Remicade, 100 mg, lyophilisate for solution for infusion, 1 pc.

Pharmacological properties of the drug Remicade

Pharmacodynamics. Infliximab is a hybrid mouse-human monoclonal antibody (IgG1) that binds with high affinity both soluble and transmembrane forms of tumor necrosis factor alpha (TNF-α), which plays an important role in the development of autoimmune and inflammatory diseases. Infliximab quickly forms stable complexes with human TNF-α, and its bioactivity decreases. Infliximab is specific to TNF-α and is not able to neutralize lymphotoxin (TNF-β). Pharmacokinetics. Single intravenous infusions of infliximab at doses of 1, 3, 5, 10 or 20 mg/kg caused a dose-proportional increase in its maximum serum concentration. The volume of distribution at steady state is independent of the administered dose and indicates that infliximab is distributed predominantly in the vascular bed. No dependence of pharmacokinetics on time was detected. The route of elimination of infliximab has not been determined. No significant differences in pharmacokinetics were detected in patients of different demographic groups, weight categories, or with mildly severe impairment of liver or kidney function. After a single dose in children and adults with Crohn's disease, no significant differences in the pharmacokinetics of the drug were identified. With a single administration of infliximab at a dose of 3, 5 and 10 mg/kg, the maximum plasma concentration was 77, 118 and 277 mcg/ml, the volume of distribution was 3 l, and the terminal half-life was 8–9.5 days. In most patients, after administration of this dose, infliximab is detected in the blood serum within 8 weeks. With a 3-fold dose of infliximab, a slight accumulation of the drug in the blood serum was observed after the second dose, which subsequently had no clinical significance. In most patients with fistula Crohn's disease, post-dose infliximab was detectable in serum for 12 weeks (range 4–28 weeks).

Indications for use of the drug Remicade

active rheumatoid arthritis in the absence of sufficient effect from methotrexate therapy or active rheumatoid arthritis without previous methotrexate therapy for:

• reducing the severity of signs and symptoms of the disease;
• prevention of structural damage to joints (erosion and reduction of interarticular space);
• improving functional status.

Remicade is a disease-controlling antirheumatic therapy. Active ankylosing spondylitis for:

• reducing the severity of signs and symptoms of the disease;
• improving functional status.

Active psoriatic arthritis for:

• reducing the severity of signs and symptoms of arthritis;
• improving functional status;
• reducing the severity of symptoms in psoriasis in accordance with the PASI index (an index that comprehensively evaluates symptoms relative to body surface area).

Severe plaque psoriasis in adults, when systemic therapy is necessary, as well as in patients with moderate disease, when phototherapy was not effective enough, or when there are contraindications to its implementation, for:

• reducing the severity of signs and symptoms of the disease;
• improving quality of life.

Crohn's disease (moderate to severe) in children and adult patients, refractory to conventional therapy, for:

• reducing the severity of signs and symptoms of the disease;
• achieving and maintaining clinical remission;
• healing of lesions of the mucous membranes in adults;
• improving quality of life.

Taking Remicade allows you to reduce or eliminate the use of corticosteroids. Crohn's disease with fistula formation in adult patients for the purpose of:

• reducing the number of enterocutaneous and rectovaginal draining fistulas (that is, it promotes the closure of fistulas);
• maintaining the achieved effect of fistula closure;
• reducing the severity of signs and symptoms of the disease;
• improving quality of life.

Active ulcerative colitis with insufficient effectiveness of traditional therapy for:

• reducing signs and symptoms of the disease;
• induction and maintenance of clinical remission;
• induction of mucosal healing;
• improving the quality of life;
• reducing or stopping the use of GCS;
• reducing the number of hospitalizations for ulcerative colitis.

Using Remicade

Treatment should be supervised by physicians experienced in diagnosing and treating the conditions for which Remicade is used. Remicade is used for intravenous administration in adult patients (≥18 years of age) and children over 6 years of age with Crohn's disease. After administration of the drug, the patient should be under medical supervision for at least 1 hour for timely identification of possible side effects. A single dose of Remicade for the treatment of rheumatoid arthritis is 3 mg/kg body weight. The drug is administered according to the schedule at weeks 0–2–6 and then every 8 weeks. To optimize clinical response, the Remicade dose may be gradually increased to 10 mg/kg body weight, or a dose of 3 mg/kg body weight may be administered at 4-week intervals. Remicade should be used concomitantly with methotrexate. The therapeutic effect, according to available data, is usually achieved within 12 weeks of treatment. If the patient has an inadequate clinical response or has lost it after this period, the dose of Remicade can be increased as described above. After achieving an adequate clinical response, treatment is continued using the selected dose or frequency of administration. The need for continued treatment should be reconsidered in patients who do not experience improvement within the first 12 weeks of therapy (or after a dose change). For the treatment of ankylosing spondylitis, Remicade is administered at a dose of 5 mg/kg body weight. The drug is administered according to the schedule at weeks 0–2–6 and then every 6–8 weeks. For the treatment of psoriatic arthritis, a single dose of Remicade is 5 mg/kg body weight. The drug is administered according to the schedule at weeks 0–2–6 and thereafter at intervals of 8 weeks. For the treatment of psoriasis, the drug is administered at a dose of 5 mg/kg body weight according to the schedule at weeks 0–2–6 and then at intervals of 8 weeks. For the treatment of severe and moderate Crohn's disease (in adults), it is recommended to administer a dose of 5 mg/kg body weight according to the schedule at weeks 0–2–6 and then maintenance therapy at intervals of 8 weeks. If the clinical response to maintenance therapy is insufficient, the dose may be increased to 10 mg/kg body weight. An alternative regimen is to administer an initial dose of 5 mg/kg body weight followed by maintenance doses of 5 mg/kg body weight when signs or symptoms of the disease reappear. However, data regarding repeated use of the drug within a 16-week interval are limited. For the treatment of Crohn's disease with the formation of fistulas (in adults), the drug is administered at a dose of 5 mg/kg body weight according to the schedule at weeks 0–2–6. If no positive clinical effect is obtained after these 3 doses, Remicade therapy should be discontinued. Continuation of treatment: additional infusions of 5 mg/kg body weight every 8 weeks or re-administration of Remicade if signs or symptoms of the disease recur - 5 mg/kg body weight every 8 weeks. In Crohn's disease, experience with re-administration of Remicade when signs or symptoms reoccur is limited; There are insufficient data comparing the benefits/risks of alternative strategies for continuing treatment. For severe and moderate Crohn's disease in children, it is recommended to administer a dose of 5 mg/kg body weight in the 0–2–6 week regimen and then maintenance therapy at intervals of 8 weeks. If the clinical response is insufficient, a decision may be made to increase the dose to 10 mg/kg body weight. Remicade should be used concomitantly with immunomodulators, including 6-mercaptopurine, azathioprine, or methotrexate. For the treatment of ulcerative colitis, the drug is administered at a dose of 5 mg/kg body weight according to the schedule at weeks 0–2–6 and then at intervals of 8 weeks. In some patients, the dose may be increased to 10 mg/kg body weight to maintain clinical response and remission. Repeated use of Remicade for Crohn's disease and rheumatoid arthritis. If the disease relapses, Remicade may be re-administered within 16 weeks after the last dose. Repeated use of alternative formulas to infliximab after 2-4 years without using the drug after the first course was accompanied by the development of delayed-type allergic reactions in 10 of 41 patients with Crohn's disease (according to clinical trials). The risk of developing these reactions between 16 weeks and 2 years is unknown. Therefore, repeated treatment at intervals of 16 weeks is not recommended. Repeated use of Remicade for ulcerative colitis. At this time, there is no data to support dosage regimens other than dosing every 8 weeks. Repeated use for ankylosing spondylitis. At this time, there is no data to support dosage regimens other than administration of the drug every 6–8 weeks. Repeated use for psoriasis and psoriatic arthritis . At this time, there is no data to support dosage regimens other than dosing every 8 weeks. Method of administration The drug is administered intravenously for at least 2 hours, at a rate of no more than 2 ml/min. The duration of infusion may be reduced to reduce the risk of infusion reactions, especially if such reactions have occurred previously. Preparation of infusion solution:

1. The dose, the number of Remicade vials required (each vial contains 100 mg of infliximab) and the volume of the drug dissolved should be calculated.
2. The contents of the vial are dissolved in 10 ml of water for injection using a syringe with a 21-gauge needle (diameter 0.8 mm) or smaller, directing a stream of water along the wall of the vial. Mix the solution carefully, rotating the bottle until the lyophilized powder is completely dissolved (do not shake or shake the bottle). When dissolved, foam may form, so the finished solution should stand for 5 minutes. The resulting solution should be colorless or pale yellow, opalescent. It may contain a small number of small translucent particles. Solutions containing dark particles, as well as solutions with a changed color, cannot be used.
3. Bring the total volume of the prepared dose of Remicade solution to 250 ml by adding 0.9% sodium chloride solution for injection. To do this, remove a volume equal to the volume of the prepared Remicade solution (in water for injection) from a glass bottle or infusion bag that contains 250 ml of 0.9% sodium chloride solution. After this, the previously prepared Remicade solution is slowly added to a bottle or infusion bag with the required volume of 0.9% sodium chloride solution and mixed carefully.
4. Due to the fact that the drug does not contain a preservative, it is recommended to administer the infusion solution immediately (no later than 3 hours after preparation). If dissolution and dilution were carried out under strict aseptic conditions, the solution can be used for 24 hours if stored at a temperature of 2–8 °C. Do not save any unused remainder of the drug for future use.
5. Remicade should not be administered in combination with other drugs through the same infusion system.
6. The infusion solution must be visually checked before administration.
7. If there are opaque particles, foreign inclusions or discolored, it cannot be used.
8. Unused infusion solution is not subject to further use.

Remicade instructions for use

Pharmacological action Remicade is a drug that has an immunosuppressive effect. Remicade contains the active component infliximab, which is a high-affinity hybrid mouse-human monoclonal antibody that binds soluble and transmembrane forms of TNFa (tumor necrosis factor a). Infliximab quickly forms stable complexes with human TNFa, thereby reducing its biological activity. Remicade has a specific effect on TNFa, without affecting lymphotoxin a. Patients with rheumatoid arthritis have increased levels of TNFa in the joints, and TNFa levels increase with exacerbation of the disease. When using the drug Remicade in patients with rheumatoid arthritis, there was a decrease in infiltration in the area of ​​​​inflamed joints, a decrease in the expression of molecules that promote cell adhesion, chemoattraction and tissue degradation. In addition, when using infliximab, patients experienced a decrease in plasma C-reactive protein and interleukin 6 (IL-6) levels and an increase in hemoglobin levels. In patients with psoriasis, Remicade reduced epidermal inflammation and normalized keratinocyte differentiation in psoriatic plaques. In psoriatic arthritis, short-term use of Remicade resulted in decreased levels of T cells and blood vessels in psoriatic skin and synovium. Histological evaluation of colon samples obtained before and 4 weeks after infliximab therapy showed a significant reduction in TNFa levels. In addition, in patients with Crohn's disease there was a decrease in the level of C-reactive protein, normalization of the level of lymphocytes, neutrophils and monocytes during therapy with Remicade. The use of Remicade in such patients also led to a decrease in the number of cells capable of expressing interferons and TNFa, a decrease in the severity of inflammatory cell infiltration and the presence of inflammatory markers in the affected areas. Endoscopic examination showed healing of the intestinal mucosa in patients who received infliximab therapy. When Remicade was administered intravenously, plasma concentrations were dose proportional. Infliximab is distributed predominantly in the vascular bed. The route of elimination of infliximab has not been established. There were no clinically significant differences in pharmacokinetics in patients of different groups, including groups divided by gender, age, kidney and liver function. The average half-life of infliximab when administered at 3.5 and 10 mg/kg body weight was 8-9.5 days. In this case, the active component of the drug Remicade in most patients was determined in plasma 8 weeks after a single administration. With three-time administration, some accumulation of infliximab is observed, which has no clinical significance. In children with Crohn's disease, the pharmacokinetics of Remicade were similar to those in adults. Indications for use Remicade is recommended to be prescribed in combination with methotrexate or as monotherapy (for patients for whom methotrexate therapy is contraindicated). Remicade is used to reduce symptoms and improve physical function in patients with rheumatoid arthritis. Specifically, Remicade is indicated for adults with active rheumatoid arthritis in whom disease-modifying antirheumatic drugs are ineffective, and for adults with severe, advanced, or active rheumatoid arthritis who have not previously received methotrexate or other disease-modifying antirheumatic drugs (in these patients, Remicade slows progression diseases). Remicade is indicated for adult patients with severe active Crohn's disease who have not responded to corticosteroids and/or immunosuppressants or are contraindicated. In addition, Remicade is prescribed to adult patients with active Crohn's disease, which is accompanied by the formation of fistulas (provided that the first-line drugs recommended in such cases are ineffective). Remicade is used to treat children over 6 years of age with active, severe Crohn's disease who have not responded to standard therapy (corticosteroids, diet, immunosuppressants) or are contraindicated. In such cases, Remicade should be prescribed only in combination with standard immunosuppressive therapy. The drug Remicade is prescribed to adults with an active form of ulcerative colitis (with moderate to severe disease), with intolerance or ineffectiveness of standard treatment regimens. Remicade is prescribed to patients with active and progressive ankylosing spondylitis and psoriatic arthritis in whom standard therapy is not sufficiently effective. Remicade can be used for the treatment of plaque psoriasis (moderate to severe forms) in the absence of a response to standard therapy or when it is impossible to prescribe it (if there are contraindications).

Directions for use Remicade should be prescribed by a physician experienced in treating the relevant diseases. Remicade lyophilisate is intended for the preparation of a solution for infusion (intravenous drip). Infusions should take place in a hospital setting under the supervision of medical personnel (monitoring of the patient's condition should continue for at least 2 hours after the end of the infusion). The facility where Remicade treatment is administered must have resuscitation equipment and emergency medications available. Patients should be informed about possible side effects, as well as what to do if they occur.

Dosing of the drug Remicade: The duration of use and dose of the drug Remicade is determined by the doctor. Patients with rheumatoid arthritis who have not previously used Remicade are usually prescribed infliximab at a dose of 3 mg/kg body weight as a 2-hour infusion. Infusion of infliximab at the same dose is repeated at weeks 2 and 6 of therapy, after which Remicade is administered at the same dose every 8 weeks. If the first infusion is well tolerated, you can subsequently reduce the time of administration of Remicade to 60 minutes (while maintaining the dose). The therapeutic effect usually develops 12 weeks after the start of treatment; in the absence of positive dynamics, the dose should be reconsidered. It is allowed to gradually increase the dose of infliximab to 7.5 mg/kg body weight once every 8 weeks or reduce the intervals between doses to once every 4 weeks while maintaining a single dose of 3 mg/kg body weight. After achieving the desired effect, the treatment regimen and dose of infliximab are not changed. For active severe forms of Crohn's disease (including the formation of fistulas), ulcerative colitis, ankylosing spondylitis, psoriasis and psoriatic arthritis, a single dose of infliximab is prescribed at a dose of 5 mg/kg body weight (in the form of a 2-hour infusion). Repeated infusion is carried out after 2 weeks, maintaining a single dose. If there is a positive response to therapy, Remicade is administered in the same single dose at 6 weeks of treatment, after which Remicade is administered every 8 weeks. If during therapy the positive response to the drug disappears, it makes sense to consider increasing the dose of infliximab. In patients with Crohn's disease, ulcerative colitis and ankylosing spondylitis, if there is no response to treatment after 2-3 infusions, Remicade should be discontinued. In patients with psoriasis, if there is no response to treatment after 4 infusions, Remicade should be discontinued. In case of interruption of maintenance therapy for Crohn's disease and rheumatoid arthritis, administration of the appropriate single dose after a break of no more than 16 weeks is effective. If maintenance therapy is interrupted and Remicade is administered with a break of 16-20 weeks after the last infusion, the risk of side effects increases and the effectiveness of infliximab decreases. Re-use of Remicade after discontinuation of maintenance therapy has not been sufficiently studied for various indications. For children over 6 years of age with Crohn's disease, Remicade is prescribed according to the same regimen as for adults with a single dose of 5 mg/kg body weight (after the first administration, infusions are carried out at weeks 2 and 6, after which they switch to administration once every 8 weeks). Remicade has not been studied in children under 6 years of age.

