release of adenosine. The drug is able to increase the expression of genes encoding the synthesis of anti-inflammatory cytokines, as well as induce apoptosis of activated T-lymphocytes.
MT is effective in all types of RA, but its use should be limited to those with diabetes, those with signs of renal or liver failure, hepatitis B or C, low serum albumin concentrations, pulmonary pathology, the elderly, and especially alcohol abusers. When taking MT, it is necessary to monitor the level of liver enzymes, the composition of peripheral blood, and urine tests (proteinuria) monthly.
Leflunomide (Arava)– an isoxazole derivative, the active principle of which is the metabolite malononitrilamide. Its mechanism of action is based on the inactivation of dihydroorotate dehydrogenase, an enzyme necessary for the formation of uridine monophosphate, which plays an important role in the activation of T lymphocytes.
To date, the results of long-term therapy of RA patients with this drug have been obtained, indicating the ability of Arava not only to stop inflammation, but also to inhibit the destruction of joints, which preserves functional ability and has a positive effect on the quality of life. The combination of Arava with MT gives a better result than MT with sulfasalazine, which is due to some differences in their mechanism of action, and therefore a broader effect on the pathogenesis of RA.
Among the side effects that occur during treatment with Arava, the most significant are gastralgia, dyspepsia, diarrhea, and increased liver enzymes. These phenomena, as a rule, are reversible with short-term drug withdrawal or dose reduction. Cytopenic reactions and alopecia were also noted. Leflunomide, like MT, can be considered a first-line drug for the treatment of RA.
Of particular importance in the presence of obvious contraindications to the systemic use of NSAIDs is local therapy, which includes intravenous administration of glucocorticosteroids and local use of NSAIDs in the form of ointments, gels and creams. In addition to the greater safety of this method, it is necessary to note the possibility of reducing the dose of NSAIDs taken orally or parenterally against this background.
With local cutaneous administration, therapeutic concentrations of the drug are created in the soft tissues directly under the site of application, and a small amount of it enters the general bloodstream, which makes it possible to practically avoid systemic adverse effects.
In recent years, requirements have been developed for NSAIDs used locally:
- the drug must be effective for the pathology to be treated, but not cause local toxic and allergic reactions
- must reach the target tissue
- its concentration in the blood serum should not reach a level leading to dose-dependent adverse effects
- metabolism and excretion of the drug should be the same as with systemic use
One of the most effective means of local therapy for inflammatory joint diseases is Diclovit gel pharmaceutical company OJSC Nizhpharm, containing 1 g of diclofenac sodium as an active ingredient.
Our study involved 30 patients with RA, predominantly female (29 years), whose average age was 46.5 ± 15.1 years (from 17 to 73 years). A 3–5 cm strip of gel was applied to the area of the inflamed joint 3 times a day for 2 weeks (14 days). During the study, patients continued taking NSAIDs, glucocorticosteroids and basic drugs prescribed earlier, the dose of which did not change during this period.
table 2. Dynamics of articular syndrome indicators during therapy with Diclovit gel (M±S)
As can be seen from table. 2, a pronounced positive dynamics of all analyzed clinical parameters was noted.
The study confirmed the high analgesic effectiveness and local anti-inflammatory effect of Diclovit gel in combination with good tolerability, which allows its widespread use as local therapy for rheumatic diseases.
The effectiveness of the treatment can be assessed according to the AKR criteria, which suggests a 20%, 50% and 70% improvement in the following indicators: the number of swollen and painful joints, disease activity according to VAS, assessed by the doctor and the patient, ESR, CRP, functional condition (HAQ), structural changes in joints. The Disease Activity Score (DAS) has been developed for the same purpose.
Table 3
Rehabilitation
In RA, physiotherapeutic methods, physical therapy, massage, reflexology and psychotherapy are widely used, the purpose of which should be individual, taking into account the activity of the process, the severity of functional deficiency, the age of the patient, and the presence of concomitant diseases. In the acute phase of arthritis, controlled rest, which can be general or local, is recommended to suppress pain and preserve joint function.
