Infliximab

Infliximab is a biological drug consisting of one third the variable (Fv) region of high-affinity neutralizing murine monoclonal antibodies to TNF-a (A2) and two thirds the fragment of the human IgG1 molecule.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ]

General characteristics

Infliximab has a high affinity for trimeric TNF-a (Kd - 100 pM) and effectively suppresses its secreted and membrane-associated forms in vitro. According to pharmacokinetic studies, in patients with rheumatoid arthritis, the maximum concentration of the drug in plasma (Cmax) and the area under the curve (AUC) are proportional to the administered dose of the substance. The volume of distribution corresponds to the intravascular one, and the half-life is 8-12 days. With repeated administration of the drug, the accumulation effect is not observed, and its concentration in the bloodstream corresponds to the administered dose.

The regimental structure does not allow infliximab to be metabolized in the liver by cytochrome P-450. Therefore, genetic polymorphism of cytochrome isoenzymes, which often causes different frequencies of toxic reactions against the background of taking medications, is of no significant importance in treatment with this drug.

How does infliximab work?

The most important mechanism of action of infliximab in rheumatoid arthritis is inhibition of the synthesis of "proinflammatory" mediators. Infliximab treatment is accompanied by a decrease in the serum concentration of IL-6, IL-1 and tissue expression of the latter. These parameters correlate with a decrease in the level of acute. proteins and mediators (IL-8, pIL-1, pCD14, monocyte chemotractant protein-1, nitric oxide, collagen, stromelysin), which play a significant role in the development of inflammation and tissue destruction in rheumatoid arthritis. Suppression of IL-1 synthesis by synovial tissue macrophages in this disease is also noted.

Another important mechanism of action of infliximab is the "deactivation" of vascular endothelium, leading to a decrease in the accumulation of leukocytes and synovial tissue. This is evidenced by a decrease in the level of soluble forms of adhesion molecules (ICAM-1 and E-selectin), which correlates with the clinical effectiveness of treatment.

According to immunomorphological studies of synovial biopsies, the following is observed during therapy:

• decreased expression of E-selectin and vascular adhesion molecule-1 (VCAM-1) on inflammatory infiltrate cells;
• decrease in the number of CD3 T-lymphocytes;
• decreased flow of neutrophils into the joint cavities.

In addition, when infliximab is prescribed, a decrease in the formation of new vessels in the synovial membrane is noted, which indicates the "antiangiogenic" activity of the drug. This effect is probably associated with the inhibition of the synthesis of vascular endothelial growth factor, since a decrease in the serum concentration of the latter was recorded during treatment.

It has also been noted that the TNF-TNF-β interaction regulates cellular apoptosis. Therefore, it is possible that inhibition of TNF-α synthesis may modulate programmed death of synovial cells and thereby inhibit the development of synovial hyperplasia.

One of the most important mechanisms of action of infliximab in rheumatoid arthritis is considered to be the normalization of the quantity and functional activity of CD4, CD25 T-regulatory cells. During treatment, patients experience restoration of the level of these elements of the immune system. This fact correlates with an increase in the suppressor activity of cells in relation to the synthesis of cytokines and spontaneous apoptosis of T per.

The mechanism of action of infliximab in spondyloarthropathies and gouty arthritis is not fully understood. There is data on an increase in interferon-y and a decrease in IL-10 during therapy. This reflects the ability of infliximab to restore the Thl-type immune response, reducing the synthesis of interferon-y and TNF-a by T-lymphocytes.

Serial morphological studies have shown that during treatment in patients with Bechterew's disease the following occurs:

• decrease in the thickness of the synovial membrane;
• decrease in the number of CD55* synoviocytes, neutrophils, as well as CD68 and CD 163 macrophages;
• decreased expression of vascular cell adhesion molecule 1 (VCAM 1) on endothelial cells.

The number of lymphocytes (CD20) and plasma cells did not change during treatment.

In patients with gouty arthritis, after the administration of infliximab, a decrease in the number of macrophages, CD31 cells and vessels was detected. The latter is due to a decrease in the expression of vascular endothelial growth factor and other stimulators of angiogenesis.

Recommendations for the use of infliximab in rheumatoid arthritis

Indications

• A definitive diagnosis of RA according to the American College of Rheumatology criteria.
• High RA activity (DAS index >5.1) (requires double confirmation within one month).
• Failure to respond to or poor tolerance of adequate therapy with methotrexate and at least one other standard DMARD.
• The adequacy of DMARD therapy is determined by taking into account the duration of treatment of at least 6 months, and during at least two of them the drug is prescribed in a standard therapeutic dose (in the absence of side effects). In the event of the latter and the need to cancel the DMARD, the duration is usually at least 2 months.

