Special agents to combat autoimmune inflammation: the place of monoclonal antibodies in modern rheumatology

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Systemic rheumatic diseases are pathologies that arise due to the aggressive effects of the immune system on one’s own tissues. Their development is based on an error of the immune system, which incorrectly recognizes the normal components of the human body - autoantigens . Immune cells mistake them for foreign agents, which they see as a threat to the body. The protective function is activated, and healthy cells are “bombarded” by factors of the immune system - autoantibodies (Fig. 1).

The basics of normal immunity and the autoimmune process are presented in an accessible form on “Biomolecule” in the article “Immunity: the fight against strangers and... our own” [1].

Figure 1. Diagram of the structure of antibodies. Antibodies are immunoglobulin proteins that have two H chains (heavy) and two L chains (light). Each protein molecule contains specific Fab fragments . These regions are responsible for binding to the antigen , the “target” that the antibody acts on. The structure of the Fab fragment is very variable, which allows it to adapt to the active centers of the antigen - epitopes . Chemical bonds (ionic, hydrogen, hydrophobic) are formed between the antibody and antigen. The other end of the molecule, the Fc fragment , is responsible for binding the resulting immune complexes to the Fc receptor located on the membranes of immune cells (neutrophils, macrophages, mast cells). Activation of immune components triggers a “killing reaction” against a foreign antigen. Antibody-dependent cytotoxicity occurs in this way.

“Antibodies, structure and functions of immunoglobulins”

The theory of autoimmunity was formulated a century ago by the German researcher Paul Ehrlich. Over the following years, many autoimmune diseases have been described. These include rheumatoid arthritis, systemic lupus erythematosus (SLE), systemic scleroderma, myopathies, vasculitis and other pathologies.

You can read more about the mechanisms of development of some rheumatic diseases in the articles: “Systemic lupus erythematosus: a disease with a thousand faces” [2] and “Rheumatoid arthritis: change the composition of joints” [3].

Diseases associated with an autoimmune component are a serious problem in modern society. Their prevalence in the world population is approximately 5%. Diseases quickly become chronic, which reduces the quality of life of patients. Autoimmune pathologies often lead to disability in patients [1], [4].

In 2021, Biomolecule published a special project dedicated to autoimmune diseases.

Despite many years of searching for new ways of pharmacotherapy, modern medicine cannot offer treatment methods that directly affect the cause of autoimmunity. Doctors can only slow down the progression of the pathology and reduce the severity of the clinic - carry out pathogenetic and symptomatic treatment. For this purpose, basic therapy has been developed and has been used for many years. However, proven drugs do not always work as they should.

Why is it necessary to look for new treatments?

A wide range of antirheumatic drugs are used to treat autoimmune diseases. Classical therapy includes nonsteroidal anti-inflammatory drugs, glucocorticoids, and cytostatics. Depending on the characteristics of the development of the disease, drugs from one or another group are selected [4].

Medicines used for rheumatic diseases

1. Major immunosuppressants:
   glucocorticoids (prednisolone, dexamethasone);
2. antibiotics (cyclosporine, tacrolimus);
3. antimetabolites (methotrexate, azathioprine, mercaptopurine);
4. cytostatics (cyclophosphamide).
5. Minor immunosuppressants:
   Plaquenil, hingamin;
6. cuprenil;
7. gold preparations (auronofin);
8. heparin;
9. non-steroidal anti-inflammatory drugs.

Let's figure out why new drugs are needed. As an example, we can consider the classical therapy of one of the most common autoimmune diseases - rheumatoid arthritis [3]. Modern strategies to combat this pathology must comply with the concept of Treat to target - “treatment until the goal is achieved.” It is aimed at remission (disappearance of symptoms) of the disease or a sharp decrease in the activity of arthritis [5], [6].

The “gold standard” in treating the disease is methotrexate (Fig. 2). The drug belongs to the group of basic anti-inflammatory drugs.

Figure 2. Structural formulas of methotrexate and folic acid. The drug ( a ) is similar in structure to folic acid ( b ). It consists of pteridine groups and para-aminobenzoic acid. The active component of methotrexate differs from the structure of folate in the absence of a hydroxyl group (–OH) and the presence of an additional methyl radical (–CH3).

