Tumor necrosis factor (TNF) is a specific protein of a group of cytokines - hormone-like substances produced by the immune system. It is of great interest in medicine due to its properties - the ability to cause cell death (necrosis) of intratumoral tissue. This is a real breakthrough in medicine, allowing the use of drugs with TNF for the treatment of cancer.
History of discovery
By the beginning of the 20th century medical practice a pattern was discovered: in some patients there was a decrease and/or disappearance tumor formations after suffering any infection. After which the American researcher William Coley began to deliberately inject infectious agents (bacteria and their toxins) into cancer patients.
The method was not considered effective, as it had a strong toxic effect on the patient’s body. But this marked the beginning of a series of studies that led to the discovery of a protein called tumor necrosis factor. The discovered substance caused the rapid death of malignant cells implanted under the skin of experimental mice. A little later, pure TNF was isolated, which made it possible to use it for research purposes.
This discovery contributed to a real breakthrough in cancer therapy. Previously, with the help of cytokine proteins, it was possible to successfully treat only some oncological formations - skin melanoma, kidney cancer. But significant progress in this direction has been made possible by the study of the properties possessed by the tumor necrosis factor. Drugs based on it are included in the chemotherapy procedure.
Mechanism of action
Tumor necrosis factor acts on a specific target cell. There are several mechanisms of action:
- Through special TNF receptors, a multi-stage mechanism is launched - programmed death. This action is called cytotoxic. In this case, either the complete disappearance of the neoplasm or a decrease in its size is observed.
- Through disruption or complete cessation of the cell cycle. The cancer cell becomes unable to divide and tumor growth stops. This action is called cytostatic. Usually the tumor either stops growing or decreases in size.
- By blocking the process of formation of new vessels in tumor tissue and damaging existing capillaries. A tumor deprived of nutrition becomes necrotic, shrinks, and disappears.
There are situations when cancer cells may be insensitive to administered drugs due to mutations. Then the mechanisms described above do not arise.
Use in medicine
Tumor necrosis factor is used in so-called cytokine therapy - treatment with specific proteins produced by blood cells responsible for immunity. The procedure is possible at any stage and is not contraindicated for people with concomitant pathologies - cardiovascular, renal, hepatic. To reduce toxicity, recombination-prone tumor necrosis factor is used.
Treatment with cytokines is a new and progressively developing direction in oncology. At the same time, the use of TNF is considered the most effective. Since this substance is highly toxic, it is used by so-called regional perfusion. The method consists in isolating an organ or part of the body infected with a tumor from the general bloodstream using special equipment. Then blood circulation is artificially started with injected TNF.
Dangerous consequences
In medical practice, tumor necrosis factor is used with caution. A number of studies prove that TNF is a key component in the development of sepsis, toxic shock. The presence of this protein increased the pathogenicity of bacterial and viral infections, which is especially dangerous if the patient has HIV. It has been proven that TNF is involved in the occurrence autoimmune diseases, (for example, rheumatoid arthritis) in which the immune system mistakes the tissues and cells of its body for foreign bodies and damages them.
To minimize high toxicity, the following measures are observed:
- used only locally at the site of tumor formation;
- combined with other drugs;
- work with mutant less toxic TNF proteins;
- neutralizing antibodies are administered.
These circumstances force limited use of tumor necrosis factor. Their treatment must be properly organized.
Diagnostic indicator
A blood test does not detect TNF in a healthy body. But its level increases sharply with infectious diseases when pathogen toxins enter the blood. Then it can also be found in urine. Tumor necrosis factor in joint fluid indicates rheumatoid arthritis.
Also, an increase in this indicator indicates allergic reactions, oncological diseases and is a sign of rejection of transplanted donor organs. There is evidence that an increase in this indicator may indicate non-communicable diseases, for example, heart failure, bronchial asthma.
For various immunodeficiencies (including AIDS) and severe viral diseases, as well as injuries and burns, conditions are created that reduce the tumor necrosis factor. A drug that has an immunosuppressive effect will have a similar effect.
Drugs
TNF-based drugs are called targeted - capable of acting specifically on a specific molecule of a cancer cell, causing the death of the latter. At the same time, the effect on other organs remains minimal, which reduces the toxicity of tumor necrosis factor. TNF-based drugs are used both independently (monotherapy) and in combination with other drugs.
Today there are several TNF-based products, namely:
- NGR-TNF is a foreign drug, active substance which is a derivative of TNF. Capable of damaging tumor vessels, depriving it of nutrition.
- "Alnorin" is a Russian development. Highly effective in combination with interferons.
"Refnot" is a new Russian drug that also contains thymosin-alpha 1. Its toxicity is extremely low, but its effectiveness is equal to natural TNF and even exceeds it due to its immunostimulating effect. The drug was created in 1990. It successfully passed all the necessary clinical trials and was registered only in 2009, which gave official permission for the treatment of malignant neoplasms.
Self-administration of any drugs based on tumor necrosis factor is strictly prohibited. Treatment of cancer is a complex process that takes place exclusively under the supervision of a specialist.
Suppression of TNF activity leads to a decrease in the synthesis of inflammatory mediators in the body, thereby achieving the necessary therapeutic effect in the treatment of the disease.
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Tumor necrosis factor
Tumor necrosis factor (TNF): determination of TNF; TNF value; treatment with anti-TNF drugs; trading safety for higher efficiency
- TNF is synthesized by activated macrophages and has cytotoxic, immunomodulatory and anti-inflammatory effects.
- TNF is involved in antiviral, antitumor and transplantation immunity.
- For some tumors, TNF has a cytostatic and cytolytic effect.
- TNF stimulates macrophages.
- In high concentrations, TNF can damage endothelial cells and increase microvascular permeability, causing activation of the hemostasis and complement systems, followed by the accumulation of neutrophils and intravascular microthrombosis (DIC syndrome).
- The action of TNF extends to lipid metabolism, coagulation, insulin sensitivity and endothelial health, as well as a number of other functions.
- TNF suppresses the growth of tumor cells and regulates a number of metabolic processes, as well as the activity of the immune response to infectious agents, which does not allow the uncontrolled use of anti-TNF drugs and raises questions about their safety.
What are the mechanisms of antitumor action of TNF:
- TNF has a targeted effect on a malignant cell through TNF receptors, provoking programmed cell death or suppressing the division process; also stimulates the production of antigens in the affected cell;
- stimulates “hemorrhagic” tumor necrosis (death of cancer cells).
- blocking angiogenesis - suppressing the process of proliferation of tumor vessels, damaging tumor vessels without harming healthy vessels.
Features of the antitumor effect of TNF:
- TNF does not act on all tumor cells; Cells resistant to cytotoxic action themselves produce endogenous TNF and the active nuclear transcription factor NF-kB.
- a number of cells exhibit a dose-dependent effect of TNF, joint use cytokines TNF and IFN-gamma in many cases gives much more pronounced effect than with treatment with one of these drugs;
- TNF targets tumor cells that are resistant to chemotherapy, and TNF-based therapy in combination with chemotherapy can effectively kill the affected cells.
- primary and secondary immunodeficiencies;
- AIDS;
- severe viral infections;
- severe burns, injuries;
- treatment with cytostatics, immunosuppressants, corticosteroids.
- DIC syndrome;
- sepsis;
- infectious diseases;
- allergic and autoimmune diseases;
- crisis of donor organ rejection in recipients;
- oncological diseases.
Device - Microlab Star ELISA.
Normal: up to 87 pkg/ml
Reference values: 0 - 8.21 pg/ml.
- Sepsis (the content may be phasic - an increase at the beginning and a decrease with severe prolonged infection due to exhaustion defense mechanisms).
- Septic shock.
- DIC syndrome.
- Allergic diseases.