At the same time, isometric (static) exercises should be prescribed in a lying or sitting position. It is necessary to do at least three maximum contractions per day for a duration of 6 seconds and a pause of 21 seconds for the quadriceps femoris muscle. In addition to isometric exercises in the affected joint, kinesitherapy (motion therapy) should be used for healthy joints in order to maintain maximum range of motion in them. Traction and exercises with a load are contraindicated at this stage. Cryotherapy relieves inflammation, pain and prevents muscle spasms. Orthoses should be used for 1–2 hours during the day and at night.
Patients with severe pain syndrome, synovitis on an outpatient basis and in a hospital are locally prescribed ultraviolet irradiation (erythemal doses), infrared laser and magnetic therapy, ultraphonophoresis with hydrocortisone or prednisolone, cryotherapy, mud applications (20–40°). The impact is carried out on the 2-3 most affected joints, 6-10 procedures for each.
In the subacute phase of RA, isometric exercises are recommended to improve coordination of movements. Before you begin to increase the range of motion in a joint, it is necessary to prepare the muscular system for this, for which you carry out active exercises to stretch the flexor muscles and strengthen the extensors. Kinesiotherapy is also recommended, which should be done on the floor or couch. At this stage, occupational therapy is mandatory.
In addition to the physical factors used in the acute period, a group of athermic physical factors is prescribed: low-frequency pulse currents, diadynamic Bernard currents, interference currents. When prescribing ultrasound, one should take into account the thermal effect, which can increase complaints and reduce the effect of treatment.
When inflammatory activity decreases or is absent, patients have arthralgia, proliferative changes in joints, muscle contractures, ultraphonophoresis of analgin or inductothermy (low heat doses), heat treatment using applications of ozokerite, paraffin, mud ( 37–40°).
If thermal procedures are contraindicated, peloid therapy at low temperatures (20–24°C) is recommended, which is quite effective in this category of patients. For muscle hypotrophy, electrical stimulation of muscles using low-frequency pulse currents (sinusoidal, modulated, diadynamic, etc.) and cryotherapy are used. It is possible to carry out electrophoresis with analgesics, copper, iodine, lithium.
In the chronic phase of arthritis, a large selection of physical methods and physical therapy (physical therapy) is used - active movements, active-auxiliary, passive with resistance and/or gradually increasing load. The main criterion is the appearance or increase in pain, fatigue or stiffness in the joints after performing exercises for 1–2 hours, which serves as justification for reducing the load.
For the cervical spine, isometric exercises are preferable. Before kinesitherapy, electrical and thermal procedures should be performed in order to achieve an analgesic effect by relaxing muscles and improving circulation.
Orthopedic surgery RA
The complex treatment of RA includes rheumoorthopedics as an additional element, conventionally divided into conservative and surgical.
In the initial period of the disease, when there are no significant dysfunctions of the joints, the role of the rheumo-orthopedist is to teach the patient the basics of preventing typical joint deformities. Positional treatment plays an important role here. To correct flexion contractures of ulnar deviation of the fingers in the metacarpophalangeal joints, as well as the hand in the radiocarpal joints, it is necessary for the patient to develop constant self-control over the correct correction of the hand in an advantageous physiological position. While sleeping, you need to wear orthoses on your hands and forearms - special devices made of polymer materials that hold the joints in the correct physiological position.
For the purpose of primary prevention of flexion contracture of the knee joint, the patient is instructed to sleep or rest on a fairly hard bed, and not to use bolsters or pillows placed in the popliteal area to relieve pain. Prolonged flexion of the knee joint leads to flexion deformity.
It is necessary to carry out exercise therapy aimed at strengthening the quadriceps femoris muscle - its prolonged voluntary contractions (“play” of the patella) and straight leg raises in a supine position. You should also use knee orthoses to keep them in a straight position. Temporary immobilization with orthoses reduces pain.