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According to the mechanism of action, methotrexate is an antimetabolite. Drugs in this group inhibit physiological reactions in the body by binding to enzymes and turning off their activity. A substance that normally participates in the reaction can no longer enter the biochemical cycle due to increased competition with the components of the drug. The main target for the action of methotrexate is the enzyme that breaks down folic acid, dihydrofolate reductase ( DHF ). This protein acts on the folate entering the body, converting it into its active form. This produces tetrahydrofolic acid. They are involved in the synthesis of building materials for DNA - purine bases and thymidylate.

Methotrexate enters the chain of reactions due to its structural similarity to the folic acid molecule (Fig. 2). Competition for the enzyme leads to the fact that the content of active folate in the tissue is significantly reduced. There is no building material - there are no new DNA molecules, without which cells cannot reproduce. Those tissues whose structural elements are constantly dividing have increased sensitivity to the effects of the drug. These also include bone marrow components from which future immune cells are formed.

Another important point in the work of methotrexate is related to the activity of its polyglutamated metabolites. These molecules are formed after activation of the drug directly in the cells of the human body. They inhibit other enzymes that interact with folic acid. This group includes thymidyl synthetase and AICAR transamylase. The activity of methotrexate derivatives triggers the production of adenosine. It has a powerful anti-inflammatory effect, which reduces the severity of symptoms of rheumatoid arthritis [7].

Methotrexate is convenient to use - it is easily dosed and can be prescribed in long courses. In addition, an important advantage of this drug is its low price, in comparison with modern drugs from imported pharmaceutical companies [8]. Despite all the advantages, treatment with methotrexate does not always lead to a decrease in disease activity. In many patients, the use of the drug is ineffective even in combination with other classical drugs [5]. This is confirmed by analyzing statistics. Studies have shown that when treated with methotrexate and combinations of disease-modifying drugs, only half of patients achieved remission [9], [10].

The failure of classical therapy forces scientists to look for new ways to treat rheumatoid arthritis. It is worth noting that, despite new developments, the fight against the disease still begins with the prescription of methotrexate and its analogues. Additional drugs are used only when the autoimmune process is highly active. In such patients, the use of one drug is often ineffective [7]. Depending on the characteristics of the pathology, a suitable treatment regimen is selected (Fig. 3).

Figure 3. Management tactics for a patient with rheumatoid arthritis when methotrexate is ineffective.

“Pharmacotherapy of rheumatoid arthritis from the perspective of evidence-based medicine: new recommendations”

The ineffectiveness of basic therapy drugs occurs not only in rheumatoid arthritis, but also in other diseases of autoimmune origin (systemic lupus erythematosus, scleroderma, ankylosing spondylitis). This motivates rheumatology specialists to develop other drugs and select new treatment regimens.

Methotrexate

Patients should be clearly informed that the drug should not be used daily, but once a week

.

Patients receiving Methotrexate therapy should be closely monitored to ensure that signs of potential toxicity and adverse reactions are identified and assessed promptly.

Methotrexate should only be prescribed by a medical specialist with sufficient knowledge and experience in antimetabolic therapy.

Due to the possible development of severe or even fatal adverse reactions, patients should be fully informed by their physician about the possible risks and recommended safety measures.

The use of the drug in children under 3 years of age is not recommended due to insufficient data on the effectiveness and safety of treatment in this group of patients.

Recommended examinations and safety measures

Before starting or resuming treatment with methotrexate

a detailed clinical blood test must be performed with a count of blood cells, including determination of the platelet count; biochemical blood test with determination of liver enzyme activity, bilirubin concentration, serum albumin; chest x-ray, kidney function test. If necessary, diagnostic measures are taken to assess the activity of tuberculosis infection and viral hepatitis.

During treatment (at least once a month in the first six months of treatment

,
then - at least once every three months)
it is necessary to carry out the studies described below.

If the dose of methotrexate is increased, the frequency of examinations should be increased.

1. Examination of the oral mucosa and pharynx to assess the condition of the mucous membrane (stomatitis, pharyngitis).

2. Detailed clinical blood test with counting of blood cells, including determination of platelet count. Suppression of hematopoiesis caused by methotrexate can occur suddenly, including when the drug is used in small doses. In any case of a significant decrease in the number of leukocytes or platelets, it is necessary to immediately interrupt treatment with methotrexate and carry out adequate supportive therapy. Patients should be advised to report any signs and symptoms of possible infections.

Patients concomitantly using drugs that inhibit hematopoiesis (for example, leflunomide) should be carefully monitored with monitoring of blood counts, including platelet counts.