Method of administration of the drug Remicade: The drug should be administered intravenously by drip slowly (the minimum time of the first infusion is 2 hours, starting from the fourth infusion, if well tolerated by patients with rheumatoid arthritis, the administration time can be reduced to 1 hour). To reduce the risk of side effects, the infusion time may be increased. The preparation and administration of the solution should be carried out under aseptic conditions; during infusion, a system with a pyrogen-free filter that has a low ability to bind proteins should be used. To prepare an infusion solution, the required dose should be calculated, taking into account that 1 bottle contains 100 mg of infliximab, as well as the volume of the dissolved drug. The contents of each vial are dissolved in 10 ml of water for injection using a syringe with a needle of 0.8 mm or less. Before introducing the solvent, remove the cap and wipe the lid with an antiseptic. The syringe needle is inserted into the bottle through the center of the rubber stopper and water is injected along the wall of the bottle. Gently swirling the bottle, the powder is dissolved, left for 5 minutes, drawn into a syringe and dissolved in a 0.9% sodium chloride infusion solution to 250 ml. To obtain an exact volume, a volume equal to the volume of the resulting Remicade solution (in water for injection) is taken from the infusion solution bottle with a syringe, after which the Remicade solution is slowly injected into the infusion bottle and carefully dissolved. It is forbidden to shake the bottle when dissolving the powder, as otherwise foam will form. Do not use Remicade if visible insoluble particles form in the solution or if there is a significant change in color (the Remicade solution should be clear and colorless or slightly yellow). Remicade does not contain preservatives; the prepared solution should not be stored. The Remicade infusion should be administered within 3 hours after its preparation, the remainder of the infusion should be disposed of. It is prohibited to administer Remicade through the same system with other drugs.

Side effects When using Remicade, patients experienced infusion-related side effects, including shortness of breath, difficulty breathing, headache and urticaria, which may require discontinuation of the drug. In addition, when using infliximab, the following undesirable effects may develop: On the blood system: leukopenia, lymphocytosis, lymphadenopathy, anemia, lymphopenia, thrombocytopenia, thrombocytopenic thrombohemolytic purpura, agranulocytosis, neutropenia. It is also possible to develop hemolytic anemia, idiopathic thrombocytopenic purpura and pancytopenia. On the nervous system: depression, anxiety, confusion, apathy, memory impairment, nervousness, disturbances in sleep and wakefulness. In addition, it is possible to develop headaches, exacerbation of multiple sclerosis, dizziness and meningitis. On the sensory organs: endophthalmitis, keratoconjunctivitis, conjunctivitis, periorbital edema. On the heart and blood vessels: hot flashes, bradycardia, syncope, cyanosis, palpitations, cardiac arrhythmias, deterioration in patients with heart failure, arterial hypertension, hematoma/ecchymosis, sensation of heat. In addition, the development of arterial hypotension, vascular spasm, thrombophlebitis, petechiae, peripheral circulatory disorders, tachycardia and vascular insufficiency, as well as myocardial ischemia and infarction, pericardial effusion and heart failure is possible. On the respiratory system: lower and upper respiratory tract infections, difficulty breathing, sinusitis, pleural effusion, interstitial lung disease. On the digestive tract: epigastric pain, stool disorders, vomiting, nausea, dyspepsia, gastroesophageal reflux, diverticulitis, intestinal stenosis and perforation, pancreatitis, gastrointestinal bleeding. On the liver and biliary tract: liver dysfunction, hepatitis, cholecystitis, increased activity of liver enzymes, autoimmune hepatitis, jaundice, hepatocellular disorders. On the musculoskeletal system: pain in the back, muscles and joints. On the urinary system: pyelonephritis, urinary tract infections. On the skin: urticaria, onychomycosis, fungal skin lesions, rosacea, hyperkeratosis, warts, furunculosis, pigmentation disorders, alopecia. Allergic reactions: serum sickness-like symptoms, lupus-like syndrome, allergic rhinitis, cough, angioedema, anaphylactic shock. In addition, the development of vasculitis, sarcoid reaction and serum sickness, as well as Lyell's syndrome, Stevens-Johnson syndrome and psoriasis, is possible. Development of infections and infestations during infliximab therapy: influenza, herpes, bacterial infections, tuberculosis, candidal lesions of the mucous membranes and skin, opportunistic infections (including pneumocystis, aspergillosis, cryptococcosis, histoplasmosis, coccidioidomycosis and blastomycosis, as well as listeriosis, salmonellosis and cytomegalovirus infection) , parasitic infections, reactivation of hepatitis B. Development of benign and malignant, as well as nonspecific tumors: lymphoma, hepatolienal T-cell lymphoma, non-Hodgkin's lymphoma, leukemia, Hodgkin's disease. Other side effects: vaginitis, increased sweating, chest pain, hyperthermia, pain and swelling at the injection site, the appearance of antibodies, changes in complement factor. If side effects develop, it is necessary to examine the attending physician and assess the severity of the side effects (based on these data, the doctor decides on the possibility of continuing therapy with Remicade).

Contraindications Remicade is not prescribed to patients with a history of intolerance to infliximab or additional components of the lyophilisate, as well as other murine proteins. Remicade is not prescribed to patients suffering from severe forms of infectious diseases, including sepsis, tuberculosis (tuberculosis, including latent tuberculosis, must be excluded before starting treatment), opportunistic infections and abscesses. Remicade is contraindicated in patients with severe or moderate heart failure. In pediatrics, Remicade can be used to treat children over 6 years of age with Crohn's disease. Remicade should be used with caution in patients with a history of severe, chronic or recurrent infections, or in patients who reside or travel in regions where fungal infections are endemic. Vaccination with live vaccines should not be performed during therapy with Remicade. Infliximab should be prescribed with caution to patients with a history of demyelinating disorders, as well as to patients with a family history of autoimmune diseases. Remicade is prescribed with caution to patients with chronic obstructive pulmonary disease (due to a higher risk of developing tumors), mild heart failure, carriage of hepatitis B and risk factors for hematopoietic disorders. There is no data on the effect of Remicade on surgical interventions; caution should be exercised when performing surgical interventions in patients receiving infliximab. There are no data on the use of Remicade in patients with impaired renal or hepatic function; caution should be exercised when prescribing infliximab to patients in these groups. It is recommended to avoid driving and operating potentially unsafe machinery during treatment with Remicade.

Pregnancy Remicade has not been studied in pregnant women. Theoretically, infliximab can affect the development of immune reactions in the fetus, so Remicade should not be used during pregnancy. During treatment with Remicade, as well as for 6 months after the last administration of infliximab, you should not plan to become pregnant (more reliable contraceptive methods should be used to prevent pregnancy). In neonates whose mothers received Remicade (including within 12 months before conception), vaccination with live vaccines before 6 months of age should be done very carefully. There is no data on the penetration of the active component of Remicade into breast milk. During lactation, the use of infliximab is not recommended; if therapy cannot be avoided, the issue of interrupting breastfeeding should be addressed.