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Rheumatoid arthritis (RA) is an inflammatory rheumatic disease of unknown etiology, characterized by symmetrical chronic erosive arthritis (synovitis) of peripheral joints and systemic inflammatory damage to internal organs.
Epidemiology
RA is one of the most common chronic inflammatory diseases, the incidence of which in the population averages 1% (0.6-1.6% in different countries). The disease occurs approximately 2.5 times more often in women than in men, but in patients seropositive for rheumatoid factor (RF) and in the elderly, gender differences in it are obvious.Etiology
RA is a multifactorial autoimmune disease of unknown etiology, the development of which involves many factors: environmental, immune, genetic, hormonal, etc. The following factors have possible etiological significance:■ Exogenous: viruses (parvovirus B19, retroviruses, Egpletein-Barr virus), bacterial superantigens (mycoplasma, mycobacteria, intestinal bacteria), toxins, incl. tobacco components.
■ Endogenous: type II collagen. stress proteins, etc.
■ Nonspecific: trauma, allergens, etc. It is assumed that potential etiological
(trigger) factors play not a direct, but an indirect role in the development of RA,
Genetic predisposition
The risk of RA is approximately 16 times higher in blood relatives of patients. Concordance for RA in monozygotic twins is 4 times higher than in dizygotic twins (15-30%). This indicates the participation of several genes in the implementation of predisposition (or resistance) to RA.RA is more common in carriers of certain class II major histocompatibility complex antigens, especially HLA-DR1 and HLA-DR4, which have similar amino acid sequences (“shared” epitope) in the third hypervariable region of the β-chain. Analysis of the structure of this epitope expressed on antigen-presenting cells showed that its composition does not limit the structure of the antigen that can be presented to T lymphocytes.
Therefore, in RA, activation of T lymphocytes can potentially be induced by a wide range of opportunistic “arthritogenic” antigens, the common property of which is a “negative charge”. It is also assumed that carriage of certain KLA-DR alleles is not associated with a “susceptibility” to RA, but determines a more severe course of the disease and seropositivity for rheumatoid factor (RF). Moreover, the existence of “protective” HLA-DR alleles and the relationship between “susceptibility” to RA and carriage of HLA-DQ alleles (DQB103-DQA103 hDQB10501-DQA101) are discussed. A very large number of other candidate genes (TNF-a, IL-1) and their receptors (IL-10, FcRIII-A, corticotropin, mannose-binding lectin, etc.) have been described, the polymorphism of which determines “sensitivity” or “resistance” "to RA,
Hormonal factors
The role of sex hormones and prolactin is evidenced by the fact that under the age of 50, RA occurs approximately 2-3 times more often in women than in men, and at a later age these differences are leveled out. Taking contraceptives and pregnancy reduce the risk of developing RA in women. On the contrary, during lactation (hyperprolactinemia), the risk of developing RA increases significantlyAn important mechanism that determines the rapid transition of acute to chronic inflammation in RA is associated with defects at the level of the hypothalamic-pituitary-adrenal (HPA) axis. This manifests itself in disruption of the synthesis of cortisol, which plays an important role in preventing excessive activation of the immune system and chronic inflammation.
In general, the contribution of genetic factors to the development of RA is 15%, and environmental factors - 85%.
Yu.B. Belousov
Epidemiology Rheumatoid arthritis is registered in all countries of the world and in all climatic and geographical zones with a frequency of 0.6 - 1.3%. At the same time, women are more likely to get sick than men. A particularly high incidence of rheumatoid arthritis was found among first-degree relatives – 3.5%. The highest percentage of rheumatoid arthritis was noted in female first-degree relatives (5.1%).
Definition Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease of connective tissue with predominant damage to peripheral joints of the type of erosive-destructive polyarthritis.