- Initial period in HIV-infected people.
- Obesity.
- IN acute period various infections.
- Heavy and protracted viral infections.
- Oncological diseases.
- AIDS.
- Secondary immunodeficiency states.
- Injuries, burns (severe).
- Myocarditis.
- Taking medications: immunosuppressants, cytostatics, corticosteroids.
How important are the functions of TNF in the human body?
The following mechanisms of influence of TNF are distinguished:
- Cyto toxic effect both on tumor cells and on cells affected by viruses.
- Stimulates the formation of other active substances - leukotrienes, prostaglandins, thromboxane.
- It has an immunomodulatory and anti-inflammatory effect (with the activation of macrophages and neutrophils).
- Increased membrane permeability.
- Increased insulin resistance (an effect leading to the development of hyperglycemia, possibly due to inhibition of the activity of insulin receptor tyrosine kinase, as well as stimulation of lipolysis and an increase in the concentration of free fatty acids).
- Damage to the vascular endothelium and increased capillary permeability.
- Activation of the hemostatic system.
- An in-depth study of the immune status in cases of severe acute, chronic, infectious and autoimmune diseases.
- Oncology.
- Severe mechanical injuries and burns.
- Atherosclerotic lesions of the blood vessels of the brain and heart.
- Rheumatoid arthritis and collagenosis.
- Chronic pathology of the lungs.
Inflammatory CD4 T cell activity
Under conditions of interaction between macrophages and inflammatory T cells, a more effective fusion of phagosomes that have captured bacteria with lysosomes, the guardians of proteolytic enzymes that destroy intracellular pathogens, is observed. The process of phagocytosis is accompanied by the so-called oxygen explosion - the formation of oxygen radicals and nitric oxide, which have bactericidal activity.
Anti-TNF therapy should not be prescribed to debilitated patients or those who have previously had infection, because in both of these cases they are at high risk of infection.
Reviews
I would also like to see the list of references
They will not present you with literature. Contradictory. Not proven. Experiments.
I took a course of treatment from Dr. Ognevaya for psoriasis. By the way, it was quite effective. And so she forces the TNF to pass!! Maybe someone can explain why and what it shows in psorics. Although the rate has decreased. TNF doubled!! And the skin is clear
Where can I buy this drug?
where can you buy tumor necrosis factor
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Anti TNF drugs
Rheumatology is a specialization of internal medicine that deals with the diagnosis and treatment of rheumatic diseases.
According to a clinical study published in the Journal of the American Medical Association, drugs that are not tumor necrosis factor (TNF) inhibitors are more effective. effective means for the treatment of patients with rheumatoid arthritis who do not respond to anti-TNF drugs.
Anti-TNF drugs are used throughout the world to treat rheumatoid arthritis. They deactivate TNF, a molecule produced immune system and causing inflammation. However, about a third of patients do not respond to this type of therapy.
The study involved 300 patients with rheumatoid arthritis who had an insufficient response to anti-TNF drugs.
All participants were divided into two groups. In the first group, patients took anti-TNF drugs such as adalimumab, etanercept, certolizumab and infliximab for 52 weeks. In the second group, patients took non-TNF drugs such as tocilizumab, rituximab and abatacept.
The study results showed that 54% of participants taking anti-TNF drugs and 69% of participants taking non-TNF drugs had a moderate response to treatment.
In addition, more patients taking non-TNF drugs had low levels of disease activity at 24 and 52 weeks of the study.
The researchers concluded that patients with rheumatoid arthritis who have not responded to anti-TNF drugs may benefit from non-TNF drugs.
Treatment with anti-TNF drugs: trading safety for higher efficiency?
Tumor necrosis factor (TNF) is an extracellular protein, an inflammatory cytokine with wide range action, which is synthesized mainly by monocytes and macrophages. Its action extends to lipid metabolism, coagulation, insulin sensitivity and endothelial health, as well as a number of other functions.
TNF was first discovered in the blood serum of mice injected with BCG and endotoxin. It turned out that the serum of such mice has a cytotoxic effect, and upon further study, the protein responsible for the development of this effect was identified.
IN last years TNF is becoming increasingly important. Increased interest is associated with the bidirectional action of this cytokine. On the one hand, it plays an important role in regulating normal differentiation, growth and metabolism various cells, and on the other hand, acts as a mediator of pathological immunoinflammatory processes in various human diseases.
Treatment of polyarthritis
Polyarthritis is a type of arthritis in which the disease affects several joints. It affects people of all genders and ages and is often associated with various autoimmune disorders.
Treatment
Basic treatment of polyarthritis (prescribed by a rheumatologist);
Symptomatic treatment (aimed at pain relief).
In the second case, non-steroidal anti-inflammatory drugs are used (in various forms), for example, brufen, indomethacin-Acri, flugalin, ortofen, roxicam. But it's worth considering side effects, as well as contraindications to taking these drugs (for example, peptic ulcer).
Treatment with medications
Nonsteroidal anti-inflammatory drugs
NSAIDs help reduce inflammation. They block the activity of prostaglandins (substances that play an important role in inflammation). They also help relieve mild to moderate pain. NSAIDs act quickly and often have fewer side effects than other stronger and more toxic drugs used to treat polyarthritis. In some cases, taking these medications can cause digestive upset and the formation of ulcers.
Corticosteroids
Treatment of polyarthritis with these medications helps relieve inflammation and also suppress the immune response. Due to the fact that polyarthritis is often caused by autoimmune disorders, for example, systemic lupus, these medications are used to suppress the immune response that accompanies such disorders.
In most cases, corticosteroids are the first to be prescribed to patients with such diseases. In order to prevent steroid-induced osteoporosis, it is recommended to use, for example, bisphosphonates. These medications often help reduce pain and other symptoms much faster than other medications.
Essential antirheumatic drugs (DMARDs)
PRPs modify the course of the disease. They can change the course of many diseases that cause polyarthritis. Due to the fact that they begin to act only 6-8 weeks after the start of treatment, during this period additional simultaneous administration NSAIDs and corticosteroids. DMARDs, as well as corticosteroids, healing effect achieve by suppressing the immune system.
Polyarthritis is often treated with methotrexate, the same drug that is sometimes used to treat cancer patients in high doses. Methotrexate sometimes causes liver damage, so the patient's blood should be tested regularly while using it to detect this and other possible side effects as early as possible.
The following DMARDs are also used to treat polyarthritis:
- Sulfasalazine.
- Hydroxychloroquine (an antimalarial drug). In 1 case, ison causes serious damage to the eyes.
Anti-TNF drugs
In many types of arthritis, including polyarthritis, tumor necrosis factor can cause inflammation. Medicines that block tumor necrosis factor are called anti-TNF drugs.
Treatment of polyarthritis requires the use of the following anti-TNF drugs:
They are administered by subcutaneous injections, or intravenously. Taking anti-TNF can sometimes cause chills, joint and muscle pain, fever, increased susceptibility to infections, headaches, and other side effects.
Physiotherapy
Physiotherapy offers the opportunity to reduce pain, inflammation and swelling. This treatment polyarthritis, such as magnetic therapy, paraffin, ozokerite treatment, ultrasound, cryotherapy is used simultaneously with drug therapy. They make it possible to restore blood flow to joints that have been damaged, as well as slow down the process of bone loss and normalize metabolism.
Completely eliminate this disease impossible. In this regard, treatment of polyarthritis is always necessary. With the help of continuous treatment, the patient will be able to maintain his quality of life for a long time, as well as his usual level of activity and excellent health.
Please note: the information posted on the site is not medical recommendation, advice or guidance for action. Before using the information presented on our portal, be sure to consult your doctor!