Drug interactions In patients with rheumatoid arthritis, Crohn's disease and psoriatic arthritis, when Remicade is used in combination with immunomodulators, a decrease in the formation of antibodies to infliximab is observed. This effect is not obligatory; for example, when using corticosteroids, there is no change in the pharmacokinetics of infliximab. The combined use of Remicade with abatacept and anakinra is prohibited. Remicade should not be used concurrently with immunization with live vaccines. Remicade solution must not be mixed with other drugs (excluding solutions intended for the preparation of Remicade solution).

Overdose There was no development of acute toxicity when using high doses of Remicade (in particular, after a single administration of the drug at a dose of 20 mg/kg body weight, no intoxication was observed in patients). If an overdose develops, the patient's condition should be monitored and symptomatic therapy should be provided if indicated.

Release form Lyophilized powder for the preparation of Remicade parenteral solution in 20 ml bottles, 1 bottle in a cardboard box.

Storage conditions Remicade should be stored away from children in rooms where the temperature is maintained between 2 and 8 degrees Celsius. It is forbidden to freeze the powder. The prepared solution is stable for 24 hours, however, from a microbiological point of view, the prepared Remicade preparation should not be stored for more than 3 hours. The unused portion of the solution should be discarded. The shelf life of Remicade powder in sealed bottles is 3 years.

Composition 1 bottle of Remicade contains: Infliximab – 100 mg; Additional substances.

Pharmacological group Medicines that correct immune processes Immunosuppressive medicines

Active ingredient: Infliximab

Side effects of Remicade

In clinical trials of infliximab, side effects were observed in 60% of patients receiving the drug and in 40% of patients receiving placebo. The table shows the likely side effects, both common (frequency 1/100, but ≤1/10), and infrequent (frequency 1/1000, but ≤1/100) and rare (1/10,000 and ≤1/1000) side effects effects. The frequency of adverse reactions was determined by comparing data when using placebo. Most of them were mild or moderate and related to the respiratory system, skin and its appendages. The most common side effects requiring discontinuation of therapy were infusion-related reactions: shortness of breath, urticaria, headache. Side effects identified in clinical studies

*Data obtained from early phase studies of the drug in patients with congestive heart failure.

Children. In general, side effects in children with Crohn's disease receiving infliximab were comparable in frequency and nature of side effects to adult patients. Adverse events that occurred more frequently in children compared to adult patients with Crohn's disease receiving the same treatment regimen in clinical trials were: anemia (10.7%), blood in the stool (9.7%), leukopenia (8.7). %), hyperemia (8.7%), viral infection (7.8%), neutropenia (6.8%), bone fractures (6.8%), bacterial infection (5.8%) and allergic reactions from respiratory system (5.8%). 17.5% of patients randomized in the clinical trial experienced one or more infusion-related reactions, with 17 and 18% of patients at 8 and 12 weeks of maintenance therapy, respectively. No serious infusion reactions were noted. Antibodies to infliximab were formed in 3% of children. During clinical trials, infections were reported in 56.3% of pediatric and 50.4% of adult patients with Crohn's disease. The most common infections reported were upper respiratory tract infections and pharyngitis, with abscess being the most serious. Serious (sometimes fatal) infections, including opportunistic infections and tuberculosis, were more frequently reported in children; infusion reactions and hypersensitivity reactions. There have been reports of the development of malignant neoplasms in children, transient changes in the activity of liver enzymes, lupus-like syndrome and the appearance of antibodies. A rare type of hepatolienal T-cell lymphoma has also been reported to develop in adolescents and young adults with Crohn's disease using Remicade. Adverse reactions in children with juvenile rheumatoid arthritis (JRA) . The safety and effectiveness of Remicade® in children aged 4–17 years with JRA was assessed in a multicenter, randomized, placebo-controlled, double-blind study lasting 14 weeks, followed by an extension to 44 weeks (double-blind control, active treatment). About the development of infusion reactions, delayed allergic reactions, the formation of antibodies to infliximab, the development of diseases of microbial etiology (see SPECIAL INSTRUCTIONS).

Remicade lyof.for injection solution for inf. 100 mg. fl. No. 1

Indications

Active rheumatoid arthritis in patients 18 years of age and older (in combination with methotrexate) with ineffectiveness of previous therapy, including treatment with methotrexate.

Severe active Crohn's disease (including fistula formation) in patients 18 years of age and older, refractory to standard therapy, including corticosteroids and/or immunosuppressants.

Crohn's disease in active, moderate or severe form in children and adolescents aged 6 to 17 years inclusive - with ineffectiveness, intolerance or contraindications to standard therapy, including corticosteroids and/or immunosuppressants.

Ulcerative colitis in adults when standard therapy is ineffective.

Moderate or severe ulcerative colitis in children and adolescents aged 6 to 17 years - with insufficient effectiveness of standard therapy using corticosteroids, 6-mercaptopurine or azathioprine, or in the presence of intolerance or contraindications to standard therapy.

Ankylosing spondylitis.

Psoriatic arthritis.

Psoriasis.

pharmachologic effect

TNFα inhibitor. Infliximab is a chimeric mouse-human monoclonal antibody. It has a high affinity for TNFα, which is a cytokine with a wide range of biological effects, is also a mediator of the inflammatory response and is involved in the processes of modulation of the immune system. It is clear that TNFα plays a role in the development of autoimmune and inflammatory diseases. Infliximab quickly binds and forms a stable compound with both forms (soluble and transmembrane) of human TNF-α, and a decrease in the functional activity of TNF-α occurs. The specificity of infliximab for TNFα is confirmed by its inability to neutralize the cytotoxic effect of lymphotoxin alpha (LTα or TNFβ), a cytokine that interacts with the same receptors as TNFα.

Elevated concentrations of TNFα were detected in the joints of patients with rheumatoid arthritis and correlated with disease activity. In patients with rheumatoid arthritis, infliximab treatment resulted in decreased infiltration of inflammatory cells into inflamed joints, as well as decreased expression of molecules mediating cell adhesion, chemoattraction, and tissue destruction. After infliximab therapy, there was a decrease in serum concentrations of interleukin-6 (IL-6) and C-reactive protein (CRP), as well as an increase in hemoglobin concentration in patients with rheumatoid arthritis with a lower hemoglobin concentration compared to baseline levels. There was no significant decrease in the number of lymphocytes in the peripheral blood or their proliferative response to mitogenic stimulation compared with the response of cells from untreated patients in vitro.

In patients with psoriasis, infliximab therapy led to a decrease in inflammation in the epidermal layer and normalization of keratinocyte differentiation in psoriatic plaques. In patients with psoriatic arthritis, short-term therapy with infliximab was accompanied by a decrease in the number of T cells and blood vessels in the synovium and areas of skin affected by the psoriatic process.

Histological examination of colon biopsies taken before and 4 weeks after infliximab administration revealed a significant decrease in the concentration of TNFα. Treatment with infliximab in patients with Crohn's disease was accompanied by a significant decrease in the concentration of a nonspecific serum marker of inflammation, CRP. The total number of peripheral blood leukocytes changed minimally during infliximab therapy, although a trend towards normalization of their numbers was observed for lymphocytes, monocytes and neutrophils. In patients treated with infliximab, the proliferative response of peripheral blood mononuclear cells to stimulation was not reduced compared with that in untreated patients. There were no significant changes in cytokine secretion by stimulated peripheral blood mononuclear cells after infliximab therapy. A study of mononuclear cells from biopsies of the lamina propria of the intestinal mucosa showed that infliximab therapy causes a decrease in the number of cells expressing TNF-α and interferon gamma. Additional histological studies confirmed that infliximab reduced inflammatory cell infiltration and inflammatory markers in affected areas of the intestine. Endoscopic studies have demonstrated healing of the intestinal mucosa in patients treated with infliximab.

Drug interactions

In patients with rheumatoid arthritis, simultaneous use of methotrexate reduces the formation of antibodies to infliximab and increases the concentration of the latter in plasma.

Dosage regimen

Injected intravenously. Single dose - 3-10 mg/kg. The frequency and duration of use are set individually, depending on the indications and treatment regimen.