3. Liver function tests: Particular attention should be paid to identifying possible toxic effects on the liver. Treatment should not be started or should be interrupted if, during appropriate examinations or liver biopsy, abnormal liver function is detected that was present before the start of treatment or developed during treatment. Typically, disorders that develop during treatment return to normal within two weeks after interruption of methotrexate therapy, after which, at the discretion of the attending physician, treatment can be resumed.

When methotrexate is used for rheumatological indications, there is no obvious need for liver biopsy to monitor liver toxicity.

The advisability of performing a liver biopsy in patients with psoriasis is associated with the issue of the effectiveness of routine chemical analyzes of liver parameters or studies of type III collagen propeptide for identifying and assessing hepatotoxicity. Appropriate assessment should be carried out individually for each case, differentiating patients depending on the presence or absence of risk factors, such as a history of excessive alcohol consumption, persistent elevation of liver enzymes, history of liver disease, hereditary predisposition to liver disease, diabetes mellitus, obesity, history of use of hepatotoxic drugs or drugs that affect hematopoiesis, long-term previous use of methotrexate, or use of methotrexate in a cumulative dose of 1.5 g or more.

Control of “liver” enzymes in the blood serum: in 13 - 20% of patients, a transient 2-3-fold excess of normal transaminase values ​​was reported. In the case of a persistent increase in liver enzyme activity, dose reduction or discontinuation of treatment should be considered.

Due to the possible toxic effects of the drug on the liver, patients during treatment with methotrexate, unless clearly necessary, should refrain from the simultaneous use of other hepatotoxic drugs; Alcohol consumption should also be avoided or at least significantly reduced.

In patients using other hepatotoxic drugs or drugs that inhibit hematopoiesis (for example, leflunomide), the activity of liver enzymes should be carefully monitored.

4. It is necessary to monitor kidney function by performing functional tests and urine analysis.

Since methotrexate is excreted primarily by the kidneys, in the case of insufficient renal function, an increase in the plasma concentration of methotrexate should be expected, which can lead to severe unwanted side effects.

In cases of possible decline in renal function (for example, in elderly patients), control examinations should be performed more frequently. This also applies to cases of simultaneous administration of drugs that affect the elimination of methotrexate, drugs that can lead to kidney damage (for example, NSAIDs), or drugs that can affect hematopoiesis.

Dehydration may also increase the toxicity of methotrexate.

5.Examination of the respiratory system: special attention should be paid to symptoms of deterioration of lung function, if necessary, appropriate tests should be carried out. Symptoms of respiratory system damage (especially dry nonproductive cough), nonspecific pneumonitis that occur during methotrexate therapy may indicate a potentially dangerous disease and require interruption of treatment and immediate thorough examination to make a diagnosis. Acute or chronic interstitial pneumonitis may develop, often accompanied by eosinophilia; associated deaths have been reported. Clinical symptoms of methotrexate-induced lung injury are varied, but typical signs are fever, cough, difficulty breathing, and hypoxemia. An X-ray examination of the chest is necessary to exclude the presence of infiltrates or infection.

In case of lung disease, rapid diagnosis and discontinuation of treatment are necessary.

The development of respiratory diseases caused by the use of methotrexate is possible at any dose of the drug used.

If the dose of methotrexate is increased, the frequency of examinations should be increased!

Methotrexate affects the immune system and, as a result, may impair the response to vaccination and affect the results of immunological tests. Particular caution is required when using the drug in patients with chronic infectious diseases outside of periods of exacerbation ( Herpes zoster

, tuberculosis, hepatitis B or C) due to the possibility of exacerbation of the disease.

Refusal from immunization is required.

Malignant lymphomas may occur in patients using low doses of methotrexate; in these cases, treatment should be discontinued. In the absence of signs of spontaneous regression of lymphoma, cytotoxic therapy is necessary. Rare cases of acute megaloblastic pancytopenia have been reported when folic acid antagonists (such as trimethoprim/sulfamethoxazole) were co-administered with methotrexate.

The use of methotrexate increases the likelihood of developing dermatitis and skin burns under the influence of solar irradiation and UV irradiation.

In patients with psoriasis, an exacerbation of the disease may occur as a result of UV irradiation during treatment with methotrexate (photosensitivity reaction).

In patients with an additional volume of distribution (presence of pleural effusion, ascites), the elimination of methotrexate is slowed down. In such patients, particularly careful monitoring of toxicity, dose reduction, and in some cases, discontinuation of methotrexate treatment is required. Before starting therapy with Methotrexate, effusion from the pleural or abdominal cavity should be drained.