Contraindications

• Pregnancy and lactation.
• Severe infections (sepsis, abscesses, tuberculosis and other opportunistic infections, septic arthritis of non-prosthetic joints within the previous 12 months).
• Heart failure III-IV functional classes (NYHA).
• History of demyelinating diseases of the nervous system.
• Hypersensitivity reactions to infliximab, other murine proteins, or any of the inactive components of the drug.
• Age under 18 years (however, if indicated, infliximab can be used in children and adolescents).

[ 6 ], [ 7 ]

Cautions

Treatment with infliximab should be carried out with particular caution and under close supervision in the presence of:

• predisposition to infectious diseases (ulcerative defects of the shins, persistent or recurrent bronchopulmonary infection, catheterization of the bladder, etc.);
• pulmonary fibrosis.

[ 8 ], [ 9 ], [ 10 ], [ 11 ], [ 12 ], [ 13 ]

Indications for discontinuation of treatment

• Development of toxic reactions.
• Lack of effect in the form of a decrease in the DAS 28 index by >1.2 or a decrease in the DAS 28 index <3.2 within 3 months of therapy. However, in the case of development of other favorable effects as a result of treatment (for example, the possibility of reducing the dose of GC, etc.), it can be extended for another 3 months. In the absence of appropriate dynamics of the DAS28 index and within 6 months, further continuation of therapy is not recommended.
• Severe intercurrent infection (temporary drug discontinuation is necessary).
• Pregnancy (temporary discontinuation of the drug is necessary).

Predicting treatment effectiveness

The treatment efficacy can be increased by increasing the drug dose or decreasing the intervals between infusions, which to a certain extent correlates with the concentration of infliximab in the systemic circulation. This strategy is especially important for patients with initially high CRF values. Probably, the latter reflects an increased level of TNF-a synthesis, suppressed by infliximab. It was noted that the absence of a tendency for CRF to decrease two weeks after the first infusion of the drug correlates with a subsequent inadequate clinical response to therapy after 12 weeks. Other studies have shown that the efficacy of infliximab treatment directly depends on the level of TNF-a biological activity. Preliminary data indicate that the treatment outcome is significantly higher in patients with RA with the TNF-a308 G/G genotype than with A/A and A/G. In addition, the treatment efficacy was lower and the incidence of post-transfusion side effects was higher with increasing AKJI titers in patients.

Recommendations for the use and evaluation of the efficacy of infliximab in ankylosing spondylitis

Indications

• A definite diagnosis of AS according to the New York criteria.
• Disease activity:
  • duration more than 4 weeks;
  • BASDAI >4;
  • rheumatologist's decision on the need to prescribe infliximab.
• Treatment failure:
  • at least two NSAIDs for more than 3 months in maximum doses in the absence of contraindications (earlier termination of therapy is possible in case of intolerance or severe toxicity of the drugs);
  • NSAIDs in adequate doses for patients with peripheral arthritis (not amenable to intra-articular administration of glucocorticoids) or sulfasalazine (for 4 months at a dosage of 3 g/day or higher; in case of intolerance to therapy, it may be discontinued earlier);
• at least two injections of glucocorticoids in patients with enteritis in the absence of contraindications.

Evaluation of therapy effectiveness

According to ASAS criteria:

• physical functions (BASPI) or Dougados functional index;
• pain assessed on a visual analogue scale (VAS), especially during the last week and at night, caused by AS;
• back mobility;
• general assessment of the patient's health status (using VAS and over the past week);
• morning stiffness (lasting for the last week);
• the condition of the peripheral joints and the presence of zythesitis (the number of swollen joints);
• acute phase indicators (ESR, CRP);
• general malaise (assessed on VAS).

According to BASDAI criteria and during the last week (with VAS assessment):

• general level of malaise/fatigue;
• degree of pain in the back, lower back, hips;
• general discomfort when pressing in any area: level and duration of morning stiffness.

[ 14 ], [ 15 ], [ 16 ], [ 17 ], [ 18 ], [ 19 ], [ 20 ], [ 21 ]

Evaluation of response to treatment

The criterion is considered to be BASDAI: 50% comparative or absolute, by 2 points (on a 10-point scale). The evaluation period is from 6 to 12 weeks.

[ 22 ], [ 23 ], [ 24 ], [ 25 ], [ 26 ]

Forecasting performance

The effectiveness of treatment with infliximab is higher in patients:

• young age with increased ESR and CRP;
• with a short duration of the disease;
• with lower BASFI index values;
• with signs of inflammation of the sacroiliac joints according to MRI data.