The etiology of the disease is unknown. Predisposing factors (in genetically predisposed individuals, associated with the spectrum of HLA histocompatibility antigens): - female gender (women suffer from RA 3 times more often than men) - hypothermia - respiratory viral infections - pregnancy - stress
Pathogenesis The pathogenesis of RA is based on a violation of the immune response with an imbalance of immunocompetent cells and a violation of their functional activity. The formation by plasma cells of the synovial membrane of antibodies against their own immunoglobulins - rheumatoid factors (RF) of the Ig class. G and Ig. M Formation of immune complexes that trigger a cascade of immunoinflammatory reactions in joints and internal organs
Pathogenesis Seropositive RA – RF is found in peripheral blood and synovial fluid. Seronegative RA – RF is found only in synovial fluid.
Clinical picture The main clinical forms of rheumatoid arthritis RA with damage to one joint (monoarthritis) RA with damage to two or three joints (oligoarthritis) RA with damage to many joints (polyarthritis) WITHOUT SIGNS OF SYSTEMICITY - the most typical clinical variant, occurring in 80% of patients
Clinical picture The main clinical forms of rheumatoid arthritis RA with systemic manifestations is a highly active, generalized form, found in 12-13% of all cases of RA, characterized by damage to internal organs - serous membranes, kidneys, heart, lungs, eyes, liver. Systemic manifestations indicate an unfavorable course of the process and its high activity.
Clinical picture I. Joint syndrome 1. subacute or gradual onset 2. morning stiffness for more than 1 hour (symptom of “tight gloves” and symptom of “corset”, which often makes independent movements difficult) 3. polyarthritis, symmetry and persistence of changes in the joints
Clinical picture 1. 2. 3. The second and third metacarpophalangeal and proximal interphalangeal joints are most often affected. Later, the wrist, knee, elbow, and ankle joints are affected, and the shoulder, hip, and spinal joints are affected less frequently and at a later stage. Some joints remain unaffected - exception joints (first metacarpophalangeal joint of the thumb, proximal interphalangeal joint of the little finger - damage in the early stages excludes the diagnosis of RA)
Clinical picture 6. exudative changes: inflammatory swelling of the periarticular tissues, joints are hot to the touch, movements in them are limited
Clinical picture Deformation of the fingers in the form of a “swan neck” is a flexion contracture in the metacarpophalangeal joints, combined with hyperextension in the proximal interphalangeal joints and flexion of the nail phalanges (Fig. c). Deformity in the form of a “boutonniere” – flexion in the metacarpophalangeal joints and hyperextension of the distal interphalangeal joints (Fig. b).
Clinical picture II. Atrophy of striated muscles, trophic changes in the skin of the hand, on the back of the hand the skin is dry, thinned, on the palms it is bright pink in color, with a cyanotic tint - “rheumatoid palm” → immobility → persistent disability
Clinical picture III. Rheumatoid nodules are painless, round, dense formations ranging in size from 2-3 mm to 2-3 cm in diameter (usually in the area of the elbow or small joints of the hands). The nodules are usually located symmetrically, but can sometimes be unilateral. They never become inflamed or suppurate. More often they are found in 2-3 groups, rarely they can be multiple. The number and size decrease with treatment. During the period of remission they disappear. Early appearance is an unfavorable prognostic sign and indicates greater activity of the process. More often found in seropositive RA.
Clinical picture IV. Heart damage is rare, in the form of myocardial dystrophy, carditis. Patients complain of slight shortness of breath, palpitations, periodic stabbing pain in the heart area, observed (persistent tachycardia, rhythm disturbance, conduction). Heart defects and heart failure are rare. The “rheumatoid” nature of the symptoms is evidenced by their development during the period of exacerbation of RA and improvement when the process subsides. V. Amyloidosis is observed in patients with a long, rapidly progressing course of the disease, on average after 3.5 years. VI. Kidney damage develops after 3-5 years and has three types of manifestations: (renal amyloidosis, focal nephritis and pyelonephritis).