Tumor necrosis factor – Alpha
Tumor necrosis factor alpha (TNF-ᵅ) is a protein consisting of 157 amino acids. It is the first multifunctional cytokine of the TFN family whose properties have been identified for the treatment of cancer. Its biological activity is regulated by TNF-alpha soluble receptors 1 and 2.
The natural effect is directly expressed by stimulating the production of interleukin-1, which is capable of recognizing healthy and cancer-affected structures at the cellular level. In this regard, tumor necrosis factor-alpha affects the cancer cell through its surface.
TNF-alpha in the body is mainly produced by active macrophages, T-lymphocytes and natural killer cells of affected tissues. It plays a key role in apoptosis and cell proliferation.
However, the influence of this natural element is closely related to the toxicity of the substance. Therefore, today more effective and less toxic versions of tumor necrosis factor are used, for example, such as Thymosin-alpha. Oncologists are also developing ways to directly supply necrosis factor to the tumor, without affecting other tissues and without being included in the general bloodstream.
Tumor necrosis factor-alpha and cancer
To date, the influence of this element, as well as its antagonists and subsequent biological elements on such forms of cancer lesions as:
Malignant formations of the stomach and breast:
Tumor necrosis factor-alpha causes the death of potentially cancerous cells.
Non-small cell lung cancer:
TNF-alpha protects the body from the effects of a variety of pathogens, thereby preventing the onset of disease.
Sarcoma and melanoma:
With these types of cancer, especially effective factor tumor necrosis-alpha recombinant.
Cancers of the uterus and ovaries:
They are also sensitive to this element.
Due to its ability to destroy the blood supply to a tumor, tumor necrosis factor-alpha can also be used for clinical therapy of metastatic cancer.
Drugs
Tumor necrosis factor-alpha is a cytokine. They are able to prevent tumor activity not only by counteracting abnormal cells, but also by combining with the main cellular mechanisms. Therefore, when creating drugs, the following types of drugs, represented by TNF inhibitors, are used:
- Monoclonal antibodies (“Infliximab”, adalimumab “Humira”, rituximab, represented by the drug “Rituxan”);
- Recombinant proteins that include immunoglobulin domains and TNF receptors, in particular interferon-1 and 2 (etanercept "Enbrel", golimumab "Simponi").
Among the Russian drugs of the cytokinic group, “Refnot”, “Reaferon”, “Roferon”, “Intron” and others stand out.
The cost of cytokine group drugs directly depends on the country of manufacture. Medicines of European and American origin will be much more expensive than Russian and Ukrainian ones.
However, this does not mean at all that domestic pharmaceuticals the specifics of the action will differ from imported ones. So, for example, let’s compare prices for packages of the drug with the same capacity of 100 thousand. units:
- preparations containing monoclonal antibodies (Russia): 1 bottle – from 1500 rubles. up to 2000 rub.; 5 bottles - bran. additional rub.;
- medicines with monoclonal antibodies (Ukraine): 1 bottle - from 500 UAH. up to 800 UAH; for 5 bottles the price is from 2000 UAH. up to 3500 UAH;
- recombinant tumor necrosis factor: the cost in Russia for one bottle is from 2000 rubles. up to 3000 rub. In Ukraine the price is higher: from 1000 UAH. up to 1800 UAH what is associated with the need for transportation;
- the price of imported products containing tumor necrosis factor-alpha per bottle ranges from 1000 USD. up to 1300 USD
Where to buy tumor necrosis factor-alpha?
Drugs containing tumor necrosis factor-alpha can be purchased in almost all countries of the world. In domestic pharmacology, drugs of the cytokine group are sold in pharmacies in large cities. But in most cases, drugs are given to the patient only with a doctor’s prescription and pre-order.
Patients in the CIS countries can purchase the drug from a Russian manufacturer, since the price of imported drugs is many times higher.
Reviews
There are different opinions about drugs in this group not only from cancer patients and their relatives, but also from oncologists themselves:
- Some point to the ability of drugs with tumor necrosis factor-alpha to independently fight cancer.
- Other experts only confirm the ability of cytokine drugs to enhance the effect of traditional therapy.
- Emphasis is placed on possible side effects, especially for patients with latent viral infections, tuberculosis, cardiovascular diseases and chronic diseases liver.
In any case, the maximum duration of treatment with tumor necrosis factor-alpha is only 2 courses. It can be carried out at home after a thorough diagnosis and collection of tests.
There are few patient reviews about the drug, but most patients report improvement with the therapeutic use of tumor necrosis factor-alpha general condition well-being, especially if you have advanced or recurrent cancer. Some, on late stages development of the disease, they perceive the drug as the only panacea. However, such an attitude is not adequate. Even despite the positive reviews, research is still underway in world practice regarding the safety of the product.
Tumor necrosis factor-alpha is one of the newest biological weapons, about which there is still a lot of debate in scientific oncology.
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Tumor necrosis factor (TNF): role in the body, determination in the blood, prescription in the form of drugs
Tumor necrosis factor (TNF) is an extracellular protein that is practically absent in the blood of a healthy person. This substance begins to be actively produced during pathology - inflammation, autoimmunization, tumors.
In modern literature you can find its designation as TNF and TNF-alpha. Last title considered obsolete, but still used by some authors. In addition to alpha-TNF, there is another form of it - beta, which is formed by lymphocytes, but much more slowly than the first - over the course of several days.
TNF is produced by blood cells - macrophages, monocytes, lymphocytes, as well as the endothelial lining of blood vessels. When a foreign antigen protein (microorganism, its toxin, tumor growth products) enters the body, TNF reaches its maximum concentration within the first 2-3 hours.
Tumor necrosis factor does not damage healthy cells, but at the same time has a strong antitumor effect. For the first time, this effect of this protein was proven in experiments on mice in which regression of tumors was observed. In this regard, the protein got its name. Later research showed that the role of TNF is not limited to the lysis of tumor cells, its action is multifaceted, it takes part not only in reactions during pathology, but is also necessary for a healthy body. However, all the functions of this protein and its true essence still raise a lot of questions.
The main role of TNF is participation in inflammatory and immune reactions. These two processes are closely related and cannot be distinguished. At all stages of the formation of the immune response and inflammation, tumor necrosis factor acts as one of the main regulatory proteins. In tumors, both inflammatory and immune processes, “controlled” by cytokines, also actively occur.
The main biological effects of TNF are:
- Participation in immune reactions;
- Regulation of inflammation;
- Influence on the process of hematopoiesis;
- Cytotoxic effect;
- Intersystem effect.
When microbes, viruses, or foreign proteins enter the body, the immune system is activated. TNF promotes an increase in the number of T- and B-lymphocytes, the movement of neutrophils to the site of inflammation, and the “sticking” of neutrophils, lymphocytes, and macrophages to the inner lining of blood vessels at the site of inflammation. An increase in vascular permeability in the zone of development of the inflammatory response is also a result of the action of TNF.
The effect of tumor necrosis factor (TNF) on body cells
Tumor necrosis factor affects hematopoiesis. It inhibits the proliferation of red blood cells, lymphocytes and white hematopoietic cells, but if hematopoiesis is suppressed for any reason, then TNF will stimulate it. Many active proteins, cytokines, have a protective effect against radiation. TNF also has these effects.
Tumor necrosis factor can be detected not only in blood, urine, but also in cerebrospinal fluid, which indicates its intersystem effect. This protein regulates the activity of the nervous and endocrine systems. The beta variety of TNF has a predominantly local effect, and the body owes systemic manifestations of immunity, inflammation and regulation of metabolism to the alpha form of the cytokine.
One of the most important effects of TNF is cytotoxic, that is, cell destruction, which fully manifests itself during the development of tumors. TNF acts on tumor cells, causing their death by releasing free radicals, reactive oxygen species and nitric oxide. Since single cancer cells are formed in any organism throughout life, TNF is also necessary for healthy people for their timely and rapid neutralization.