[ 27 ], [ 28 ], [ 29 ], [ 30 ]

Features of the administration of infliximab in various situations

[ 31 ], [ 32 ], [ 33 ]

Surgical treatment

Planned operations

• Operations in a "sterile environment" (for example, for cataracts).
• The operation is performed at least 1 month after the final infusion of infliximab.
• Resumption of therapy is indicated immediately after healing in the absence of signs of infection.
• Operations in a “septic environment” (for example, with sigmoiditis) or with a high risk of infectious complications (for example, with hip replacement).
• The operation is performed at least 2 months after the final infusion of infliximab.
• Treatment is resumed 4 weeks after surgery (provided that the surgical wound has healed and there are no signs of infection).

When performing emergency surgical interventions the following are indicated:

• Discontinuation of infliximab therapy:
• prescribing perioperative antibiotic prophylaxis, if possible, if there is a risk of developing infectious complications (for example, peritonitis);
• careful monitoring of the patient in the postoperative period;
• resumption of infliximab therapy after healing of the surgical wound, completion of the course of possible antibiotic therapy and in the absence of signs of infection.

Vaccination

The use of live vaccines (BCG; measles, rubella, mumps; chickenpox; yellow fever; oral polio, as well as those administered in epidemic cases) is contraindicated. Inactivated vaccines (influenza; hepatitis A and B; diphtheria, tetanus, whooping cough and for the prevention of diseases caused by Haemophilus influenzae type b; meningococcal infection; pneumococcus; typhoid fever; injectable polio) can be administered during treatment with infliximab.

It is recommended to carry out all necessary vaccinations (especially against measles, rubella and mumps in children) before prescribing infliximab. However, if the Mantoux test is negative, BCG vaccination is not prescribed before starting therapy. Immunization with pneumococcal vaccine is indicated in risk groups (in patients with diabetes mellitus, after splenectomy, in nursing homes, etc.).

During treatment with infliximab, annual influenza vaccination may be given.

Malignant neoplasms

The role of infliximab therapy in the development of malignancies is unknown.

• Before prescribing treatment, it is necessary to conduct a thorough examination of the patient to exclude malignant neoplasms. In patients with a history of tumor or precancerous diseases, treatment should be carried out with particular caution after a mandatory assessment of the benefit-risk ratio, as well as after consultation with an oncologist. It is indicated for patients with:
  • burdened family history;
  • anamnestic indications of the presence of malignant neoplasms;
  • high risk of developing cancer (heavy smoking, etc.);
  • newly identified neoplasms.
• There are no data on an increased risk of malignant neoplasms during treatment with infliximab.

Lupus-like syndrome

Against the background of treatment with infliximab, the development of lupus-like syndrome and an increase in the titer of autoantibodies to DNA, cardiolipin have been described. Its manifestations are independently stopped within 1-14 months after the cessation of therapy and do not lead to severe complications.

Recommended:

• stop taking infliximab;
• prescribe appropriate treatment if necessary.

Heart failure

Patients with compensated heart failure (NYHA class I and II) should undergo echocardiography (EchoCG). If the ejection fraction is normal (>50%), infliximab therapy can be administered with careful monitoring of clinical manifestations.

Recommended:

• discontinue treatment in patients with developed heart failure; do not prescribe high doses of infliximab if the patient has this pathology.

Demyelinating diseases and neurological complications

Infliximab use has been associated with rare cases of:

• development of optic neuritis:
• the occurrence of epileptic seizures;
• the appearance or exacerbation of clinical and radiological symptoms of demyelinating diseases (including multiple sclerosis).

The benefits and risks of infliximab therapy should be carefully weighed when it is administered to patients with pre-existing or recent-onset demyelinating diseases of the central nervous system.

[ 34 ], [ 35 ], [ 36 ], [ 37 ], [ 38 ], [ 39 ], [ 40 ], [ 41 ], [ 42 ], [ 43 ], [ 44 ]

Hematological complications

If severe hematological disorders occur, treatment with infliximab should be discontinued.

Pregnancy and lactation

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

There are no data on the excretion of infliximab during lactation, therefore, when prescribing the drug, breastfeeding should be discontinued. Resumption is possible no earlier than 6 months after the end of treatment.

Features of the drug use

• Infliximab is administered intravenously by drip at a dose of 3-10 mg/kg. The duration of the infusion is 2 hours. Additional administrations of the drug are prescribed 2 and 6 weeks after the first administration, then repeated every 8 weeks.
• Patients should be monitored for 2 hours after infliximab administration for post-transfusion side effects. Infusion reactions are classified into 2 types:
  • acute (itching, urticaria, Quincke's edema, hypotension, brady- or tachycardia, anaphylactic shock, fever), developing during the procedure or 2 hours after its completion;
  • slow systemic (arthralgia, joint stiffness).