Contraindications for use

Severe infectious process (including abscess, sepsis, tuberculosis, opportunistic infections), increased sensitivity to infliximab and other mouse proteins.

Use in children

The safety and effectiveness of infliximab in children and adolescents under 17 years of age with rheumatoid arthritis or Crohn's disease have not been studied.

Restrictions for children

Contraindicated

Use in elderly patients

The effectiveness and safety of infliximab in elderly patients has not been established.

Restrictions for elderly patients

Contraindicated

Use for liver dysfunction

The effectiveness and safety of infliximab in patients with liver disease has not been established.

Restrictions for liver dysfunction

Contraindicated

Use during pregnancy and breastfeeding

Infliximab is not recommended for use during pregnancy because it may affect the development of the fetal immune system. Women of childbearing age should use reliable methods of contraception during treatment and for at least 6 months after treatment.

It is not known whether infliximab is excreted into human breast milk. If use is necessary during lactation, breastfeeding should be discontinued. Resumption of breastfeeding is permitted no earlier than 6 months after the end of treatment.

Restrictions when breastfeeding

Contraindicated

Restrictions during pregnancy

Contraindicated

Use for renal impairment

The effectiveness and safety of infliximab in patients with kidney disease has not been established.

Restrictions for impaired renal function

Contraindicated

special instructions

When using infliximab, acute allergic reactions and delayed allergic reactions may develop.

Some patients may develop antibodies to infliximab, which in rare cases cause the development of severe allergic reactions. In the absence of tolerance to methotrexate or to other non-steroidal immunosuppressants (for example, azathioprine, 6-mercaptopurine) and interruption of their use before or during the use of infliximab, the risk of the formation of these antibodies increases.

Delayed hypersensitivity reactions were observed with a high frequency (25%) in Crohn's disease after repeated treatment was prescribed 2-4 hours after the initial one.

Since infliximab elimination occurs within 6 months, the patient should be under medical supervision during this period to promptly identify signs of an infectious process. Infliximab should be discontinued if severe infection or sepsis develops.

If active tuberculosis is suspected, treatment should be discontinued until a diagnosis is made and appropriate treatment is provided.

Before initiating infliximab therapy, patients should be carefully assessed for both active and latent tuberculosis. It should be taken into account that in severely ill patients and patients with immunosuppression, a false-negative tuberculin test may be obtained. When latent tuberculosis is detected, measures must be taken to prevent activation of the process, and the ratio of the expected benefits and potential risks of using infliximab in this category of patients should be assessed.

If symptoms resembling lupus syndrome (persistent rash, fever, joint pain, fatigue) appear during treatment, and antibodies to DNA are detected, infliximab should be discontinued.

The effectiveness and safety of infliximab in elderly patients, as well as in patients with liver and kidney diseases, have not been established.

The safety and effectiveness of infliximab in children and adolescents under 17 years of age with rheumatoid arthritis or Crohn's disease have not been studied. Until appropriate data are available, use in this category of patients should be avoided.

Side effect

From the nervous system:

often - headache, dizziness, feeling tired; rarely - depression, psychosis, anxiety, amnesia, apathy, nervousness, drowsiness.

From the digestive system:

often - nausea, diarrhea, abdominal pain, dyspepsia; rarely - constipation, gastroesophageal reflux, cheilitis, diverticulitis, liver dysfunction, cholecystitis.

From the hematopoietic system:

rarely - anemia, leukopenia, lymphadenopathy, lymphocytosis, lymphopenia, neutropenia, thrombocytopenia.

From the cardiovascular system:

often - hot flashes, chest pain; rarely - arterial hypertension, arterial hypotension, fainting, thrombophlebitis, bradycardia, palpitations, vasospasm, cyanosis, peripheral circulatory disorders, arrhythmia, edema.

From the respiratory system:

often - shortness of breath, viral infection (flu, herpes), fever, upper respiratory tract infections, bronchitis, pneumonia; rarely - bronchospasm, pleurisy, pulmonary edema.

From the side of the organ of vision:

rarely - conjunctivitis, keratoconjunctivitis, endophthalmitis.

From the urinary system:

rarely - urinary tract infections, pyelonephritis.

From the blood coagulation system:

rarely - ecchymosis/hematoma, petechiae, nosebleeds.

Dermatological reactions:

often - rash, skin rash, itching, urticaria, sweating, dry skin; rarely - fungal dermatitis (onychomycosis, eczema), seborrhea, erysipelas, warts, furunculosis, periorbital edema, hyperkeratosis, skin pigmentation disorders, alopecia, bullous rash.

Allergic reactions:

urticaria, itching, swelling of the face, lips, hands, myalgia and/or arthralgia with fever, formation of autoantibodies, lupus syndrome.

Other:

often - fever; rarely - abscesses, cellulitis, sepsis, bacterial and fungal infections, myalgia, arthralgia, vaginitis, infusion syndrome, reaction at the injection site.