Transplantation of organs and tissues is accompanied by the introduction of foreign antigens into the body, even if the organ is the most suitable for a set of specific individual antigens. Transplantation is often accompanied by activation of local inflammatory reactions, which are also based on the action of TNF. Any foreign protein stimulates an immune response, and transplanted tissue is no exception.
After transplantation, an increase in the level of cytokine in the blood serum can be detected, which indirectly may indicate the onset of a rejection reaction. This fact underlies research on the use of drugs - antibodies to TNF, which can inhibit the rejection of transplanted tissues.
The negative effect of high concentrations of TNF can be seen in severe shock against the background of septic conditions. The production of this cytokine is especially pronounced during bacterial infection, when a sharp suppression of immunity is combined with cardiac, renal, and liver failure, leading to the death of patients.
TNF is able to break down fat and deactivate the enzyme involved in the accumulation of lipids. Large concentrations of the cytokine lead to exhaustion (cachexia), which is why it was also called cachectin. These processes cause cancer cachexia and exhaustion in patients with long-term infectious diseases.
In addition to the described properties, TNF also plays a reparative function. Following damage at the site of inflammation and an active immune reaction, healing processes increase. TNF activates the blood coagulation system, due to which the zone of inflammation is demarcated through the microvasculature. Microthrombi prevent further spread of infection. Activation of fibroblast cells and their synthesis of collagen fibers promotes healing of the lesion.
Determination of TNF level and its significance
Laboratory testing of TNF levels is not a frequently used test, but this indicator is very important for certain types of pathology. Determination of TNF is indicated for:
- Frequent and prolonged infectious and inflammatory processes;
- Autoimmune diseases;
- Malignant tumors;
- Burn disease;
- Injuries;
- Collagenosis, rheumatoid arthritis.
An increase in cytokine levels can serve not only as a diagnostic, but also as a prognostic criterion. Thus, in sepsis, a sharp increase in TNF plays a fatal role, leading to severe shock and death.
For the study, venous blood is taken from the patient; before the analysis, you are not allowed to drink tea or coffee, only plain water is acceptable. You should avoid eating any food at least 8 hours in advance.
An increase in TNF in the blood is observed when:
- Infectious pathology;
- Sepsis;
- Burns;
- Allergic reactions;
- Autoimmune processes;
- Multiple sclerosis;
- Meningitis and encephalitis of a bacterial or viral nature;
- DIC syndrome;
- Graft versus host disease;
- Psoriasis;
- Diabetes mellitus type 1;
- Myeloma and other tumors of the blood system;
- Shocked.
In addition to an increase, it is also possible to decrease the level of TNF, because normally it should be present, albeit in minute quantities, to maintain health and immunity. A decrease in TNF concentration is typical for:
- Immunodeficiency syndromes;
- Cancer of internal organs;
- The use of certain medications - cytostatics, immunosuppressants, hormones.
TNF in pharmacology
The variety of biological responses mediated by TNF has prompted research into the clinical use of tumor necrosis factor drugs and its inhibitors. The most promising antibodies appear to be those that reduce the amount of TNF in severe diseases and prevent fatal dangerous complications, as well as a recombinant synthetic cytokine prescribed to cancer patients.
Analogue drugs are actively used human factor tumor necrosis in oncology. For example, such treatment, along with standard chemotherapy, shows high effectiveness against breast cancer and some other tumors.
TNF-alpha inhibitors have anti-inflammatory effects. When inflammation develops, there is no need to immediately prescribe medications from this group, because in order to recover, the body must go through all the stages on its own inflammatory process, build immunity and ensure healing.
Early suppression of natural defense mechanisms is fraught with complications, so TNF inhibitors are indicated only in case of an excessive, inadequate reaction, when the body is unable to control the infectious process.
TNF inhibitor drugs - Remicade, Enbrel - are prescribed for rheumatoid arthritis, Crohn's disease in adults and children, ulcerative colitis, spondyloarthritis, psoriasis. As a rule, these drugs are used if standard therapy with hormones, cytostatics, antitumor drugs is ineffective, if it is intolerant or if there are contraindications to drugs from other groups.
Antibodies to TNF (infliximab, rituximab) suppress excess production of TNF and are indicated for sepsis, especially with the risk of developing shock; in case of developed shock, they reduce mortality. Antibodies to cytokines can be prescribed in case of long-term infectious diseases with cachexia.
Thymosin-alpha (timaktide) is classified as an immunomodulatory agent. It is prescribed for diseases with impaired immunity, infectious pathology, sepsis, to normalize hematopoiesis after irradiation, for HIV infection, and severe postoperative infectious complications.
Cytokine therapy is a separate direction in the treatment of oncopathology, which has been developing since the end of the last century. Cytokine drugs show high effectiveness, but independent use they are not justified. The best result is possible only with an integrated approach and the combined use of cytokines, chemotherapy and radiation.
Medicines based on TNF destroy the tumor, prevent the spread of metastases, and prevent relapses after removal of tumors. When used simultaneously with cytostatics, cytokines reduce their toxic effects and the likelihood of adverse reactions. In addition, due to their beneficial effect on the immune system, cytokines prevent possible infectious complications during chemotherapy.
Among the TNF drugs that have antitumor activity, Refnot and Ingaron, registered in Russia, are used. These are drugs with proven effectiveness against cancer cells, but their toxicity is an order of magnitude lower than the cytokine produced in the human body.
Refnot has a direct destructive effect on cancer cells, inhibits their division, and causes hemorrhagic tumor necrosis. The viability of a tumor is closely related to its blood supply, and refnot reduces the formation of new vessels in the tumor and activates the coagulation system.
An important property of refnot is its ability to enhance the cytotoxic effect of drugs based on interferon and other antitumor drugs. Thus, it increases the effectiveness of cytarabine, doxorubicin and others, thereby achieving high antitumor activity of the combined use of cytokines and chemotherapeutic drugs.
Refnot can be prescribed not only for breast cancer, as indicated in the official recommendations for use, but also for other neoplasms - lung cancer, melanoma, tumors of the female reproductive system
Side effects from the use of cytokines are few, usually a short-term increase in temperature and skin itching. The drugs are contraindicated in case of individual intolerance, pregnant women and nursing mothers.
Cytokine therapy is prescribed exclusively by a specialist, self-medication in in this case is out of the question, and the drugs can only be purchased with a doctor's prescription. An individual treatment regimen and combination with other antitumor drugs is developed for each patient.
Tumor necrosis factor inhibitors - modern drugs for the treatment of rheumatoid arthritis
TNF-α (tumor necrosis factor alpha) plays a key role in triggering and maintaining the inflammatory process in rheumatoid arthritis (RA). Suppression of TNF activity leads to a decrease in the synthesis of inflammatory mediators in the body, thereby achieving the necessary therapeutic effect in the treatment of the disease.
One of the disadvantages of therapy with TNF-α inhibitors is high price. However, this method of treatment also has significant advantages: proven effectiveness; safety; persistence of the achieved remission.
Let us consider the use of TNF-α inhibitors in clinical practice using the example of the drug widely used over the past 10 years in the USA, Canada and European countries a drug called etanercept. This TNF inhibitor is intended for subcutaneous administration, allowing RA patients to avoid costly and lengthy hospitalizations.
Etanercept is used in the treatment of rheumatoid arthritis with moderate or high inflammatory activity. The drug has a stimulating effect on TNF-α receptors present in the patient’s body. As a result, receptors more actively capture excess TNF-α, thereby reducing its concentration, which leads to a decrease in the inflammatory process.
Like other TNF-α inhibitor drugs, etanercept differs significantly in its pharmacological action from the immunosuppressants also used in some RA treatment regimens. Immunosuppressants affect virtually the entire immune system, while TNF-α inhibitors are active against specific targets that represent specific sites in the pathogenesis of rheumatoid arthritis.
