Infliximab

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

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

General characteristics

Infliximab has a high affinity for trimer TNF-a (Kd-100 pM) and in vitro effectively inhibits its secreted and membrane-associated forms. 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 intravascular. And the half-life is 8-12 days. With the repeated administration of the drug, the effect of accumulation is not noted, 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, the genetic polymorphism of cytochrome isoenzymes, often causing a different frequency of toxic reactions against the background of drug intake, is not significant in the treatment of this drug.

How does infliximab work?

The most important mechanism of action of infliximab in rheumatoid arthritis is the inhibition of the synthesis of "pro-inflammatory" mediators. In the treatment with infliximab, a decrease in the serum concentration of IL-6, IL-1, and tissue expression of the latter is noted. These indices correlate with a decrease in the level of acute proteins and mediators (IL-8, raIL-1, pCD14, monocytic chemotractant protein-1, nitric oxide, collagens, stromomelysin), which play a significant role in the development of inflammation and tissue destruction in rheumatoid arthritis. It was also noted that the synthesis drug of IL-1 suppressed the synovial tissue macrophages, in this disease.

Another important mechanism for the action of infliximab is the "deactivation" of the vascular endothelium, which leads 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 efficacy of treatment.

According to the data of immunomorphological studies of synovial biopsy specimens against the background of therapy, one observes:

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

In addition, with the appointment of infliximab, a decrease in the formation of new vessels in the synovial membrane is noted, which indicates the "anti-angiogenic" activity of the drug. This effect is probably due to the inhibition of vascular endothelial growth factor synthesis, since a decrease in serum concentration of the latter was observed during treatment.

It was also noted that the interaction of TNF-TNF-P regulates cellular apoptosis. Therefore, it is possible that inhibition of TNF-a synthesis can modulate the programmed death of synovial cells and thereby inhibit the development of synovial hyperplasia.

One of the most important mechanisms of the action of infliximab in rheumatoid arthritis is the normalization of the amount and functional activity of CD4, CD25 T-regulatory cells. Against the background of treatment in patients, the restoration of the level of these elements of the immune system is noted. This fact correlates with an increase in the suppressor activity of cells with respect 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 evidence of an increase in the background of therapy with interferon-y and decreased IL-10. 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.

In a serial morphological study, it was noted that against the backdrop of treatment in patients with Bekhterev's disease occurs:

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

The number of lymphocytes (CD20) and plasma cells in treatment has not changed.

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

Recommendations for the use of infliximab in rheumatoid arthritis

Indications

• Reliable diagnosis of RA according to the criteria of the American College of Rheumatology.
• High activity of the RA (DAS index> 5.1) (two-time confirmation is necessary within one month).
• No effect or poor tolerance of adequate therapy with methotrexate and at least one more standard BPVP.
• The adequacy of therapy with DMARD is determined by considering the duration of treatment for at least 6 months, and for at least two of them the drug is prescribed in a standard therapeutic dose (in the absence of side effects). In the case of the appearance of the latter and the need to abolish the BPAP, the duration is usually not less than 2 months.

Contraindications

• Pregnancy and lactation.
• Heavy infections (sepsis, abscesses, tuberculosis and other opportunistic infections, septic arthritis of unprocessed joints during the preceding 12 months).
• Heart failure of III-IV functional classes (NYHA).
• Data on demyelinating diseases of the nervous system in the anamnesis.
• Hypersensitivity reactions to infliximab, other murine proteins, as well as to any of the inactive components of the drug.
• Age younger than 18 years (however, in the presence of indications, infliximab can be used in children and adolescents).

[6], [7]

Caveats

Treatment with infliximab should be carried out with extreme caution and under close supervision if:

• predispositions to infectious diseases (ulcerous shin defects, persistent or recurrent bronchopulmonary infection, catheterization of the bladder, etc.);
• pulmonary fibrosis.

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

Indications for cessation of treatment

• Development of toxic reactions.
• No effect in the form of a decrease in the DAS 28 index by> 1.2 or a decrease in the DAS index of 28 <3.2 for 3 months of therapy. However, if other beneficial effects result from the treatment (for example, the possibility of reducing the dose of HA, etc.), it can be extended for another 3 months. In the absence of appropriate dynamics, the index a DAS28 and the course of 6 months further continuation of therapy is not a recommendation.
• Severe intercurrent infection (temporary withdrawal of the drug is necessary).
• Pregnancy (temporary withdrawal of the drug is necessary).