If diarrhea and ulcerative stomatitis occur, methotrexate therapy must be interrupted, since in such cases the development of hemorrhagic enteritis and death as a result of interstitial perforation are possible.

Vitamin supplements and other products containing folic acid, folinic acid or their derivatives may reduce the effectiveness of methotrexate.

In patients with psoriasis, methotrexate should be used only in cases of severe, persistent, disabling forms of the disease that are difficult to treat with other treatment regimens, and only after confirmation of the diagnosis by biopsy and/or after consultation with a dermatologist.

The drug contains less than 1 mmol of sodium per dose, i.e. practically free of sodium, which is important for patients on a sodium diet.

Before prescribing the drug, women need to make sure that they are not pregnant, since methotrexate is embryotoxic and can cause abortions and fetal defects. Methotrexate affects spermatogenesis and oogenesis, which may lead to decreased fertility during treatment. These effects are reversible after discontinuation of therapy.

Patients of childbearing potential of both sexes should use reliable contraception during treatment with methotrexate and for at least 6 months after its completion.

Patients of childbearing potential and their partners should be properly informed of the possible risks to fertility and pregnancy associated with the use of methotrexate.

Genetically engineered drugs: addition to basic therapy

monoclonal antibodies has provided new insight into the treatment of autoimmune diseases [11]. A fundamentally new class of drugs has been obtained thanks to the achievements of genetic engineering. To understand the mechanism of action of these drugs, it is worth remembering how immune cells work in health and disease [1], [12].

The immune system is a complex mechanism consisting of many “cogs” - immune cells. Each of them has its own functions and occupies a certain place in the overall structure of the protective system. In response to the arrival of an “enemy” agent (antigen), components of the innate immune system—nonspecific protective factors—are activated. These are neutrophils, eosinophils and basophils, which are the first to stand in the way of harmful effects.

The cogs turn and new components of the immune system are activated. T- and B-lymphocytes enter the fight against the pathogen. They include more subtle defense mechanisms - specific cytotoxicity. Antibodies are produced, T-killers look for their “victim”... Fine regulation of the process with the help of cytokines allows you to quickly achieve your goal. The coordinated action of all components of immunity leads to the implementation of the program - the destruction of the pathological agent.

During the selection of suitable “parts” for the mechanism - during the selection of lymphocytes - errors inevitably arise. The immune system produces autoreactive clones—cells that are specific to body tissue antigens. Normally, they are eliminated in the “workshops” - the thymus and lymph nodes. Those clones of lymphocytes that do not distinguish between self and foreign antigens are immediately destroyed even before they begin to perform their function. But what happens when the cogs fall out of the immune machine? The breakdown occurs in a specific part of the mechanism - in the work of T- and B-lymphocytes. If the selection process is disrupted, autoreactive cells are released into the blood. They look for their “victims” and find them in the normal elements of their own tissues.

Depending on the type of reaction, the pathophysiological process underlying autoimmune aggression differs. T-lymphocytes can kill body cells on their own, or they can work “by proxy” - activating the production of autoantibodies by B-lymphocytes. When B-cell immunity is damaged, autophagy is realized through the complement system, as well as through the formation of cytotoxic immune complexes [13], [14]. You can read more about the mechanisms of normal and altered immune responses on Biomolecule [1], as well as in articles [15], [16].

In autoimmune diseases, it is possible to suppress the entire complex mechanism of immunity at once, which is what classical therapy drugs do. But this leaves a person without protection from enemy agents - bacterial infections, viruses and other pathogens. Therefore, it is preferable to preserve the activity of the immune system as a whole, saving a person from auto-aggression of certain of its components. This is exactly how new drugs—monoclonal antibodies—work.

Biological agents affect individual “cogs” of the immune defense mechanism. Their targets may be cytokines and their receptors, membrane molecules of lymphocytes. Depending on the point of application of the drug, monoclonal antibodies are divided into groups (Fig. 4):

1. TNF (tumor necrosis factor) inhibitors - infliximab, etanercept, certolizumab, golimumab, adalimumab.
2. Interleukin receptor blockers - tocilizumab (IL-6R), canakinumab (IL-1R), secukinumab (IL-17R).
3. Anti-B-cell antibodies (antibodies to membrane molecules CD20) - rituximab, belimumab [17].
4. Anti-T-cell antibodies (antibodies to CD80 and CD86 molecules) - abatacept [18].