Clinical picture Nephritis (membranous and membranoproliferative) is found in young patients with a short history of RA, with high activity and rapid progression of the disease, often with symptoms of pseudoseptic syndrome and the presence of other visceritis. Kidney damage is a poor prognostic sign, indicates an unfavorable course of the disease and significantly limits treatment options
Clinical picture Focal nephritis is characterized by: microhematuria, slight proteinuria without hypertension and edema 3. occurs during an exacerbation of arthritis 4. usually renal failure does not develop 5. in rare cases, diffuse glomerulonephritis can be observed, resulting in nephrosclerosis with the development of renal failure 1. 2.
Clinical picture Amyloidosis is observed in patients with a long, rapidly progressing course of the disease, on average 3.5 years from the onset of RA. 1. persistent and progressive proteinuria. 2. Nephrotic syndrome may develop (edema, massive proteinuria, hypoproteinemia). 3. In these cases, anti-inflammatory therapy has no effect and renal failure quickly develops.
Clinical picture VII. Lung damage (exudative pleurisy, interstitial alveolitis) VIII. Eye damage (iritis, iridocyclitis, episcleritis, scleritis) occurs simultaneously with exacerbations of the underlying rheumatoid disease. Morphological examination reveals nonspecific inflammatory changes in the tissues of the eye. There are isolated reports of the detection of rheumatoid granulomas in the sclera of patients with RA.
Clinical picture IX. Rheumatoid vasculitis can be asymptomatic, but in severe cases it is manifested by damage to internal organs, skin symptoms (polymorphic rash, sometimes hemorrhagic), nasal and uterine bleeding, cerebral or abdominal syndromes (severe headaches, dizziness, memory loss, peritoneal phenomena)
Clinical picture X. Damage to the nervous system (rheumatoid polyneuropathy - organic damage to the peripheral nerves, manifested by severe pain in the limbs, motor and sensory disorders, general muscle weakness) XI. Liver damage occurs in 60-86% of patients with severe RA (clinically, only 25% of patients have a slight enlargement of the liver). Significant and permanent enlargement of the liver and spleen is more often observed with Felty's syndrome, Still's disease, and amyloidosis. The liver is usually painless. The mechanisms of liver damage in RA have not been studied. It is assumed, in addition to the influence of the main pathological process, the intensive use of various medications by these patients.
Clinical picture XII. Damage to the gastrointestinal tract (signs of hypoacid gastritis: loss of appetite, heaviness in the epigastric region, flatulence. Long-term drug therapy is also important in the mechanisms of occurrence of these phenomena. When using GCS and NSAIDs, pain in the stomach, gastric and duodenal ulcers may occur. XIII. Endocrine system little studied (most authors note a decrease in thyroid function)
Clinical picture XIV. Lymph nodes 1. 2. 3. Lymphadenopathy – 25-30%, more often in severe cases, accompanied by weight loss and visceritis. From the size of a pea to a nut, they are dense, painless, mobile, palpable in the submandibular region, on the neck, in the armpit, and in the groin. The presence of lymphadenopathy indicates an active rheumatoid process. When remission occurs, it decreases or disappears. May be combined with an enlarged spleen, anemia, leukopenia, thrombocytopenia.
Clinical picture Rheumatoid arthritis with pseudoseptic syndrome is the most severe variant of the clinical course of the disease (“malignant”). in young people, the onset of acute articular syndrome is expressed significantly in the form of polyarthritis with rapid involvement of articular cartilage and bone in the process with rapid impairment of joint function
Clinical picture: high fever of the hectic type with chills and heavy sweats, weight loss, anemia, visceritis (enlarged liver, spleen with lymphadenopathy), multiple vasculitis (signs of skin vasculitis quickly appear in the form of a rash, bleeding already in the first year of the disease), rheumatoid carditis or lung damage develops less frequently as it progresses diseases damage to the kidneys and eyes the disease progresses rapidly
Clinical picture 1. 2. 3. 4. 5. 6. 7. Felty's syndrome (described in 1924) Develops at the age of 40-60 years Begins with fever, pain and swelling of the joints. Polyarthritis (articular syndrome characteristic of RA), splenomegaly, lymphadenopathy. In some cases, hepatomegaly, pigmentation of exposed parts of the body, rheumatoid nodules, polyneuropathy. Weakness, weight loss, muscle atrophy. Leukopenia, neutropenia, anemia, thrombocytopenia. RF, ANA, LE cells
Clinical picture Still's syndrome (described in 1987) occurs in 10-15% of patients with JRA, acute phases of exacerbation and remission; acute onset of polyarthritis with damage to large and small joints and the spine, severe exudative phenomena with subsequent development of deformities; damage to the eyes; rarely damage to internal organs (pericarditis , nephritis, polyserosite, etc.)