The results of studies of etanercept showed that the new drug, a TNF inhibitor, leads to a significant reduction in the severity of symptoms of the disease, achieving stable and long-term remissions. Etanercept can be used both for monotherapy of RA (treatment with this medicine only) and as part of complex treatment. TNF inhibitors can be combined with nonsteroidal anti-inflammatory drugs (NSAIDs), immunosuppressants (methotrexate), glucocorticoids (GCs), and pain medications.
Etanercept is injected under the skin. “Injections” are performed twice a week. Possible injection areas: under the skin of the shoulder, anterior abdominal wall or thighs. Hospitalization of patients for treatment with a TNF inhibitor is not required; injections can be given nurse in the treatment room of a clinic or at home.
It should be noted that the use of TNF inhibitors may be accompanied by certain undesirable effects: fever, diarrhea, abdominal pain, leukopenia (decreased white blood cell count), headache, dizziness, respiratory disorders. In addition, local reactions sometimes occur at the injection site (skin itching and rashes).
It has not been reliably established what effect TNF-α inhibitors have on the protective function of the immune system. Therefore, patients receiving etanercept should be warned that the use of the drug may potentially provoke infection by various infections. Etanercept should not be used to treat patients with weakened immune systems because in this case, patients may develop serious infectious diseases that can lead to sepsis and death. Etanercept is also contraindicated in patients with certain heart diseases (the drug can lead to severe cardiovascular failure). TNF-α inhibitors are not intended for the treatment of RA without the assistance of a physician.
The introduction of TNF-α inhibitors into widespread clinical practice can be considered one of the biggest achievements medicine in the treatment of RA over the past decades. The use of drugs in this group makes it possible to achieve remission of the disease or a significant reduction in the activity of the inflammatory process, even in patients who were resistant (not sensitive) to other types of basic antirheumatic therapy. The use of TNF-α inhibitors for the treatment of RA significantly slows down the progression of destruction (destruction) of the affected joints, which is confirmed X-ray methods research.
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Immunotherapeutic agents are currently represented by four groups of drugs. Immunosuppressants. Anti-TNF drugs. Intravenous immunoglobulins (IVIGs). IFN
IMMUNOSUPPRESSANTS
The choice of immunosuppression protocol (dose, combination of drugs, duration of therapy) depends on the disease, type of transplantation and the degree of histocompatibility of the donor and recipient.
Indications to the use of immunosuppressants: . treatment of autoimmune diseases. prevention and treatment of graft-versus-host disease after bone marrow transplantation. prevention and treatment of transplant rejection.
GK have systemic anti-inflammatory and immunosuppressive activity.
Mechanism of action and changes in the immune system. After passive diffusion through the cytoplasmic membrane, they bind to an intracellular receptor. During translocation of the resulting complex in the cell nucleus, it interacts with specific DNA sequences ( GREs, from. English glucocorticoid responsive elements) and gene transcription factors... For example, GCs activate a gene I kappa B alpha factor that negatively regulates NF-k B (from English. nuclear factor k B - nuclear factor k B). NF-k B is a transcription factor for granulocyte-monocyte colony-stimulating factor (GM-CSF) genes. ), IL-2, IL-6, IL-8. Thus, steroid-induced suppression of NF-k B causes a decrease in the secretion of these cytokines... In addition, GCs inhibit the expression of genes IL-1, IL-3, IL-4, TNF and neutrophil secretion products: collagenases, elastases and plasminogen activator .. GCs reduce the number of all circulating leukocytes with the exception of neutrophils. However, due to decreased adhesion to endothelial cells, neutrophils lose the ability to leave the bloodstream and penetrate infected and damaged areas. The bactericidal activity of neutrophils and monocytes is also suppressed. The immunosuppressive effect depends on the dose of GC. At low or medium doses (<2 мг/кг/сут эквивалентной дозы преднизона для детей и <40 мг/сут для взрослых) наблюдают кожную анергию. Умеренно снижается количество циркулирующих Т-лимфоцитов, причём CD4 + -клеток в большей степени, чем CD8+-клеток. Дозы преднизона >2 mg/kg/day for children and >40 mg/day for adults suppress lymphocyte activation and AT production.
Risk infectious complications glucocorticoid therapy was significantly increased at a dose of prednisone >10 mg/day. The relative risk of opportunistic infections (Pneumocystis pneumonia) is significantly higher than that of typical viral (herpes viruses), bacterial ( Staphylococcus aureus etc.) and fungal ( Candida) infections. Protozoal infections and helminthiases are uncommon, with the exception of endemic pathogens (e.g. Plasmodium falciparum).
Some properties of commonly used GCs.. Betamethasone: half-life 5.6 hours, relative glucocorticoid activity 25, relative mineralocorticoid activity 0.. Dexamethasone: half-life 3.3 hours, relative glucocorticoid activity 30, relative mineralocorticoid activity 0.. Hydrocortisone: period half-life 1-2 hours, relative glucocorticoid activity 1, relative mineralocorticoid activity 2.. Methylprednisolone: half-life 2-3 hours, relative glucocorticoid activity 5, relative mineralocorticoid activity 0.. Prednisolone: half-life 2.6-3 hours, relative glucocorticoid activity 4, relative mineralocorticoid activity 1.. Prednisone: half-life 1.7-3 hours, relative glucocorticoid activity 3.5, relative mineralocorticoid activity 1.. Triamcinolone: half-life 2-3 hours, relative glucocorticoid activity 5, relative mineralocorticoid activity 0
Methotrexate inhibits dihydrofolate reductase, inhibiting the synthesis of thymidine and some amino acids, and slows down cell division. At a dose of >20 mg/kg used for the treatment of cancer, the drug suppresses the primary and secondary cellular and humoral immune responses and can cause bone marrow depression, hemorrhage and sepsis. At basic therapy rheumatoid arthritis and other rheumatoid diseases (1/5-1/10 of the immunosuppressive dose - 7.5-15 mg/week once orally, IM, IV), methotrexate has an anti-inflammatory effect by inhibiting the expression of adhesion molecules and cytokines. At a dose of 10-25 mg/week once, methotrexate is used to treat psoriasis.
Mycophenolate mofetil is a new effective immunosuppressant for the prevention of kidney transplant rejection. The drug is in clinical trials for the treatment of rheumatoid arthritis and SLE.
After oral administration, mycophenolate mofetil undergoes hydrolysis to form active component- mycophenolic acid, excreted mainly in the urine. The half-life is 6 hours.
Mycophenolic acid reversibly inhibits the enzyme inosine monophosphate dehydrogenase, thereby suppressing de novo biosynthesis of purines. Lymphocytes are significantly dependent on purine synthesis de novo and to a lesser extent from the hypoxanthine-guanine phosphoribosyl transferase-mediated purine biosynthesis pathway. Therefore, the drug acts predominantly on lymphocytes, in which the concentration of guanine nucleotides is significantly reduced, which limits the synthesis of DNA and RNA and suppresses proliferation.
Mycophenolic acid suppresses: .. AT production.. cytotoxic T-lymphocytes.. NK-cell activity.. production of cytokines IL-1 a, IL-1 b, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IFN-g, IFN-a, TNF-b, GM-CSF... expression of selectins by lymphocytes and monocytes.. recruitment of neutrophils, lymphocytes and monocytes.
Dosage: 1 g 2 times a day orally.
Side effects: fever, headache, infections, arterial hypertension, skin rash, insomnia, anemia, thrombocytopenia, leukopenia, dyslipidemia, hyperglycemia, electrolyte disturbances.
Leflunomide- an isoxazole derivative with an antiproliferative effect.