Figure 4. Pathophysiological “victims” of monoclonal antibodies - interleukins, TNF, surface proteins of lymphocytes.

“Individualization of treatment for rheumatoid arthritis: a course to achieve optimal results”

TNF inhibitors

Tumor necrosis factor inhibitors are the first monoclonal antibodies introduced into rheumatological practice. This group includes infliximab, etanercept, certolizumab, golimumab, adalimumab.

Tumor necrosis factor ( TNF ) is a pro-inflammatory cytokine (a substance that stimulates the development of an inflammatory response). Normally, when it is released, vascular cell proliferation, macrophage activation, and lysis of tumor agents occur. These effects play an important role in protecting the body from pathogens. Inflammation can be considered a response to damaging factors.

However, the effect of TNF on joints in rheumatic diseases cannot be called positive. Thus, in rheumatoid arthritis, the cytokine stimulates the proliferation of synovial fibroblasts - cells of the joint lining. This leads to the formation of pannus - growths of aggressive tissue. As the disease progresses, the process of inflammation and destruction spreads to the articular cartilage and underlying bones (Fig. 5). The joint tissues are filled with immune cells - macrophages, T- and B-lymphocytes, neutrophils. These mechanisms underlie the development of chronic inflammation. You can refresh your knowledge about the pathogenesis of rheumatoid arthritis in the article “Rheumatoid arthritis: change the composition of the joints” [3].

Figure 5. Pathological changes in the joint in rheumatoid arthritis. The autoimmune process causes erosions, synovitis (inflammation of the synovial membrane), and destruction of articular cartilage.

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One of the TNF inhibitors is the drug infliximab. It has "human" and "mouse" areas. Approximately 25% of all amino acids in the monoclonal antibody are derived from mice. This is a Fab fragment - a specific region responsible for binding to TNF. The Fc fragment of the protein is formed from IgG1, a human antibody.

This structure is associated with the mechanism for obtaining the drug. Initially, an antibody to tumor necrosis factor is synthesized in the mouse. The resulting immunoglobulin is specific to TNF and can already neutralize it, but completely foreign proteins, of course, cannot be introduced into the patient’s body. This will cause an active immune reaction - the production of antibodies against therapeutic agents. Therefore, mouse immunoglobulin domains are replaced with similar regions of human proteins. Antibodies that have fragments of different origins are called chimeric. In fact, they take the best qualities of their predecessors. The mouse part provides high sensitivity to TNF, and the human fragments reduce immunogenicity - the likelihood of developing an immune response.

The mechanism of action of infliximab is clear from its structure. The Fab fragment of the molecule binds tumor necrosis factor, forming a stable complex with it. This interaction completely blocks the activity of the cytokine, preventing its connection with the membrane receptors p55 and p57. Infliximab “neutralizes” both soluble and membrane-associated forms of TNF (Fig. 6). The content of other pro-inflammatory factors, such as IL-1, IL-6, and nitrogen monoxide, also decreases in joint cells.

Figure 6. Main effects of TNF and monoclonal antibodies blocking it (infliximab and etanercept). The targets for monoclonal antibodies are free and membrane-associated forms of tumor necrosis factor. The drugs prevent the cytokine from binding to the receptor, thereby reducing the activity of rheumatoid arthritis.

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Another effective drug from the group of TNF inhibitors, etanercept, . It contains the extracellular part of the receptor for tumor necrosis factor. It “connects” to human IgG1. The hybrid molecule enters into fierce competition for free TNF and neutralizes it before the cytokine has time to contact receptors and trigger an inflammatory response. An additional effect of etanercept that other TNF inhibitors do not have is the neutralization of lymphotoxin. This substance also belongs to pro-inflammatory cytokines. The production of lymphotoxin stimulates proliferative processes in the joints. Accordingly, blocking its action reduces the activity of inflammation in rheumatological diseases [18].

TNF inhibitors have shown good results not only in the treatment of rheumatoid arthritis, but also in other autoimmune pathologies. For example, new drugs are widely used in patients with ankylosing spondylitis. Slowing the progression of pathology in this case is very important, since auto-aggression is aimed at the joint and bone formations of the spine. Over time, the disease turns the spinal column into a “bamboo stick” - a monolithic, rigid formation. Ankylosis develops gradually, but inevitably. Every year the motor abilities of patients become more and more limited. The use of biological drugs can reduce the activity of inflammation in the spine. This slows down the process of ankylosis formation [19].