Predicting the effectiveness of treatment

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

Recommendations for the use and evaluation of infliximab in ankylosing spondylitis

Indications

• A reliable diagnosis of AS in accordance with the New York criteria.
• Activity of disease:
  • duration of more than 4 weeks;
  • BASDAI> 4;
  • a rheumatologist's decision to prescribe infliximab.
• Ineffective treatment:
  • at least two NSAIDs for more than 3 months at maximum doses in the absence of contraindications (possibly earlier cessation of therapy for intolerance or severe toxicity of drugs);
  • NSAIDs in adequate doses of patients with peripheral arthritis (not firing for intra-articular glucocorticoid administration) or sulfasalazine (for 4 months at a dosage of 3 g / day or more, in the case of intolerance of therapy, it may be earlier discontinued);
• at least two injections of glucocorticoids of patients with enteritis in the absence of contraindications.

Assessment of the effectiveness of therapy

According to ASAS criteria:

• physical functions (BASPI) or functional index Dougados;
• pain with visual analogue scale assessment (VAS), especially during the last week and at night, due to AS;
• mobility in the back;
• general assessment of the state of health in the opinion of the patient (with the help of VAS and during the last week);
• morning stiffness (duration during the last week);
• the condition of peripheral joints and the presence of zitesis (the number of swollen joints);
• acute phase parameters (ESR, CRP);
• general malaise (with an assessment according to YOUR).

According to the criteria of BASDAI and during the last week (with the assessment by VASH):

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

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

Assessment of response to treatment

The criterion is 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 effectiveness

The effectiveness of treatment with infliximab is higher in patients:

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

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

Features of infliximab administration in various situations

[31], [32], [33]

Surgery

Scheduled operations

• Operations in a "sterile environment" (for example, with cataracts).
• The operation is performed at least 1 month after the final infusion of infliximab.
• The resumption of therapy is shown immediately after healing, with no signs of infection.
• Operations in the "septic environment" (for example, with sigmoiditis) or at 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 the wound is healed and no signs of infection).

During emergency operations, the following are shown:

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

Vaccination

The use of live vaccines (BCG, vaccines against measles, rubella, mumps, chicken pox, yellow fever, oral against poliomyelitis, and also introduced in epidemic cases) is contraindicated. Inactivated vaccines (against influenza, hepatitis A and B, diphtheria, tetanus, pertussis and for the prevention of diseases caused by Haemophilus influenzae type b, against meningococcal infection, pneumococcus, typhoid, injection against poliomyelitis) can be administered during treatment with infliximab.

It is recommended to carry out all the necessary vaccinations (especially against rubella and mumps in children) before the appointment of infliximab. However, with a negative Mantoux test, BCG vaccination is not prescribed before the start of 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, an annual influenza vaccine can be administered.

Malignant neoplasms

The role of therapy with infliximab in the development of malignant neoplasms is not known.

• Before the appointment of a treatment, a thorough examination of the patient should be conducted to exclude malignant tumors. Patients with a history of tumor or premalignant disease should be treated with extreme caution after an obligatory assessment of the benefit / risk ratio, and after consultation with the oncologist. It is indicated to patients with:
  • burdened family history;
  • anamnestic indications on the presence of malignant neoplasms;
  • high risk of developing cancer (abundant smoking, etc.);
  • newly diagnosed neoplasms.
• Data on the increase in the risk of malignant neoplasms in the presence of treatment with infliximab are absent.

Lupus-like syndrome

On the background of treatment with infliximab, the development of lupus-like syndrome and an increase in the titer of autoantibodies to DNA, cardiolipin are described. Its manifestation is self-extinguished within i-14 months after discontinuation of therapy and do not lead to serious complications.

Recommended:

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

Heart failure

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

Recommended:

• stop treatment of patients with advanced heart failure; o Do not prescribe high doses of infliximab if the patient has this pathology.

Demyelinating diseases and neurological complications

The use of infliximab is associated with rare cases:

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

We should carefully weigh the benefit / risk ratio from infliximab therapy when it is administered to patients with pre-existing or newly emerging demyelinating CNS diseases.

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

Hematologic complications

When severe hematologic disorders occur, treatment with infliximab should be discontinued.