The drug is used to prevent transplant rejection. Leflunomide is also approved for the treatment of rheumatoid arthritis as monotherapy or in combination with methotrexate.
Mechanism of action.. The active metabolite of leflunomide - A77 1726 - has a half-life of more than 2 weeks and is excreted in urine and feces.. The antiproliferative effect of A77 1726 in lymphocytes is realized by two mechanisms: ... in low concentrations the drug inhibits de novo biosynthesis of pyrimidines in the G 1 phase of the cell cycle... in high concentrations A77 1726 suppresses IL-2-induced phosphorylation of Jak1 and Jak3 kinases and the IL-2 receptor b chain.. Leflunomide also inhibits the humoral response, because suppresses the proliferation of B-lymphocytes in the S-phase of the cell cycle, as well as the adhesion of mononuclear cells peripheral blood and synovial fluid.
Dosage: on days 1-3, 100 mg orally in one dose, then 10-20 mg orally in one dose.
Side effects: gastrointestinal disorders, infections of the respiratory and urinary systems, arterial hypertension, headache, baldness, skin rash, hypokalemia, diabetes, dyslipidemia, anemia, leukopenia, thrombocytopenia.
Cyclosporine- a cyclic peptide consisting of 11 amino acid residues, produced by a fungus Tolypocladium inflatum.
The drug is used for organ transplantation and autoimmune diseases.
Mechanism of action: Cyclosporine binds to the cytoplasmic receptor protein cyclophylline. The resulting complex inhibits the calcium-dependent phosphatase calcineurin, which is responsible for the activation of the transcription factor NF-AT (from the English. nuclear factor of activated T cells- nuclear factor of activated T cells). This molecule is necessary for the transcription of genes for a number of cytokines (GM-CSF, IL-2, IL-3, IL-4, IL-5, IL-8, IL-13, TNF, TNF g) and the membrane molecule CD40L (CD40 ligand) .. In addition, cyclosporine inhibits TCR-dependent activation (TCR - T-lymphocyte receptor, from English. T cell receptor) signaling pathway in T-lymphocytes and Ag-presenting function of monocytes/macrophages. Thus, the drug predominantly suppresses cellular immunity; however, its effect is not associated with significant lymphopenia or leukopenia.
Dosage: maintain therapeutic serum concentrations of 100-300 mcg/l; dynamic monitoring of serum levels of cyclosporine is indicated.
Side effects: nephrotoxicity, arterial hypertension, electrolyte disturbances, hepatotoxicity, hirsutism, acne, viral, bacterial pneumonia, fungal sepsis.
Sirolimus- a macrolide of fungal origin, forms a complex with FK-binding proteins from the cyclophyllin family, different from cyclosporine-binding cyclophyllins. The drug is used to prevent transplant rejection. Sirolimus does not inhibit calcineurin. Mechanism of action. Sirolimus binds to a specific cytosolic protein - immunophilin (FK-binding protein-12), the FKPB-12-sirolimus complex suppresses the activation of the mammalian target of rapamycin kinase (from the English mTOR - mammalian target of rapamycin), which plays a major role in cell cycle.. Inhibition of mTOR leads to the blockade of several specific signal transduction pathways and, ultimately, to the suppression of lymphocyte activation and a decrease in immune strength. Dosing: initial dose 6 mg, then 2 mg orally 1 time / day or under the control of serum concentrations (therapeutic concentration 4-12 ng / ml in combination with cyclosporine for the first 2-3 months, after discontinuation of cyclosporine - 12 -20 ng / ml).
ANTI-TNF DRUGS
Tumor necrosis factor a (TNF a) is a proinflammatory cytokine that plays an important role in the pathogenesis of rheumatic and inflammatory diseases. New data on the importance of TNF a in the pathophysiology of rheumatoid arthritis and Crohn's disease have led to the development of a new class of anti-TNF a drugs.
Infliximab (a humanized monoclonal antibody against TNF a) is approved for the treatment of rheumatoid arthritis and active Crohn's disease. Dosage: 5 mg/kg over 2 hours IV. Side effects: viral infections, bronchitis, pneumonia, sinusitis, infections urinary system, vomiting, diarrhea, headache, dizziness, arterial hypertension. Contraindications: sepsis, overt infection, abscess, pregnancy, age under 17 years.
IMMUNOGLOBULINS FOR INTRAVENOUS ADMINISTRATION
Immunoglobulins for intravenous administration (IVIG) are the standard of care for the treatment of humoral and combined immunodeficiencies, as well as a number of autoimmune diseases.
Manufacturing method. All IVIGs are prepared by cold precipitation with ethanol. After screening for infectious pathogens, sera from several thousand donors are mixed to produce one batch of the drug. IVIGs contain antibodies against the most common native viral and bacterial Ags, as well as Ag vaccines. To reduce the risk of pathogen transmission, pasteurization or detergent treatment is used. The final product usually contains more than 99% IgG in terms of protein. Up to 10% of IgG molecules form polymer complexes. The half-life in serum ranges from 15 to 30 days. The content of IgA and complement components varies depending on the manufacturer.
Mechanisms of action of IVIG: .. blockade and modulation of the expression of Fc g receptors.. suppression of the proliferative response of lymphocytes.. modulation of the production and secretion of cytokines (IL-1, IL-1ra [IL-1 receptor antagonist], TNF a, TGF-b 1 [from English transforming growth factor b - transforming growth factor b], IL-2, IL-10) .. inhibition of the damaging effects of complement.. suppression of endothelial cell proliferation.. stimulation of catabolism of IgG autoantibodies.. suppression of Fas-mediated apoptosis (Fas is one of the glycoproteins of the cell membrane ) .. regulation of idiotype-anti-idiotypic interactions.
Indications for use... Indications approved by the FDA:... X-linked agammaglobulinemia... Hyper-IgM syndrome... Transient hypogammaglobulinemia of the newborn... IgG subclass deficiency... AT deficiency syndrome... Severe combined immunodeficiency ... Common variable immunodeficiency... DiGeorge syndrome... Wiskott-Aldrich syndrome... Ataxia-telangiectasia... Chediak-Higashi syndrome... X-linked lymphoproliferative syndrome... Hyper-IgE syndrome... Chronic lymphocytic leukemia with hypogammaglobulinemia... Immunoprophylaxis ( varicella) ... Kawasaki disease ... Recurrent infections during bone marrow transplantation ... Idiopathic thrombocytopenic purpura ... HIV infection in children ... Indications based on the results of controlled clinical trials: ... Prevention of RSV and CMV infections ... Guillain-Barré syndrome... Chronic inflammatory demyelinating polyneuropathy.
Conditions in which the effectiveness of IVIG is being studied: .. autoimmune neutropenia .. autoimmune hemolytic anemia .. bronchial asthma .. atopic dermatitis.. chronic urticaria.. lupus nephritis.. Wegener's granulomatosis.. autoimmune thyroiditis.. glomerulonephritis.. Lyell's syndrome.. secondary immunodeficiencies.
Dosing. The serum IgG concentration in patients with hypogammaglobulinemia should be above 500 mg%. The dose of IVIG required to achieve and maintain this level depends on the initial IgG concentration, the frequency of drug administration, and the intensity of immunoglobulin catabolism in the individual patient. For most patients, a dose of 300 mg/kg once every 3 weeks or 400 mg/kg once every 4 weeks is sufficient.
Side effects... From 5 to 15% of patients experience adverse reactions to IVIG: facial flushing, lower back pain, nausea, chills. Symptoms may disappear when the infusion rate is reduced. The first dose of the drug should be administered at a rate of 30 ml/hour in adults and 10-15 ml/hour in children. If well tolerated, subsequent infusions begin at a rate of 40 ml/h and increase the rate by 25% every 30 minutes. Other side effects include acute renal failure, thrombosis, migraine, aseptic meningitis, hemolytic anemia.