Interleukin receptor blockers

Interleukins play an important role in the development of autoimmune inflammation , which, like TNF, are proinflammatory cytokines (Fig. 7). The main representatives of this group are IL-6, IL-1, IL-17. The function of interleukins is the control of the processes of differentiation, proliferation and death (apoptosis) of immune cells, which is carried out through the corresponding target genes [20].

Figure 7. The mechanism of action of interleukins in autoimmune inflammation (using the example of IL-6). The cytokine affects T- and B-lymphocytes, hematopoietic cells, and hepatocytes. It stimulates the production of autoantibodies by B cells, as well as the formation of autoreactive T clones, which are directly involved in the autoimmune process. The effect on the bone marrow is to stimulate the production of new blood cells - the number of leukocytes and platelets increases. Inflammation is accompanied by a response of liver cells, the appearance of characteristic symptoms of an autoimmune disease.

[21]

The influence of interleukins is one of the “triggers” of the inflammatory process. Therefore, blocking their activity improves the condition of patients with autoimmune diseases. You can stop the work of interleukins by binding their receptors - molecules that transmit a signal to immune cells. This is the basis of the mechanism of action of monoclonal antibodies from the group of interleukin receptor inhibitors.

Tocilizumab is a drug that blocks IL-6. The receptor for this substance consists of two components: membrane IL-6R (α chain) and glycoprotein g130 (β chain). The membrane part of the receptor binds to IL-6, forming a stable complex. Together they activate the g130 component, causing a change in its structure (homodimerization). A receptor complex of two g130 molecules is formed, which in turn activates JAK1 kinase. This enzyme triggers a cascade of reactions in the cell, which leads to the appearance of the biological effect of the cytokine - the development of inflammation. In some cases, IL-6 binds not the membrane, but the soluble form of the α-chain (Fig. 8). The mechanism of action of the receptor does not change in this case [21].

Tocilizumab works by competitive inhibition. Signaling molecules actively bind to the monoclonal antibody. The vacant place is filled - interleukin cannot form a complex with the receptor, which means it is not able to activate the inflammation process.

Figure 8. Mechanism of action of tocilizumab. The drug binds soluble and membrane IL-6 receptors, blocking signal transmission.

"Modern targets for targeted therapy of rheumatoid arthritis: from monoclonal antibodies to signal molecule blockers"

Tocilizumab is considered one of the safest drugs in the group of monoclonal antibodies. This allows it to be used for juvenile idiopathic arthritis, which occurs before the age of 16 years. Children react particularly acutely to toxic effects, so the drugs used in their treatment should have a minimum number of adverse reactions. The use of tocilizumab allows one to achieve the desired treatment effect without causing severe complications.

Anti-B cell therapy

One of the main elements involved in autoimmune inflammation are B lymphocytes . They produce autoantibodies that bind to healthy cells in the body. The resulting complex of antibody and autoantigen attacks the complement system or cytotoxic lymphocytes. This process underlies the inflammatory response in rheumatic diseases such as systemic lupus erythematosus. A separate article on “Biomolecule” is devoted to it: “Systemic lupus erythematosus: a disease with a thousand faces” [2].

Anti-B cell therapy drugs ( rituximab and belimumab ) block the activity of B cells by binding to their membrane CD20 molecules. Only certain categories of B cells have these substances. They are specific for pre-B lymphocytes and mature B lymphocytes. CD20 is not present in stem elements and pro-B cells, from which new lymphocytic elements will be formed. Membrane molecules of this type are not found in plasma cells that produce immunoglobulins [22].

Thanks to this feature, the CD20 protein is an ideal “victim” for biological drugs. When its activity is “turned off,” neither the formation of new lymphocytes nor the production of normal antibodies is disrupted. One drug with this mechanism of action is rituximab. The monoclonal antibody binds to the CD20 molecule. This leads to the launch of immunological reactions in relation to B-lymphocytes, which ensure the destruction (lysis) of these cells (Fig. 9).

Figure 9. Mechanism of action of rituximab. The Fab fragment of the monoclonal antibody binds to CD20 on the surface of the B lymphocyte. This triggers cell lysis, which can occur in several ways: through the complement system, the apoptosis program, or the aggression of natural killer cells and macrophages.