Special instructions for the use of Remicade

Infusion reactions and hypersensitivity. Infliximab may cause acute infusion-related reactions and delayed allergic reactions. The development time of these reactions varies. Therefore, all patients receiving Remicade should be observed for at least 1 hour after infusion. Acute infusion reactions may develop immediately or within several hours after administration. If an acute infusion reaction occurs, administration should be stopped immediately. Some of these effects have been described as anaphylaxis. Emergency equipment and medications should be available for infusion reactions (e.g. paracetamol, antihistamines, corticosteroids, epinephrine and/or paracetamol). To prevent reactions (mild or transient), the patient can be given an antihistamine, hydrocortisone and/or paracetamol before starting the infusion. Some patients may develop antibodies to infliximab, which increases the frequency of infusion reactions and, in some cases, causes the development of severe allergic reactions. In patients with Crohn's disease, there was an association between the formation of antibodies to infliximab and a decrease in the duration of clinical response to treatment. The simultaneous use of immunomodulators reduces the formation of antibodies and reduces the frequency of infusion reactions. The effect of concomitant use of immunosuppressives was greater in patients treated episodically than in patients treated with maintenance therapy. Patients not receiving immunosuppressive medications during Remicade therapy are at a potentially high risk of developing antibodies. These antibodies are not always detected in blood serum. If severe reactions develop, symptomatic therapy should be prescribed and Remicade should be discontinued. Delayed-type hypersensitivity reactions have been observed with a high frequency (25%) in Crohn's disease after re-administration 2-4 years after the last administration of Remicade. They were characterized by the development of myalgia and/or arthralgia with fever and/or rash within 12 days from the start of re-therapy. Some patients also developed itching, swelling of the face, lips, dysphagia, rash such as urticaria, pharyngitis, and headache; in some cases these manifestations were similar to those of serum sickness. Patients should be warned about the possibility of developing such reactions. When prescribing re-treatment after a long period, the patient should be under constant observation due to the possibility of delayed-type hypersensitivity reactions. Infections. TNF-α is a mediator of inflammation and a modulator of cellular immunity. Experimental data indicate the need for TNF-α to participate in the fight against intracellular infections. Clinical experience has shown an impaired immune response to infections in some patients receiving infliximab. Remicade should be used with caution when treating patients with a history of chronic or recurrent infections, as well as when using immunosuppressive drugs simultaneously. Cases of opportunistic infections, including tuberculosis and other infections, including sepsis and pneumonia, have been reported during treatment with infliximab. Before starting Remicade therapy, the patient should be thoroughly examined to exclude tuberculosis, including latent tuberculosis. The examination should include a thorough medical history, including information about a history of tuberculosis, probable contacts with tuberculosis patients, and previous or concomitant immunosuppressive therapy. It is mandatory for all patients to undergo a tuberculin skin test and chest x-ray before starting therapy. It must be taken into account that in seriously ill patients and in patients with a compromised immune system, a pseudo-negative tuberculin test can be obtained. Patients with overt infections and/or abscesses should be adequately treated before initiating Remicade therapy. Treatment should not be given if active tuberculosis is diagnosed. In the case of latent tuberculosis, specific anti-tuberculosis treatment must be carried out before starting Remicade therapy. Patients should be monitored by a physician during and after Remicade therapy to rule out infections, including milliary tuberculosis. Inhibition of TNF-α may also mask symptoms of infection such as fever. Treatment with Remicade should be interrupted if the patient develops severe infection or sepsis. Since elimination of infliximab can occur over a period of 6 months, the patient should be under medical supervision throughout this period. In patients with Crohn's disease with acute suppuration of fistulas, Remicade therapy should not be started until the source of infection, including an abscess, has been excluded or eliminated. The safety of surgical interventions during Remicade therapy has not been sufficiently studied. Patients who require surgery should be evaluated to rule out infections. All patients should be warned to consult a physician if signs/symptoms consistent with tuberculosis (eg, persistent cough, weight loss, low-grade fever) occur during or after treatment with Remicade. Concomitant use of a TNF-α inhibitor and anakinra. Serious infections were observed during clinical trials with concomitant use of anakinra (a recombinant non-glycosylated form of the interleukin-1 receptor antagonist) and etanercept (a TNF-α inhibitor), which had no therapeutic benefit compared with etanercept monotherapy. Based on the nature of the adverse events observed during combination treatment with etanercept and anakinra, such toxicity may result from the combination of anakinra and another TNF-α inhibitor. Therefore, the combination of Remicade and anakinra is not recommended. Vaccination. There are no data regarding the safety and effectiveness of vaccination with live vaccines in patients receiving anti-TNF therapy. Therefore, it is recommended to refrain from simultaneous vaccination with live vaccines. Autoimmune processes. The relative deficiency of TNF-α caused by anti-TNF therapy may initiate the development of an autoimmune process in genetically predisposed patients. If the patient develops symptoms resembling lupus syndrome, and at the same time antibodies to double-stranded DNA are detected, treatment should be stopped. Neurological effects. When using infliximab and other TNF-α inhibitors, isolated cases of optic neuritis, seizures, the appearance or exacerbation of clinical symptoms and/or radiographic signs of demyelinating diseases, including multiple sclerosis, were observed. A careful assessment of the benefits/risks of treatment with Remicade in patients with existing demyelinating diseases of the central nervous system is recommended. Lymphomas. In controlled clinical trials of TNF-blocking agents, more cases of lymphoma were observed among patients receiving a TNF-blocking agent than among control patients. During clinical trials with Remicade in patients with rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis, the incidence of lymphoma in patients receiving Remicade was reported to be higher than in the general population (although the overall incidence was rare) . Patients with Crohn's disease or rheumatoid arthritis, especially those with high disease activity and/or patients chronically taking immunosuppressive therapy, may be at increased risk (several times that of the general population) for developing lymphoma, even in the absence of TNF-blocking therapy. therapy. In a clinical study evaluating the use of Remicade in patients with moderate to severe COPD, a higher incidence of malignancies was reported in patients receiving Remicade compared to control patients. All patients, according to their medical history, were heavy smokers. The potential significance of TNF-blocking therapy in the development of malignancies is unknown. Therefore, caution should be exercised when deciding to use TNF-blocking therapy in patients with a history of malignancy or when deciding to continue therapy in patients who have developed malignancy. Heart failure. Remicade is used with caution in the treatment of patients with mild heart failure (NYHA I/II). Changes in the hepatobiliary system. In post-marketing studies, very rare cases of jaundice and non-infectious hepatitis, sometimes with signs of autoimmune hepatitis, have been observed. There have been isolated cases of liver failure resulting in liver transplantation or death. A causal relationship between the use of Remicade and the development of these phenomena has not been established. Patients with symptoms or signs of hepatic dysfunction should be evaluated for liver damage. If bilirubin and/or ALT levels increase to more than 5 times the upper limit of normal, Remicade should be discontinued and changes detected should be carefully assessed. As with the use of other immunosuppressive drugs, reactivation of hepatitis B occurred during treatment with Remicade in patients who were chronic carriers of this virus (for example, HBsAg-positive). Therefore, chronic carriers of the hepatitis B virus should be observed and monitored before and during treatment with Remicade. Anemia in patients with rheumatoid arthritis. There is a possibility that TNFα plays a role in the inhibition of erythropoiesis in patients with chronic inflammatory diseases. In clinical trials, 39.8% of patients with rheumatoid arthritis whose baseline hemoglobin level was ≤120 g/L experienced an increase of ≥10 g/L at week 22 of treatment with infliximab and methotrexate, compared with 19.3% of patients who received methotrexate monotherapy. In 12.1% of patients treated with infliximab and methotrexate, hemoglobin levels increased by ≥20 g/l versus 4.5% of patients using methotrexate. Significant improvement was also observed in patients with initial hemoglobin levels ≤100 g/L. Analysis of clinical data showed that infliximab therapy has a positive effect on the course of anemia in patients with rheumatoid arthritis, regardless of its effect on ACR20 response (American College of Rheumatology criteria). It was shown that among ACR20 responder patients, therapy with infliximab and methotrexate had a significantly better effect on the course of anemia than therapy with methotrexate alone. Increases in hemoglobin levels were associated with improvements in functional status and quality of life at 22 weeks of treatment. Hepatolienal T-cell lymphoma. In post-marketing experience, the development of hepatolienal T-cell lymphoma has been rarely reported in adolescents and young adults with Crohn's disease using Remicade. This rare type of T-cell lymphoma is very aggressive and usually fatal. The above cases occurred in patients using Remicade® in combination with azathioprine or 6-mercaptopurine. Cases of hepatolienal T-cell lymphoma have also been reported in patients with Crohn's disease who used azathioprine and did not use Remicade®. No cases of hepatolienal T-cell lymphoma have been reported in patients who received Remicade® alone. The causal relationship between the development of hepatolienal T-cell lymphoma and Remicade® therapy remains unclear. Use for the treatment of elderly patients. There were no significant differences in the pharmacokinetics of the drug in elderly people (65–80 years) with rheumatoid arthritis. Specific studies regarding the treatment of Remicade in persons with Crohn's disease, as well as in persons with liver and kidney diseases, have not been conducted. Use in children . Remicade is used to reduce signs and symptoms of the disease and to induce and maintain clinical remission in children with moderate to severe active Crohn's disease. It should be kept in mind that all pediatric patients in phase III clinical trials required a constant dose of 6-mercaptopurine, or azathioprine, or methotrexate. A pharmacokinetic study was conducted in children aged 11–17 years with Crohn's disease. No significant differences in pharmacokinetics were found with a single dose of the drug in children and adults with Crohn's disease. Remicade has not been studied in children under 6 years of age with Crohn's disease. The safety and effectiveness of Remicade in patients with juvenile rheumatoid arthritis have not been established. Use during pregnancy and lactation. It is unknown whether Remicade has adverse effects on the fetus when used during pregnancy, so it is not recommended to use Remicade during this period unless absolutely necessary. Pregnancy should be avoided by using appropriate contraception during treatment and for at least 6 months after the last Remicade infusion. It is unknown whether infliximab is excreted into breast milk. It is therefore recommended that you stop breastfeeding during and after treatment with Remicade. Breastfeeding is allowed no earlier than 6 months after completion of treatment (taking into account the importance of therapy for the mother). studies have been conducted regarding the effect on the ability to drive vehicles and operate complex equipment . Patients should refrain from driving or operating machinery if they experience increased fatigue during treatment with Remicade.