INTERFERONS
Pharmacological effects: antiviral, antiproliferative, immunomodulatory.
Indications: chronic viral hepatitis, various acute viral infections, multiple sclerosis, chronic granulomatosis.
Side effects: fever, sweating, fatigue, arthralgia, myalgia, arrhythmias, depression, tremor, paresthesia, gastrointestinal disorders, hair loss, exanthema, itching.
Contraindications: heart disease, central nervous system disease, renal failure, liver failure, bone marrow suppression.
Abbreviations. NF-k B - nuclear factor k B (from English. nuclear factor k B), GM-CSF - granulocyte-monocyte colony-stimulating factor (from English. granulocyte-macrophage colony-stimulating factor), IVIG - immunoglobulins for intravenous administration.
Note. FDA is a US federal agency that controls the production, storage and sale of food, drugs and cosmetics ( The Food and Drug Administration).
Researchers point to various benefits associated with other diseases that the drugs may provide. You may take one or more medications to control RA. Your doctor will likely adjust your treatment regimen to keep disease activity as low as possible. The common side effects of RA medications are well known, but researchers have identified potential benefits for overall health.
It turns out that many of the medications we use to treat RA provide benefits we didn't realize.
The following are medications that may help.
What does he do for RA:
Methotrexate is considered the gold standard treatment for RA and is often the first drug taken by patients with newly diagnosed RA.
The tablets reduce pain and slow the progression of RA by blocking certain enzymes in the immune system.
Known Risks:
the drug increases the risk of infection and liver damage.
Potential Benefits:
According to some studies, methotrexate may reduce the risk cardiovascular diseases.
A review of 18 studies in England found that methotrexate use was associated with a lower risk of cardiovascular disease. This is a key benefit for those RA patients who are at increased risk of cardiovascular disease.
Protecting the heart may be due to two factors: atherosclerosis (deposition of fatty plaques in the arteries, the main cause of heart attacks) is an inflammatory disease, and methotrexate turns off inflammation and thus reduces the risk of cardiovascular disease.
Researchers don't yet know what dose of methotrexate reduces the risk of heart disease or how long it should be taken for protection. But a standard dose of 10 to 20 mg per week is enough to reduce the risk.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
What they do for rheumatoid arthritis:
NSAIDs control pain and inflammation.
Known Risks:
may cause stomach bleeding, kidney and heart problems.
Potential Benefits:
a 2011 study of 1,173 women with colorectal cancer showed that the use of NSAIDs before diagnosis cut the risk of death from cancer by half. Protection is primarily triggered when the tumor is in the upper part of the colon, farthest from the rectum.
Reduced inflammation in the body (from NSAIDs) is likely one of the factors contributing to the reduction in mortality from colorectal cancer.
Other studies have shown a reduction in mortality from colon cancer. However, tumors in different parts of the colon have different molecular profiles, so they may respond better or worse to drugs.
The use of NSAIDs can also worsen the course of hypertension. Therefore, the risks and benefits of using NSAIDs should be assessed by your doctor.
Biologics (including TNF inhibitors)
What they do for RA:
Inhibit parts of the immune system that cause inflammation, slowing disease progression.
Known Risks:
The TNF alpha inhibitor, infliximab, is given intravenously, so there may be pain or rash at the injection site. Biologics also increase the risk of infection.
Potential Benefits:
In 2013, researchers in Foggia, Italy, found that many biologics showed benefits in reducing bone loss, which may result from reduced inflammation.
TNF inhibitors reduce markers of bone destruction and increase markers of bone formation. Some studies have also shown an increase in bone mineral density, i.e. bone strength.
A 2011 German study of 5,432 RA patients also found that patients treated with biologics had decreased fatigue at 3 and 6 months.
TNF inhibitors (tumor necrosis factor inhibitors)
What they do for RA:
TNF inhibitors block the action of TNF, one of the inflammatory proteins.
Known Risks:
TNF inhibitors increase the risk of developing infections and may increase the risk of developing lymphoma (cancer of the lymph nodes).
Potential Benefits:
A 2011 study of 1,881 RA patients found that TNF inhibitors were associated with a 51% reduction in diabetes risk compared to those who had never taken these drugs.
According to WHO, 52% of people with diabetes have arthritis.
It is possible that TNF and other inflammatory proteins play a central role in the development of both RA and insulin resistance. Insulin resistance may predispose to diabetes. Therefore, reducing insulin resistance may lead to a reduced risk of developing diabetes.
The use of TNF inhibitors may also lead to a reduction in the use of steroids, another risk factor for diabetes.
Diabetes is a major risk factor for cardiovascular disease, and RA is also associated with a high risk of heart disease. It is very good to use medications that can control disease activity and reduce the risk of developing diabetes.
Hydroxychloroquine
What does he do for RA:
Hydroxychloroquine is a basic antirheumatic drug that reduces pain and swelling and may prevent progression of the disease.
Known Risks:
the most common side effects are nausea and diarrhea, which often improve over time or when the drug is taken with food.
Potential Benefits:
The drug may reduce the risk of developing diabetes. According to a 2011 study at Geisenger Health System of 1,127 patients newly diagnosed with RA who did not have diabetes. After 23 to 26 months, 48 people developed diabetes, and only three of them were taking hydroxychloroquine. The reduced risk of diabetes may be due to the drug lowering blood sugar levels.
Tumor necrosis factor ( TNF): definition of TNF; TNF value; treatment with anti-TNF drugs; trading safety for higher efficiency
Tumor necrosis factor(TNF) - (TNF-alpha, or cachectin), is a non-glycosylated protein. The name TNF comes from its antitumor activity.
Effects:
- TNF is synthesized by activated macrophages and has cytotoxic, immunomodulatory and anti-inflammatory effects.
- TNF is involved in antiviral, antitumor and transplantation immunity.
- For some tumors, TNF has a cytostatic and cytolytic effect.
- TNF stimulates macrophages.
- In high concentrations, TNF can damage endothelial cells and increase microvascular permeability, causing activation of the hemostasis and complement systems, followed by the accumulation of neutrophils and intravascular microthrombosis (DIC syndrome).
- The action of TNF extends to lipid metabolism, coagulation, insulin sensitivity and endothelial health, as well as a number of other functions.
- TNF suppresses the growth of tumor cells and regulates a number of metabolic processes, as well as the activity of the immune response to infectious agents, which does not allow the uncontrolled use of anti-TNF drugs and raises questions about their safety.
What are the mechanisms of antitumor action of TNF:
- TNF has a targeted effect on a malignant cell through TNF receptors, provoking programmed cell death or suppressing the division process; also stimulates the production of antigens in the affected cell;
- stimulates “hemorrhagic” tumor necrosis (death of cancer cells).
- blocking angiogenesis - suppressing the process of proliferation of tumor vessels, damaging tumor vessels without harming healthy vessels.
Features of the antitumor effect of TNF:
- TNF does not act on all tumor cells; Cells resistant to cytotoxic action themselves produce endogenous TNF and the active nuclear transcription factor NF-kB.
- a number of cells exhibit a dose-dependent effect of TNF, the combined use of the cytokines TNF and IFN-gamma in many cases gives a much more pronounced effect than when treated with one of these drugs;
- TNF targets tumor cells that are resistant to chemotherapy, and TNF-based therapy in combination with chemotherapy can effectively kill the affected cells.
Diagnostics:
| TNF content is reduced when: | TNF content is increased when: | Study: |
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| Preparation for the study: in the morning on an empty stomach Material: serum Method: ELISA Device - Microlab Star ELISA. Normal: up to 87 pkg/ml Reference values: 0 - 8.21 pg/ml. |
| Data interpretation | |
| Increased concentration | Decreased concentration |
|
|
How important are the functions of TNF in the human body?