In this regard, the ability to use resuscitation equipment in a timely manner is extremely important.

Re-administration of infliximab 2 to 4 years after previous therapy has been associated with delayed hypersensitivity reactions in a significant number of patients. The risk of these complications with repeated infusions and intervals of 16 weeks to 2 years is unknown, therefore administration of the drug after an interval of more than 16 weeks is not recommended.

If the efficacy is insufficient, the dose of infliximab may be increased or the interval between infusions may be shortened. If there is no response to therapy, it is advisable to use another TNF-a inhibitor (adalimumab) or prescribe rituximab.

Infliximab therapy is administered under the supervision of a rheumatologist with experience in the diagnosis and treatment of rheumatoid arthritis and the use of biological agents.

Infliximab side effects

Treatment with infliximab is relatively safe and well tolerated by patients. The most common side effects affect the respiratory system, skin and its appendages. Dyspnea, urticaria, headache, and intercurrent infections are noted as reasons for discontinuing treatment.

Treatment with infliximab is not associated with kidney, lung, liver damage or increased incidence of malignant neoplasms, however, there are reports of rare severe opportunistic infections, CNS damage and autoimmune syndromes. Therefore, careful selection of patients for drug administration and monitoring during treatment are necessary.

Prevention of side effects

Prevention of infections.

• Infliximab is contraindicated in patients with severe concomitant infectious diseases.
• It is necessary to stop treatment if a severe infection develops, and then resume the course after complete recovery.
• Infliximab is not recommended for use in HIV-infected patients because the effects of its use are unknown.
• Treatment with the drug is not recommended for patients with active and chronic hepatitis, since in this case the data regarding its use are contradictory.
• Chronic carriers of hepatitis B virus should be carefully examined before using infliximab and closely monitored during therapy due to possible exacerbation of the disease.

Prevention of tuberculosis infection is of particular importance, since its dissemination is considered the most severe complication of infliximab therapy.

• All patients must undergo a tuberculin skin test (Mantoux test) and a chest X-ray before or during treatment with infliximab.
• In patients receiving infliximab therapy, a false-negative skin test result may occur due to immunosuppression. Therefore, they require careful clinical monitoring with x-ray examination of the lungs and dynamics.
• If the Mantoux reaction is negative, the test must be repeated in a week (10-15% of patients may have a positive result). If the test is repeated negative, infliximab may be prescribed.
• If the skin test is positive (>0.5 cm), an X-ray examination of the lungs is indicated. If there are no changes on the X-ray images, treatment with isoniazid at a dose of 300 mg and vitamin B6 for 9 months is recommended. Infliximab may be prescribed one month after completion.
• In case of a positive skin test and the presence of typical signs of tuberculosis or calcified mediastinal lymph nodes (Ghon complex), isoniazid and vitamin B0 therapy should be administered for at least 3 months before infliximab is prescribed. In this case, patients over 50 years of age are recommended to have liver enzymes studied dynamically.

Overdose

Cases of single administration of infliximab at a dose of up to 20 mg/kg were not accompanied by the development of toxic effects. There are no clinical data on overdose.

Efficacy of infliximab in various diseases

[ 45 ], [ 46 ], [ 47 ], [ 48 ], [ 49 ]

Rheumatoid arthritis

In rheumatoid arthritis, infliximab is prescribed to patients in case of inadequate effectiveness of methotrexate therapy in the "early!" and "late" forms of the disease. The advantages of the drug in relation to standard DMARDs are considered to be the rapid achievement of the effect and the relatively rare development of adverse reactions requiring interruption of treatment. In most patients with rheumatoid arthritis, against the background of infliximab therapy, the progression of joint destruction slows down or stops, regardless of the dynamics of clinical indicators.

There is evidence of the drug's effectiveness in patients "resistant" to other DMARDs (leflunomide, cyclosporine), as well as to combination therapy with methotrexate and cyclosporine.

The BeST (Behandel STrategienn) study is of particular importance for the development of scientifically based approaches to the management of patients with early rheumatoid arthritis. Patients with a disease duration of less than two years were divided into 4 groups:

• Group 1 (sequential monotherapy): methotrexate monotherapy, if there was no effect, it was replaced by sulfasalazine or leflunomide, or infliximab was added;
• Group 2 (“step-up” combination therapy): methotrexate (if there was no effect in combination with sulfasalazine, hydroxychloroquine and GC), subsequently replaced with a combination of methotrexate with infliximab;
• Group 3 (“step-up” triple combination therapy): methotrexate in combination with sulfasalazine and GC in high doses (if necessary, cyclosporine was prescribed instead of sulfasalazine), subsequently replaced by a combination of methotrexate with infliximab:
• Group 4: combination therapy with methotrexate and infliximab (leflunomide, sulfasalazine, cyclosporine and prednisolone were added if necessary).