Pregnancy and lactemia

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

Data on the excretion of infliximab in lactation are absent, so when prescribing the drug should stop breastfeeding. Renewal is possible not earlier than 6 months after the end of treatment.

Features of the drug

• Infliximab is administered intravenously drip in a dose of 3-10 mg / kg. The duration of the infusion is 2 hours. After 2 and 6 weeks after the first application, additional injections are prescribed, repeated every 8 weeks.
• Patients should be monitored for 2 hours after the administration of infliximab to detect posttransfusion side effects. Infusion reactions are divided into 2 types:
  • acute (itching urticaria, edema Quincke, hypotension, brady- or tachycardia, anaphylactic shock, fever) developing during the procedure or 2 hours after its completion;
  • delayed systemic (arthralgia, stiffness in the joints).

In this regard, the possibility of timely use of resuscitation equipment is extremely important.

Repeated administration of infliximab 2-4 g after the previous therapy was associated with delayed-type hypersensitivity reactions in a significant number of patients. The risk of these complications in the appointment of repeated infusions and from 16 weeks to 2 years is unknown, so the introduction of the drug after a break more than 16 weeks is not recommended.

With insufficient effectiveness, an increase in the dose of infliximab or a reduction in the interval between infusions is possible. In the absence of response to therapy, it is advisable to use another inhibitor of TNF-a (adalimumab) or the administration of rituximab.

Therapy with infliximab is carried out under the supervision of a rheumatologist with experience in the diagnosis and treatment of rheumatoid arthritis, and the use of biological agents.

Side effects of infliximab

Treatment with infliximab is relatively safe and well tolerated by patients. The most frequent side effects affect the respiratory system, the skin and its appendages. As reasons for the abolition of treatment, shortness of breath, hives, headache, and intercurrent infections,

Treatment with infliximab is not accompanied by a lesion of the kidneys, lungs, liver, or an increase in the incidence of malignant neoplasms; however, there are data on the rare development of severe opportunistic opportunistic infections, CNS lesions and autoimmune syndromes. Therefore, careful selection of patients for prescribing the drug and monitoring during treatment are necessary.

Prevention of side effects

Prevention of infections.

• Contraindicated the appointment of infliximab in patients with severe concomitant infectious disease.
• It is necessary to stop treatment with the development of a serious infection with the subsequent resumption of the course after full recovery.
• It is not recommended to prescribe infliximab to HIV-infected patients, as the consequences of its use are not known.
• It is not recommended to treat patients with active and chronic hepatitis with the drug, since in this case the data regarding its use are inconsistent.
• It is necessary to conduct a thorough examination of chronic carriers of hepatitis B virus before infliximab application and carefully monitor them during therapy in connection with possible exacerbation of the disease.

Of particular importance is the prevention of tuberculosis infection, as its dissemination is considered the most severe complication of infliximab therapy.

• All patients before the beginning or already in the process of treatment with infliximab should conduct a skin tuberculin test (Mantoux reaction) and a radiographic examination of the lungs.
• In patients receiving therapy with infliximab, due to immuno-suppression, a false-negative result of the skin test is possible. Therefore, they need careful clinical observation with a reptogenological study of the lungs and dynamics.
• If the Mantoux reaction is negative, the test should be repeated through a pedal (10-15% of patients have a positive result). In the case of a second negative test, infliximab may be administered.
• With a positive skin test (> 0.5 cm), an X-ray examination of the lungs is indicated. In the absence of changes on radiographs, isoniazid is recommended in a dose of 300 mg and vitamin B6 for 9 months. A month after the end, it is possible to prescribe infliximab.
• With a positive skin test and the presence of typical signs of tuberculosis or calcified lymph nodes of the mediastinum (Gona complex) before the appointment of infliximab, it is necessary to use isoniazid and vitamin B therapy for at least 3 months. Patients older than 50 years are shown in this case the study of liver enzymes in the dynamics.

Overdose

The cases of single administration of infliximab in a dose of up to 20 mg / kg were not accompanied by the development of toxic effects. Clinical data on overdose are absent.

Effectiveness of infliximab in various diseases

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

Rheumatoid arthritis

In rheumatoid arthritis, infliximab is prescribed to patients in the case of nedosattochnoy efficiency of methotrexate therapy in the "early! And the "late" form of the disease. Advantages of the drug in relation to standard DMBs are the rapid achievement of the effect and the relatively rare development of adverse reactions requiring interruption of treatment. In the majority of patients with rheumatoid arthritis, treatment with infliximab slows or slows the progression of joint destruction, regardless of the dynamics of clinical indices.