TNF plays an important role in the immunological defense of the human body against infections and the control of tumor growth. Based on data from 3,500 patients treated with anti-TNF antibody therapy (Infliximab-Remicade and Adalimumab-Humira), the study found that TNF inhibition increased the incidence of serious infections by 2-fold and tumor growth by 3.3-fold in these patients.
The following mechanisms of influence of TNF are distinguished:
- Cytotoxic effect on both tumor cells and cells affected by viruses.
- Stimulates the formation of other active substances - leukotrienes, prostaglandins, thromboxane.
- It has an immunomodulatory and anti-inflammatory effect (with the activation of macrophages and neutrophils).
- Increased membrane permeability.
- Increased insulin resistance (an effect leading to the development of hyperglycemia, possibly due to inhibition of the activity of insulin receptor tyrosine kinase, as well as stimulation of lipolysis and an increase in the concentration of free fatty acids).
- Damage to the vascular endothelium and increased capillary permeability.
- Activation of the hemostatic system.
Meaning of TNF definition:
TNF plays an important role in the pathogenesis and choice of therapy for various pathologies: septic shock, autoimmune diseases (rheumatoid arthritis), endometriosis, ischemic brain lesions, multiple sclerosis, dementia in patients with AIDS, acute pancreatitis, neuropathies, alcohol impairment liver, transplant rejection. TNF is considered one of the important markers of damage to the liver parenchyma and, along with other cytokines, has diagnostic and prognostic significance in the treatment of hepatitis C.
An elevated level of TNF in the blood indicates severe chronic heart failure. Exacerbation bronchial asthma is also associated with increased TNF production.
Indications for prescribing an analysis to determine the level of TNF:
- An in-depth study of the immune status in cases of severe acute, chronic, infectious and autoimmune diseases.
- Oncology.
- Severe mechanical injuries and burns.
- Atherosclerotic lesions of the blood vessels of the brain and heart.
- Rheumatoid arthritis and collagenosis.
- Chronic pathology of the lungs.
Inflammatory CD4 T cell activity
For some bacteria (causative agents of tuberculosis, leprosy, plague), macrophages provide a “habitat”. Once in phagolysosomes as a result of phagocytosis, pathogens become protected from both antibodies and cytotoxic T-lymphocytes.
By suppressing the activity of lysosomal enzymes, these bacteria actively multiply inside the cell and thus become the cause of an acute infectious process. It is no coincidence that the diseases mentioned as an example are classified as particularly dangerous infections.
This one has enough difficult situation However, the body has forces that prevent the spread of pathogens, and they are primarily associated with inflammatory CD4 T cells.
The participation of this type of lymphocytes in organizing the immune response is realized through the activation of macrophages. Activated macrophages not only cope with intracellular pathogens, but also acquire in some cases additional properties not related to antibacterial effect, for example, the ability to destroy cancer cells.
Macrophage activation requires two signals
The first of them is interferon-gamma (IF-gamma). It is the most characteristic cytokine produced by inflammatory CD4 T cells. Helper T cells do not secrete this cytokine and cannot activate macrophages in the usual way.
The second signal for macrophage activation is superficial TNF-alpha, which is induced to expression after inflammatory T cells recognize an immunogen on the macrophage membrane. Antibodies to TNF-alpha cancel the effect of the second signal.
Cytotoxic T cells become active immediately after antigen recognition, realizing the potential readiness of the molecular apparatus to destroy target cells through the process of apoptosis or necrosis. In contrast, inflammatory CD4 T cells, after recognizing antigen on the surface of macrophages, spend hours de novo synthesizing mediators that activate macrophages. Newly synthesized cytokines, collected in microvesicles, enter macrophages at the site of contact with T cells. This direct route, as in the case of cytotoxic T lymphocytes, is the most economical and functionally justified, since it does not affect neighboring, uninfected cells.
In macrophages activated through contact with inflammatory T cells and as a result of the secretion of IF-gamma, a series of biochemical changes are initiated that provide these cells with strong antibacterial properties.
 |
| In the figure: Functional activity of inflammatory CD4 T cells. The main target of inflammatory CD4 T cells is infected macrophages. As a result of recognition of the immunogenic complex on macrophages, CD4 T cells express tumor necrosis factor-alpha (TNF-alpha) on their surface and increase the production of interferon-gamma (IF-gamma). The combined action of cytokines ensures more efficient formation of phagolysosomes, accumulation of oxygen radicals and nitric oxide, which have bactericidal properties, increased expression of MHC class II molecules, and increased production of tumor necrosis factor-alpha. Such activation of biochemical processes in macrophages not only contributes to the intracellular destruction of bacteria, but also determines the additional inclusion of T cells in the immune response |
Under conditions of interaction between macrophages and inflammatory T cells, a more effective fusion of phagosomes that have captured bacteria with lysosomes, the guardians of proteolytic enzymes that destroy intracellular pathogens, is observed. The process of phagocytosis is accompanied by the so-called oxygen explosion - the formation of oxygen radicals and nitric oxide, which have bactericidal activity.
Under conditions of costimulation of TNF-alpha and IF-gamma, this process is much more active. In addition, activated macrophages upregulate the expression of MHC class II molecules and TNF-alpha receptor, leading to the recruitment of additional naïve T cells. This entire complex of events provides a fairly strong barrier against intracellular pathogens.
Inflammatory T cells interacting with macrophages not only contribute to the enhancement of intramacrophage biochemical processes, but at the same time they themselves are activated and act as organizers of a multifaceted immune response to the antigen.
The infectious process provoked by reproducing pathogens reflects the struggle of two forces - the pathogen itself and the host's immune system. For example, the plague pathogen Yersenia pestis has the ability to inducibly synthesize highly polymerized protein I, which begins to be expressed on the cell wall at an acidic pH value.
Is anti-TNF therapy really associated with an increased risk of developing severe infections?
The increased risk of developing infections, including tuberculosis, is a major point of discussion when discussing the safety of TNF inhibitors. Previous studies of anti-TNF therapy have not found a significant increase in the incidence of serious infections, although evidence has been found indicating this possibility. An analysis of data from the German Biological Register revealed a 2-fold increase in the risk of serious infections. In subsequent studies, the dependence of the risk on time also remained unchanged. One possible explanation for this relationship is the assumption that the degree of risk is due to a decrease in the dose of glucocorticoids with the effectiveness of anti-TNF drugs, a decrease in the severity of the disease, as well as a decrease in the number of susceptible patients (in patients belonging to the group high risk, infections occurred early, at the beginning of treatment, as a result of which therapy was discontinued, due to which treatment continued only in a cohort of patients with a low risk of infection).
In a study by Grijalva et al. absolute incidence of infections in comparison group patients was much higher than in other studies of patients treated with rheumatoid arthritis disease-modifying drugs.
Contraindications:
Anti-TNF therapy should not be prescribed to weakened patients, as well as those who have previously had an infectious disease, because in both of these cases they are at high risk of infection.
The antitumor effect of TNF is enhanced by the combination of TNF with IFN-gamma
The engineered tumor necrosis factor α-thymosin-a1 (TNF-T) fusion protein has potent immunostimulatory effects. In terms of the spectrum and activity of action on tumor cells, the TNF-T drug is not inferior, and on some tumors it is superior to human TNF. Moreover, TNF-T has 100 times less overall toxicity than TNF, which has been confirmed clinical trials at the Russian Scientific Research Center named after. N. N. Blokhin (Moscow) and the Research Institute of Oncology named after. N. N. Petrova (St. Petersburg). For the first time in the world, the clinic confirmed that the addition of thymosin-a1 to TNF reduced its overall toxicity and gave it new properties.
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