"Modern targets for targeted therapy of rheumatoid arthritis: from monoclonal antibodies to signal molecule blockers"

Anti-T cell therapy

Blocking the action of T-lymphocytes is possible due to the peculiarities of their activation. In order for a T lymphocyte to enter the autoimmune process and bind to an antigen, it must receive two signals from antigen presenting cells (APCs). The first signal ensures recognition of a specific autoantigen by T-cell receptors. The second signal is a nonspecific process of binding of membrane molecules CD80 and CD86 on the surface of APC with the CD28 receptor of the lymphocyte. The combination of these interactions causes activation of T cells, which in turn stimulate the production of proinflammatory cytokines. This is the main contribution of T lymphocytes to the autoimmune process.

Knowledge of the mechanism of T cell activation was used in the development of monoclonal antibodies. The main representative of anti-T-cell agents is abatacept . The drug is a protein consisting of two parts. The specific part is formed by the CTLA-4 molecule (cytotoxic lymphocyte antigen 4). The nonspecific region is the Fc fragment of human immunoglobulin G1 [23].

The effect of abatacept is aimed precisely at a nonspecific (costimulatory) signal. The CTLA-4 component binds the CD80 and CD86 proteins on the surface of antigen-presenting cells. The CD28 lymphocyte receptor can no longer interact with them, which is why the activation of the T cell is not completed (Fig. 10).

Figure 10. Mechanism of action of abatacept. Abatacept modulates the immune response through binding to CD80/CD86 on antigen presenting cells. This prevents CD80/CD86 from binding to CD28 T cells, i.e. T cell activation is abolished through blocking costimulation.

"Modern targets for targeted therapy of rheumatoid arthritis: from monoclonal antibodies to signal molecule blockers"

conclusions

So, the main difference between the two indicated drugs is in the area of ​​their application: Methoject is successfully used in the treatment of skin diseases and joints, Methotrexate is used in oncology. In the first case, the medicine quickly eliminates joint pain and actively fights inflammation.

The use of Methotrexate for cancer allows one to achieve a stable improvement in general condition . The drugs are considered analogues of each other, however, treatment of psoriasis with Methotrexate is not advisable, since positive dynamics are observed only during the course of administration and are absent when it is discontinued.

There is also a difference in shelf life: Methoject has a 2-year shelf life, while Methotrexate has only 3. Due to the high toxicity of Methoject, it is rarely prescribed to older people or the prescribed dosage is significantly reduced. Prices for these medications, depending on the manufacturer, vary from 500 to 1200 rubles.

Not everything is so simple: possible problems when using monoclonal antibodies

Monoclonal antibody preparations have been used in rheumatological practice for quite some time. However, they are not prescribed to everyone - not to every first or even every second patient. The main limitation that doctors and patients face is the truly “exorbitant” cost of drugs in this group. Rheumatic diseases cannot be cured in a week or a month - they require many years (or even lifelong) use of therapy. Therefore, when selecting a drug, not only its effectiveness is important, but also its price.

For example, one pack of methotrexate costs approximately 200 rubles. The price of a package of infliximab is about 43 thousand rubles. The difference is obvious. For a year of treatment with methotrexate, even at the maximum dosage, the patient will spend 1–2 thousand rubles on the medicine (depending on the manufacturer, treatment regimen and the cost of the drug in local pharmacies). The price of annual therapy with infliximab is approximately 700 thousand rubles. It is clear that only a very limited group of patients will be able to provide themselves with this medicine.

Therefore, treatment of rheumatic diseases is carried out according to strict algorithms. If a pathology is detected, the patient is prescribed a basic drug. For example, for rheumatoid arthritis, methotrexate will most likely be the main drug. Doctors will add monoclonal antibodies to the standard treatment regimen only in exceptional cases. In Russia, they are considered reserve drugs—additional drugs that should be “left for later,” even despite their high effectiveness. So, if the severity of symptoms does not decrease for a long time (at least 6 months!), a biological drug can be added to methotrexate. Basic therapy is not canceled.

If the disease is initially highly active, progresses rapidly and is accompanied by extra-articular complications, then the patient can immediately be prescribed a combination treatment with basic drugs and monoclonal antibodies. This is due to the fact that biological drugs work best in the “acute period”, when the severity of symptoms is maximum. In addition, the effect of their use is observed faster. Treatment with infliximab produces results within 2–4 weeks, while methotrexate “starts working” only after several months.

The use of biological drugs is permissible in cases where the patient develops intolerance to basic drugs. Patients experience severe side effects from the medication, which further worsens their condition. The use of drugs with a different mechanism of action, including monoclonal antibodies, allows minimizing side effects [18].