Experience in the treatment of rheumatoid arthritis with Remicade (infliximab)

About the article

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Regular issues of "RMZh" No. 24 dated November 27, 2005 p. 1590

Category: General articles

Authors: Chichasova N.V. 1, 2 , Lukina G.V. 2, 3, Sigidin Y.A. , Imametdinova G.R. 4, Nasonov E.L. 1 Federal State Budgetary Educational Institution of Further Professional Education RMANPE of the Ministry of Health of Russia, Moscow, Russia 2 Federal State Budgetary Institution NIIR named after. V.A. Nasonova, Moscow, Russia 3 Moscow Clinical Research Center named after A.S. Loginova Department of Health, Moscow, Russia 4 Federal State Budgetary Educational Institution of Higher Education “First Moscow State Medical University named after. THEM. Sechenov" Ministry of Health of the Russian Federation

For quotation:

Chichasova N.V., Lukina G.V., Sigidin Y.A. and others. Experience in the treatment of rheumatoid arthritis with the drug Remicade (infliximab). RMJ. 2005;24:1590.

Rheumatoid arthritis (RA) is a chronic disease, the obligatory manifestation of which is the development of aggressive synovitis, difficult to treat with anti-inflammatory drugs, leading to the destruction of joint structures, periarticular tissues and disability of patients (Fig. 1). Extra-articular manifestations of RA, when immune inflammation remains active for many years, can lead to life-threatening complications, such as amyloidosis and early atherosclerosis. In the treatment of RA in the last decade, certain successes have been achieved, which is primarily due to improved diagnosis of the disease and the widespread introduction into clinical practice of the concept of early prescription of disease-modifying anti-inflammatory drugs (DMARDs) [1]. Nevertheless, the life expectancy of patients with RA remains 10–15 years shorter than in the population [2], more than half of patients become disabled within the first 5–7 years of the disease [3]. It is known that the selection of adequate therapy for RA is a difficult task for a rheumatologist. Having prescribed a DMARD, the doctor should evaluate after 1.5 months (for methotrexate, leflunomide, cyclophosphamide) - 3-6 months (for sulfasalazine, gold preparations, D-penicillamine), whether a clinical and laboratory effect appears, evaluate after 3-6 months its expression. If improvement is not achieved according to the ACR [4] or EULAR [5] criteria, the clinician should either adjust the drug dose if possible, initiate combination therapy, or change DMARDs (Fig. 2). Rheumatologists are well aware that sometimes the 2nd or 3rd prescribed drug can be effective for a particular patient, that is, it takes months and sometimes years to select effective therapy. Maintaining the activity of rheumatoid inflammation over time inevitably leads to progression of the disease (Table 1). Even if the activity of rheumatoid inflammation is suppressed by 50% or more in the first 6–12 months of treatment, new erosions continue to appear in patients, and destruction of large joints increases. The use of glucocorticoids (GC) also does not solve the problem of treating RA [6]. Being highly effective anti-inflammatory drugs with rapid action, GCs, when used for a long time as monotherapy, lose their effectiveness, so that after a year their effect becomes equal to the effect of non-steroidal anti-inflammatory drugs (NSAIDs) [7]. Therefore, GCs, like NSAIDs, are a symptomatic type of therapy and should be used only in combination with DMARDs, which allows the use of GCs within a relatively safe dose range, that is, no more than 7.5 mg/day of prednisolone. But when using GC and in these doses, complications of steroid therapy obligately develop: cortisone dependence, osteoporosis, Cushingoid syndrome, etc.