Clinical picture: high fever, polymorphic rashes on the face, trunk and limbs; rapid appearance of lymphadenopathy (lymph nodes are dense, painless, mobile); enlarged spleen; in some cases, the disease takes on a continuously relapsing course with sudden weight loss and delayed development of the child
Diagnosis on an x-ray of the joints - osteoporosis, some narrowing of the joint space, cysts (bone erosion and ankylosis do not occur in 70% of patients); an increase in ESR, anemia, leukopenia as the process progresses can end in a somewhat fatal outcome
Diagnostics Course of RA Rapidly progressive (significant increase in deformity, involvement of more than 3 new joints, increase in radiological stage by 2 steps and deterioration of their function by 50%) Slowly progressive (slight increase in deformity, involvement of 2-3 new joints, increase in radiological stage by one stage and slight deterioration in their function) Without noticeable progression (no clinical dynamics for 2-3 years)
Diagnostics Criteria for rheumatoid arthritis: 1. 2. 3. 4. 5. 6. 7. 8. arthritis of 3 or more joints, more than 6 weeks arthritis of the joints of the hand symmetrical arthritis morning stiffness for at least 1 hour rheumatoid nodules positive RF in the blood serum x-ray -signs typical of rheumatoid arthritis 4 out of 7 are enough to make a diagnosis
Diagnostics Biochemical blood test: C-reactive protein Hypoalbuminemia γ and α 2 – globulins of circulating immune complexes Detection of rheumatoid factors (a marker of autoimmune disorders) (85%) Fibrinogen Glycoproteins ANA (30%) in severe LE-cells (5 -10%) in severe cases
Diagnostics 1. 2. 3. 4. 5. Study of synovial fluid Decreased viscosity of synovial fluid Mucin clot becomes loose The number of leukocytes increases sharply Synovial fluid is rich in protein The cytoplasm of leukocytes may contain round greenish inclusions - vacuoles, similar to grapes (ragocytes)
Diagnostics Biopsy of the synovial membrane Villous hypertrophy with an increase in their number and volume, proliferation of synovial integumentary cells, proliferation of lymphoid and plasma cells with the formation of infiltrates near the vessels. Fibrin deposition on the surface of the synovial membrane or in interstitial tissue, vascular dilatation, edema. Foci of necrosis with erosions may form on the surface of the synovial membrane.
Diagnostics X-ray examination of joints I x-ray stage: periarticular osteoporosis II x-ray stage: I + narrowing of the joint space, single usuras III x-ray stage: I + narrowing of the joint space + multiple usuras IV x-ray stage: I+ III + the presence of bone ankylosis
Diagnostics Degrees of activity of rheumatoid arthritis (clinical and laboratory data) I degree of activity: morning stiffness for about 1 hour, moderate hypergammaglobulinemia (up to 12%), minimal titers of C-reactive protein II degree of activity: morning stiffness until noon, moderate hyperthermia, hypergammaglobulinemia (12 -15%), increase in ESR (20 -40 mm/h), moderate increase in C-reactive protein titer
Diagnostics Degrees of activity of rheumatoid arthritis (clinical and laboratory data) III degree of activity: morning stiffness during the day, hyperthermia of the periarticular tissues of the affected joints, hypergammaglobulinemia (15%), increased ESR (40 mm/h), high increase in C-reactive protein titer
Treatment 1. There is no etiotropic therapy 2. Anti-inflammatory therapy: NSAIDs (suppress the activity of the cyclooxygenase enzyme): non-selective COX inhibitors (diclofenac, ibuprofen, indomethacin) selective COX-2 inhibitors (nimesulide, meloxicam)
Treatment Selective COX-2 inhibitors are highly effective, safer, and less likely to cause gastrointestinal complications. Used for a long time (almost constantly). Lack of effect within 7-10 days is an indication for changing the drug.