The prescription and sale of biological drugs is controlled by the state. Many drugs from the group of monoclonal antibodies (infliximab, etanercept, tocilizumab, golimumab) are included in the “List of Vital and Essential Medicines”. In accordance with it, a list of medications is formed that are supplied to hospitals throughout Russia. Of course, biological drugs are not available in every hospital today. They are usually used in regional centers or specialized hospitals.

If they are unable to provide themselves with medications, patients receive disability and undergo therapy at state expense. This right is enshrined in the current “Program of State Guarantees for the Provision of Free Medical Care.” Treatment with biological drugs is provided for rheumatoid arthritis, ankylosing spondylitis, SLE, dermatopolymyositis, juvenile arthritis and other diseases. At the same time, doctors must determine clear indications for prescribing this or that drug. Getting expensive treatment is quite difficult - you need to undergo a full examination and collect documents. However, the provision of a state quota for many patients is the last chance for a full life.

Another difficulty that can be encountered when using biological drugs is adverse reactions. In parallel with the accumulation of data on the effectiveness of the use of drugs, new undesirable effects from their use are being identified. Most of these reactions are associated with the process of immunosuppression. By suppressing the activity of immune cells, monoclonal antibodies reduce the body's protective function. Anti-infective and anti-tumor immunity are primarily affected [18], [24].

Paradoxically, the use of new drugs against autoimmunity can cause acute autoimmune reactions. All biological drugs are protein molecules that are foreign to the body to one degree or another. Therefore, when therapeutic agents penetrate the patient’s body, the immune system can recognize them as antigens. An active immune response appears - antibodies are produced against the components of the drug.

Autoimmune syndromes provoked by drug administration are usually represented by vasculitis, SLE, antiphospholipid syndrome, and psoriasis [25]. Infliximab, which contains foreign murine fragments, is highly immunogenic. Fully “human” drugs provoke immunity less actively. But even with their use, there is a high risk of developing adverse autoimmune reactions. To eliminate these disorders, it is necessary to adjust the patient’s treatment regimen. It includes additional immunosuppressants that will suppress complications. This may be why combinations of biological drugs with disease-modifying drugs are often more effective than isolated therapy, even with the newest drugs [24].

Despite all possible difficulties, monoclonal antibodies have firmly entered the register of drugs used in rheumatology. The future of biologics and their place in rheumatology will depend on the results of many years of research that remain to be done. But even now we can say that the development of therapeutic monoclonal antibodies is an important step towards defeating autoimmune inflammation.

Methotrexate: description, composition

This drug also has an antitumor purpose due to the presence in its composition of the same active substance - methotrexate. Its use leads to a pronounced inhibition of DNA synthesis, as well as a slowdown in the processes of cellular mitosis.

Methotrexate is most effective against tissues with rapid growth: malignant tumors, epithelium of the intestinal mucosa, bladder, oral cavity, bone marrow. Along with the antitumor effect, the drug has immunosuppressive properties.

Methotrexate is available not only in the form of solutions, but also in tablets, which is often preferable to injections.

Indications

The medicine is widely used in the treatment of cancer:

• Cancer of the esophagus, skin, liver, kidneys, genitals, lungs, breast.
• Trophoblastic pathology.
• Nakhodgkin's lymphoma, acute lymphoblastic leukemia.
• Ewing's sarcomas.
• Medulloblastoma, retinoblastoma.

The drug is also indicated for use in the treatment of severe psoriasis and rheumatoid arthritis when other medications are ineffective.

Contraindications

The medication is not prescribed if there are:

• Profound degree of kidney and liver dysfunction.
• Bone marrow hypoplasia, thrombocytopenia, leukopenia, anemia.
• Infections in the acute stage.
• Insufficient activity of the immune system.
• State of pregnancy or lactation.
• Children up to 3 years old.
• Severe hypersensitivity to the components of the drug.

Cautious use of Methotrexate is acceptable for:

1. Diseases accompanied by ulcerative lesions of the gastrointestinal tract.
2. Pleural effusions.
3. Dehydration.
4. Previous radiation or chemotherapy.

Side effects

Just like Methoject, Methotrexate has similar side effects related to disorders in the cardiovascular, digestive, nervous, genitourinary and other systems of the body. However, according to patients, they occur much less frequently than when using Metoject.

It should be noted that the toxicity of the drug directly depends on the dose and frequency of administration. Side effects can be observed in patients even after complete withdrawal of use of the drug, since the active substance accumulates in the kidneys, liver, spleen and remains there for a long time.

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