Thus, the complexity of RA treatment lies in the impossibility of predicting the effectiveness of one or another basic drug, as well as the duration of its action, in the long period necessary to assess the clinical and laboratory effect, and even longer to assess the “basic” effect of anti-inflammatory drugs, namely – suppressing the progression of destruction of joint structures and preserving the function of patients. As a rule, the choice of drug is determined by the level of inflammation activity [8], and further success of therapy depends to a very large extent on monitoring the effectiveness and tolerability of the drug and timely correction of therapy. In recent years, for the treatment of chronic autoimmune inflammation, biological agents have begun to be used, the action of which is aimed at selective binding of proinflammatory inflammatory mediators produced by synovial membrane cells. One of the most significant cytokines in the pathogenesis of RA and other inflammatory diseases of the musculoskeletal system is tumor necrosis factor-a (TNF-a). An increase in its production leads to an increase in the production of other pro-inflammatory cytokines (interleukin-1, interleukin-6, etc.); the passage of these substances through the liver leads to an increase in the concentration of CRP, fibrinogen and other proteins, reflecting the intensity of the inflammatory process, and to a decrease in the level of albumin and transferrin (Fig. 3). The molecular mechanism of the “pro-inflammatory” action of TNF-a is determined by the binding of the transcription factor NF-kB, which leads to the proliferation of synovial tissue, the attraction of leukocytes to the inflammatory zone, the release of aggressive metalloproteases, and the activation of osteoclasts [9]. The most effective way to block TNF-a is to bind it with a monoclonal antibody. A drug with this mechanism of action, infliximab (Remicade), has been successfully used in recent years abroad [10,11] and in Russia [12,13]. Its effectiveness has been shown not only in RA, but also in the treatment of seronegative spondyloarthropathies (ankylosing spondylitis and psoriatic arthropathy) [14,15], Crohn's disease [16], systemic vasculitis [17], juvenile arthritis [18], SLE and dermato/ polymyositis [19,20], as well as in the treatment of secondary amyloidosis [21]. In this report, we would like to share our own experience in treating patients with inflammatory arthropathy with infliximab. The majority of patients to whom we prescribed infliximab were patients (37 patients) with a severe variant of RA: high disease activity (mainly stage III), despite a persistent attempt to select basic therapy, cortisone dependence (4 patients), and the presence of severe extra-articular manifestations. Treatment with infliximab is carried out for RA in combination with methotrexate 10–15 mg/week, which should be prescribed at least 1 month before starting infliximab therapy. When treating RA with any anti-inflammatory drug, you should know the main side effects of this drug. These adverse effects of infliximab have been covered in detail in the domestic literature [22,23]. Treatment with infliximab is contraindicated during pregnancy and lactation, as well as in cases of suspected or presence of malignant neoplasms. The dose of infliximab is calculated per kilogram of weight: the minimum dose is 3 mg/kg, the maximum is 10 mg/kg of weight. The drug is administered according to the following standard scheme: after the first infusion, the next infusion is prescribed after 2 weeks, then after another 4 weeks and then every 8 weeks. Increasing the dose if the effect is insufficient can be done either by increasing the amount of the drug itself during infusion (3 mg/kg, 5 mg/kg and 10 mg/kg) or by decreasing the interval between infusions (8-6-4 weeks). According to experience, a dose of 3 mg/kg of body weight with a standard infliximab administration regimen is effective in most patients with RA, even at the maximum degree of activity, and increasing the dose to 5 mg/kg allowed us to achieve an effect in all of our patients. Reducing the administration intervals when using a single dose of infliximab 10 mg/kg does not lead to an increase in effectiveness, which was also shown in foreign studies (Fig. 4) [11]. Treatment should begin with a minimum dose of infliximab according to the standard regimen. The duration of treatment for the majority of our RA patients (25 people) was 1 year (52 weeks). In 10 patients, treatment with infliximab was carried out for 16–24 weeks, and drug withdrawal was accompanied by an increase in activity in only 1 case. The effect of infliximab appears after 2–3 days: morning stiffness disappears (which confirms the theoretical justification of the effect of infliximab directly on synovial inflammation, since joint stiffness is the clinical equivalent of synovitis), joint pain and swelling of the joint areas begin to decrease (Fig. 5). Further, the clinical effect increases and reaches a maximum in most patients by 3–4 infusions, remaining throughout the entire period of drug administration. In a number of patients, after 7–8 months of treatment with infliximab, there was a slight increase in joint damage compared to the maximum effect, which requires addressing the issue of increasing the dose of the drug. All RA patients showed a fairly rapid regression of extra-articular manifestations: a decrease in size after 1-2 infusions of rheumatoid nodules and their disappearance after 3-4 infusions, relief of fever after the 1st infusion, a decrease in the manifestations of lymphadenopathy, peripheral neuropathy, digital arteritis after 1- 2 and their disappearance after 3–5 infusions, relief of anemia (up to 76 g/l at the start of infliximab treatment) after 2–3 infusions. Starting from the 4th–5th infusion, the patients' body weight began to increase. The dynamics of laboratory parameters reflecting the level of inflammation were somewhat different from the dynamics of clinical manifestations. As can be seen from Figure 6, a decrease in the average concentration of CRP and ESR to normal levels was observed already 2 weeks after the start of treatment with infliximab, however, after 5–7 infusions (22–38 weeks of treatment), approximately half of the patients showed an increase in the concentration of CRP above 2 mg% and ESR on average up to 35–40 mm/hour. During this period of treatment with infliximab, it seems especially relevant to evaluate the clinical and laboratory effect of therapy and decide whether it is necessary to increase the dose of the drug (5 mg/kg body weight once every 8 weeks or 3 mg/kg body weight once every 6–4 weeks). It should be noted that despite the increase in laboratory markers of inflammation and some activation of joint damage, the condition of the patients was strikingly better than before treatment with infliximab, which was manifested primarily in an increase in their functional capabilities. Thus, all patients who, before treatment with infliximab, had difficulty moving around the room with outside help (8 people) or were bedridden (2 people), after the first 2 infusions of infliximab, began to independently arrive for the next administration of the drug. The first 2 infusions were carried out inpatiently only if patients were unable to move; in other cases, Remicade was administered on an outpatient basis. The technique for administering the drug infliximab is described in detail in the booklet of the pharmaceutical company Schering-Plough (USA). In 5 patients, it was possible to completely discontinue GCs during treatment with infliximab and in another 3, their daily dose was reduced; in approximately half of the patients, the need for NSAIDs sharply decreased (even to long breaks in their use). In 9 patients (25%) with severe RA refractory to active basic therapy, treatment with infliximab allowed to achieve clinical and laboratory remission of the disease. Quantitative assessment of the severity of destruction using the Larsen method [24] showed the absence of progression of destruction of the joints of the hands and feet both in our study (Fig. 7) and in the foreign study ATTRACT (Fig. 8). After discontinuation of infliximab, the achieved effect persists in many patients for months and even years, that is, rheumatologist clinicians finally received a drug capable of modifying the course of RA. Of our 25 RA patients who were treated with infliximab for 1 year, 4 patients experienced gradual disease activation after discontinuation of the drug. But at the same time, a very interesting fact should be noted: even with an increase in the concentration of CRP or ESR to high values ​​(5–6 mg% or 50–55 mm/hour, respectively), not a single patient returned to the initially severe functional state. And, in addition, for another 12–18 months after the end of treatment with infliximab, our patients, despite the activation of RA, did not experience the appearance of new erosions in the hands and feet. Tolerability of infliximab in our patients was satisfactory in most cases. Of the 25 patients treated with infliximab for 12 months, 13 patients experienced short-term reactions during the infusion (increase in blood pressure, tachycardia, increase in body temperature to 38.4°), which required stopping the infusion only in one case when a temperature reaction developed and in one case with the development of collapse. One patient developed angioedema during the 4th infusion; this patient had a history of seasonal allergic reactions in the form of rhinitis, which was not taken into account by the attending physician, although the next infusion was carried out in April. Infectious complications included acute respiratory infections, bronchitis, and acute pneumonia (2 cases). In one case, the patient developed a panaritium of the toe (after a pedicure performed by the patient herself with 8 years of active RA). The patient did not report the development of the infection to the attending physician; after a few days, subfebrile and then febrile fever appeared (up to 38.5–39°), which was regarded by the patient as the flu, and only when sharp pain appeared in the left knee joint did the patient turn to doctors. The patient was urgently hospitalized; examination revealed purulent arthritis, which was relieved by massive antibacterial therapy in the purulent surgery department. From the moment of development of felon until the appearance of symptoms of purulent arthritis, 9 days passed, provided that the doctor was notified in a timely manner and antibacterial therapy was started, perhaps the development of purulent arthritis could have been avoided. During treatment with infliximab, one should pay close attention to the biochemical parameters that reflect the functional state of the liver, since, in addition to possible intolerance to methotrexate, the development of viral hepatitis is possible, the course of which may worsen when infliximab is administered in the “pre-icteric” stage of hepatitis. In general, treatment with infliximab with constant contact between the patient and the doctor is not more dangerous than treatment with any other DMARD. Adverse infusion reactions, as a rule, are not severe; infectious diseases with a timely interruption in treatment with infliximab are not protracted in most cases. Among our patients with seronegative spondyloarthropathies (Bechterew's disease and psoriatic arthropathy - 5 people), a very good effect of therapy developed in all cases after the 1st infusion of a dose of 3 mg/kg (3 patients) and 5 mg/kg (2 patients); The duration of treatment ranged from 3 to 6 infusions with the development of clinical and laboratory remission in all cases, while the tolerability of infliximab was excellent. From a practical point of view, it should be remembered: 1. Due to the fact that “traditional” basic anti-inflammatory drugs in many cases are not able to effectively control the progression of joint destruction in RA or cause toxic reactions leading to treatment interruption, it is necessary to use new approaches to “pathogenetic “therapy of inflammatory rheumatic diseases. 2. The largest achievement in the pharmacotherapy of inflammatory rheumatic diseases is associated with the development of a group of drugs, united under the general term – “biological” agents or biological modifiers of the immune response (“biologics”). The most extensive and long-term clinical experience has been accumulated with the drug infliximab (Remicade), a chimeric monoclonal antibody to TNF-a. According to international recommendations, infliximab should be used primarily in patients with RA who are “resistant” to “standard” basic anti-inflammatory drugs: • lack of effect (“unacceptable disease activity”) to treatment with methotrexate prescribed at the most effective and tolerable dose (up to 20 mg /week for 3 months), • ineffectiveness of other basic anti-inflammatory drugs (if there are contraindications for prescribing methotrexate). Successful infliximab therapy is defined as: • a 20% decrease in the number of swollen joints, • a 20% decrease in laboratory parameters (ESR, CRP). In addition, if there are contraindications to the use of “standard” basic anti-inflammatory drugs, infliximab can be used as a “first” basic drug. 3. Infliximab is a protein substance - the patient should be asked whether he has a history of reactions to protein drugs; in patients with an allergic history, it is necessary to especially carefully monitor the tolerability of infliximab after 3-4 infusions, take into account whether the administration of infliximab coincides with a seasonal exacerbation of allergic reactions, and, if necessary, premedicate with antihistamines. 4. The most common adverse reactions of infliximab are infectious complications (including the possibility of development or activation of tuberculosis infection) - before starting infliximab therapy, an X-ray examination of the chest organs, a Mantoux test should be performed, to exclude the presence of infection of the skin and its appendages, tonsils, urinary tract, intestines; During treatment, the patient should immediately inform the attending physician about the development of any infectious conditions (acute respiratory infections, boils, panaritium, etc.). 5. The use of infliximab can aggravate the course of congestive heart failure (CHF), therefore its use is contraindicated in persons with III–IV degrees of CHF; During the infliximab infusion, blood pressure, heart rate and body temperature are assessed every half hour. 6. Before each infliximab infusion, it is advisable to conduct a study of peripheral blood (HB, leukocytes and formula, platelets) and biochemical parameters (AST, ALT, bilirubin, alkaline phosphatase, g-glutamyl transpeptidase), and a urine test to exclude urinary infection. We hope that the inclusion of infliximab in the list of vital and preferential drugs will allow more active successful treatment of patients with RA and other inflammatory joint diseases that are refractory to DMARD therapy. Wider use of this drug will make it possible to evaluate the individual duration of treatment, assess the “survival” of the effect of therapy after discontinuation of infliximab against the background of the developed effect, and determine the possible optimal frequency of infusions during infliximab therapy. References 1. Wolfe F, Cathey MA.” The assessement and prediction of functional disability in rheumatoid arthritis.” J Rheumatol 1991;18:1298–306. 2. T. Riise, B. K. Jacobsen, J. T. 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