Features of this study:

• achieving low disease activity (DAS <2.4);
• intensive monitoring of the effectiveness of therapy: if there is no effect (reduction in DAS <2.4), change the protocol;
• transition to DMARD monotherapy when the effect was achieved (DAS <2.4) (glucocorticoids and infliximab were discontinued first);
• resumption of the treatment regimen in case of exacerbation of the disease (however, glucocorticoids were prescribed no more than once);
• the duration of patient observation is at least 5 years.

By the end of the first year of the study, clinical improvement was noted in all patients. However, in the 3rd and especially the 4th group, a more rapid positive dynamics of disease symptoms, improvement of joint function, and slowing of their erosion were noteworthy. Analysis of the long-term results showed that the ineffectiveness of the initial therapy was less often determined in patients who began treatment with infliximab. After 3 years of observation, the drug was discontinued in 53% of patients while maintaining low disease activity against the background of methotrexate monotherapy, and in almost a third of cases, persistent remission developed. The administration of infliximab at the onset of rheumatoid arthritis effectively suppresses the progression of destructive processes in the joints in patients with such markers of an unfavorable prognosis as:

• carriage of HLA-DR4 (“shared” epitope);
• increased concentrations of rheumatoid factor and antibodies to cyclic citrullinated peptide.

Other studies have shown that in patients receiving methotrexate monotherapy, progression of joint destruction was significantly associated with a basal increase in CRP concentration (more than 30 mg/L) and ESR (more than 52 mm/h), as well as a high joint count. However, combination therapy with infliximab and methotrexate effectively suppressed progression of joint destruction in this category of patients.

Thus, combination therapy with infliximab and methotrexate in early rheumatoid arthritis is highly effective and allows achieving remission in one third of patients. It is the method of choice in patients with severe, rapidly progressing RA, which is characterized by rapid hospitalization and, in general, an unfavorable prognosis.

Ankylosing spondylitis

The effectiveness of infliximab in Bechterew's disease has been proven by many studies. Preliminary results indicate the advisability of using the drug in undifferentiated spondyloarthritis and spondyloarthritis associated with the disease.

[ 50 ], [ 51 ], [ 52 ], [ 53 ]

Psoriatic arthritis

Infliximab has proven itself to be an extremely promising drug for the treatment of psoriasis and psoriatic arthritis.

Still's disease in adults

The efficacy of infliximab in this disease has been demonstrated in a series of clinical observations in patients refractory to standard therapy (NSAIDs, high doses of glucocorticoids, methotrexate). After administration of the drug, a number of patients experienced significant improvement in the clinical picture (reduction of joint pain, disappearance of signs of arthritis, fever, skin rash, hepatosplenomegaly and lymphadenopathy) and laboratory parameters (normalization of ESR and CRV).

Juvenile idiopathic arthritis

Preliminary results of the studies indicate the prospects of using infliximab for the treatment of patients with juvenile idiopathic arthritis refractory to standard therapy (including glucocorticoids, methotrexate, cyclosporine, cyclophosphamide). The drug was used for all subtypes of the disease. The age of patients ranged from 5 to 21 years and older. The dose of infliximab ranged from 3 to 20 mg / kg (ultra-high), and the duration of treatment varied from several months to one year. Although in some patients the treatment was discontinued due to the development of side effects or inefficiency, most patients showed reliable positive dynamics of clinical and laboratory parameters.

Behcet's disease

Randomized clinical trials to evaluate the efficacy and safety of infliximab in Behçet's disease have not yet been conducted.

[ 54 ], [ 55 ], [ 56 ], [ 57 ], [ 58 ], [ 59 ]

Secondary amyloidosis

A decrease in proteinuria after the administration of infliximab indicates its positive effect on the course of secondary amyloidosis in patients with RA and AS. The basis for the use of the drug in this pathology is the data that TNF-a induces the formation of serum amyloid protein A (SAA) in hepatocytes during the acute phase response along with increased synthesis of IL-1 and IL-6. In addition, it was noted that the introduction of recombinant TNF-a enhances the deposition of amyloid fibrils in the tissues of laboratory animals, and also induces the expression of receptors for the final products of protein glycation. The interaction of the latter with amyloid fibrils enhances their cytotoxic activity and the ability to cause tissue damage.