There are data on the effectiveness of the drug in patients who are "resistant" to other BPVP (leflunomide, cyclosporine), as well as to combination therapy with methotrexate and cyclosporine.

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

• group 1 (sequential monotherapy): monotherapy with methotrexate, in the absence of the effect it was replaced with sulfasalazine or leflunomide, or infliximab was added;
• group 2 ("step-uр" -combined therapy): methotrexate (in the absence of an effect in combination with sulfasalazine, hydroxychloroquine and HA), was subsequently replaced with a combination of methotrexate and infliximab;
• group 3 ("step-up" triple combination therapy): methotrexate in combination with sulfasalazine and HA in high doses (if necessary instead of sulfasalazine prescribed cyclosporine), was subsequently replaced by a combination of methotrexate with infliximab:
• group 4: combined therapy with methotrexate with infliximab (if necessary, leflunomide, sulfasalazine, cyclosporine and prednisolone were added).

Features of this study:

• achievement of low disease activity (DAS <2.4);
• intensive monitoring of the effectiveness of therapy: in the absence of effect (reduction of DAS <2.4) protocol change;
• transition to the monotherapy of DMARD when the effect is achieved (DAS <2.4) (firstly, glucocorticoids and infliximab were started);
• resumption of the treatment regimen for exacerbation of the disease (however, glucocorticoids were administered no more than once);
• duration of observation of patients not less than 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, the faster positive dynamics of the symptoms of the disease, the improvement of the function of the joints, and the slowing of their erosion paid attention. An analysis of the long-term results showed that the ineffectiveness of initial therapy was less often determined in patients who started treatment with infliximab. After 3 years of observation, 53% of the patients managed to cancel the drug while maintaining low activity of the disease against monotherapy with methotrexate, and in almost a third of cases a stable remission developed. The administration of infliximab in the onset of rheumatoid arthritis effectively suppresses the progression of destructive processes in the joints in patients with such unfavorable prognostic markers as:

• carrier of HLA-DR4 ("shared" epitope);
• an increase in the concentration of rheumatoid factor and antibodies to the cyclic citrulline peptide.

In other studies, it was shown that the progression of joint destruction was significantly associated with a basal increase in the concentration of SRV (> 30 mg / L) and ESR (> 52 mm / h) in patients receiving methotrexate monotherapy and a high articular score. However, combination therapy with infliximab and methotrexate effectively suppressed the 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 one to achieve remission in a third of patients. It is a 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 efficacy of infliximab in Bechterew's disease has been proven by many studies. Preliminary results indicate the expediency of using the drug in undifferentiated snondyloarthritis and spondyloarthritis associated with the disease.

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

Psoriatic arthritis

Infliximab has established itself as an extremely promising drug for the treatment of psoriasis and psoriatic arthritis.

Still's disease in adults

The effectiveness of infliximab in this disease was demonstrated and a series of clinical observations in patients with refractory to standard therapy (NSAIDs, high doses of glucocorticoids, methotrexate). After the appointment of the drug in a number of patients, the clinical picture (reduction of pain in the joints, disappearance of the signs of arthritis, fever, skin rash, hepatosplenomegaly and lymphadenopathy) and laboratory indicators (normalization of ESR and SRV) significantly improved.

Juvenile idiopathic arthritis

Preliminary results of the studies indicate the prospective application of infliximab for the treatment of refractory to standard therapy (including glucocorticoids, methotrexate, cyclosporine, cyclophosphamide) in patients with juvenile idiopathic arthritis. The drug was used for all subtypes of the disease. The age of the patients ranged from 5 to 21 years and older. The dose of infliximab was 3 to 20 mg / kg (super-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, in the majority of patients there was a significant positive dynamics of clinical and laboratory indicators.

Behcet's disease

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

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

Secondary amyloidosis

Decreased proteinuria after the appointment 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 for this pathology is the evidence that TNF-α induces the formation of serum amyloid protein A (SAA) in hepatocytes during the acute phase response, along with the enhancement of the 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 glycation products of proteins. The interaction of the latter with amyloid fibrils increases their cytotoxic activity and the ability to cause tissue damage.