Treatment Side effects: toxic effect on the gastrointestinal tract may increase blood pressure may retain water and sodium leukopenia, agranulocytosis
Treatment Glucocorticosteroids (prednisolone) q are used for RA with a high degree of activity and the presence of visceritis when other treatment methods are ineffective q have a rapid desensitizing, anti-inflammatory, antiproliferative effect, and also inhibit the production of antibodies q are used when NSAIDs are contraindicated q increase the risk of osteoporosis and bone fractures
Treatment Contraindications to the use of GCS: peptic ulcer diabetes mellitus mental illness hypertension stages II and III, thromboembolism, circulatory failure II and III degrees active tuberculosis severe osteoporosis angina pectoris myocardial infarction thrombophlebitis
Treatment Basic anti-inflammatory therapy (suppresses inflammation and/or pathological activation of the immune system) Indications for prescribing basic drugs are: 1. reliable RA 2. when using NSAIDs for 3 months, arthralgia, morning stiffness, ESR or C-reactive protein and/or persist signs of erosive arthritis
Treatment Basic therapy reduces the need for NSAIDs and glucocorticoids reduces the likelihood of side effects improves long-term prognosis the therapeutic effect occurs no earlier than 2-3 months from the start of treatment
Treatment Basic therapy 1. Quinoline drugs (chloroquine, hydroxychloroquine, delagil, plaquenil) are used in the initial articular form of the disease and minimal activity 2. Sulfonamide drugs (sulfasalazine) in the initial stages of RA, in the absence of systemic manifestations of the disease
Treatment Basic therapy 3. Cytostatics (methotrexate, azathioprine) are prescribed for moderate and high activity of RA with systemic manifestations and a rapidly progressive course. suppress the formation, development and function of immunocompetent cells and have a pronounced antiproliferative effect; the therapeutic effect usually occurs after 2-3 weeks, but is not persistent, as a result of which it is necessary to be on maintenance doses of drugs for up to 1 year.
Treatment When RA progresses or side effects of basic therapy are used, Biological modifiers of the immune response - Infleximab (selective effect on the most important parts of the immunopathogenesis of RA) treatment is well tolerated; side effects are rare
Treatment Gold preparations (krizanol, auranophil) block the functional activity of macrophages, preventing the progression of immune inflammation - they are rarely used (complications are common). D-penicillamine inhibits T-helper function and RF production. Side effects: leukopenia, thrombocytopenia, anemia, skin rashes, fever, taste disturbance, gastrointestinal disorders. Contraindications: proteinuria, hematuria, thrombocytopenia, leukopenia, pregnancy, drug intolerance. Rarely used (complications are common).
Treatment Intra-articular administration of anti-inflammatory drugs (hydrocortisone, cyclophosphamide) - to suppress the activity of the local inflammatory process. Local application of physical factors (ultraviolet rays, x-rays, general hydrogen sulfide and radon baths) Spa treatment annually outside the acute phase Clinical observation by a rheumatologist
Prognosis: the disease reduces life expectancy by 5-10 years, leads to disability, unfavorable prognosis for life in the presence of chronic renal failure, respiratory failure, complications of basic therapy (agranulocytosis)
Prognosis Functional ability of the patient A. Preserved B. Impaired 1. professional ability preserved 2. professional ability lost 3. ability to self-care lost
