Rituximab

Rituximab is a chimeric monoclonal antibody to the CD20 antigen of B cells (rituximab, MabThera). Rituximab has been used since 1997 to treat B-cell non-Hodgkin's lymphomas, as well as other lymphomas that are resistant to standard therapy.

B-lymphocytes of the immune system cells involved in the development and maintenance of adaptive immunity, they are formed from hematopoietic progenitor cells in the bone marrow throughout the life of a person. B-lymphocytes express membrane receptors, including autoreactive, and are involved in maintaining immunological tolerance to their own antigens (autoantigens). Defects in B-cell tolerance, manifested, in particular, in the violation of the repertoire of autoreactive B cells, lead to the synthesis of autoantibodies. However, the importance of B cells in the development of autoimmune diseases is not limited to the synthesis of autoantibodies. It has been established that B cells (as well as T cells) participate in the regulation of the immune response both in normal and against the background of the development of immunoinflammatory processes, therefore, B cells can be promising therapeutic "targets" for rheumatoid arthritis and other autoimmune rheumatic diseases .

The choice of the CD20 molecule as a target for monoclonal antibodies is related to the peculiarities of B cell differentiation. During the maturation of stem cells into plasma cells, B-lymphocytes undergo several successive stages. For each stage of differentiation of B cells, the presence of certain membrane molecules is characteristic. CD20 expression is observed on the membrane of "early" and mature B lymphocytes (but not stem cells), "early" pre-B, dendritic and plasma cells, so their depletion does not "cancel" the regeneration of the B-lymphocyte pool and does not affect the synthesis of antibodies by plasma myrtle. In addition, SB20 is not released from the B-lymphocyte membrane and is absent in the circulating form, which could potentially interfere with the interaction of anti-CD20 antibodies with B cells. It is believed that the ability of rituximab to eliminate B cells is realized through several mechanisms, including complement-dependent and antibody-dependent cellular cytotoxicity, as well as the induction of apoptosis.

[1], [2], [3], [4], [5], [6], [7], [8],

Indications for use and dosage

• Inadequate response to TNF-a inhibitors.
• Intolerance to TNF-a inhibitors.
• Inadequate response to BPD.

Dosing regimen: 2 infusions of 1000 mg (days 1 and 15), application of the drug at a dose of 500 mg is also significantly more effective than placebo in patients resistant to therapy with standard BPVP. To reduce the severity of infusion reactions prior to the introduction of rituximab, premedication is recommended (administration of 100 mg of methylprednisolone intravenously, and if necessary, antihistamines and paracetamol). To enhance the effect, it is recommended to simultaneously prescribe methotrexate. If necessary, a second course of treatment is carried out after 24 weeks.

According to Edwards, who has extensive experience in the long-term use of rituximab, until the indication for repeated administration of the drug is expressed signs of exacerbation or increased concentration of CRP by 50% of the initial (as well as titres of IgM RF) plus increased intensity of morning stiffness and joint pain.

Indications for repeated courses of rituximab therapy:

• residual activity: DAS 28 is greater than 3.2;
• reactivation of the disease with low activity; Increase DAS 28 to 3.2.

Mechanism of action of rituximab

In patients with rheumatoid arthritis, the administration of rituximab leads to an almost complete (more than 97%) depletion of the B-cell pool (CD19) in the blood stream for several days. This effect persists in the vast majority of patients for at least 6 months. Along with the decrease in the number of synovial B cells, the decrease in the infiltration of the synovium by T cells (CDS) and monocytes / fibroblasts (CD68) was noted. At the same time, a clear connection between the number of B cells and the effectiveness of rituximab therapy has not been established. 80% of rituximab B-resistant cells are CD27-positive, which is characteristic of memory B-cells. Regeneration of CD27 B lymphocytes occurs slowly, the number of these cells does not reach 50% of the baseline level for more than 2 years after the infusion of the drug. Repeated courses of treatment with rituximab lead to a progressive decrease in the number of CD27 B cells. Since the concentrations of "pathogenic" autoantibodies (RF, antigen to cyclic citrulline peptide (anti-CCP)) significantly decrease, it is suggested that rituximab eliminates autoreactive B cells involved in the development of the pathological process in rheumatoid arthritis.The effectiveness of rituximab in rheumatoid arthritis is associated with a significant change in function monocytes / macrophages: a decrease in the synthesis of TNF-a and an increase in IL-10 production, which has anti-inflammatory activity The effectiveness of rituximab in rheumatoid arthritis e correlates with a decrease in the concentration of biological markers reflecting the severity of autoimmune reactions and inflammation (RF titers and anti-CCP, IL-6, CRP, serum amyloid protein A, calcium-binding protein S100 A8 / 9), and an increase in the concentration of bone metabolism markers N-terminal propeptide prokollagen type 1 and osteocalcin).

In the pathogenesis of SLE, disruption of the mechanisms of suppression of the autoimmune response is of particular importance. On the background of treatment with rituximab, the change in the amount of CD4 / CD25 T-regulatory cells and their suppressor function, capable of suppressing the proliferation of autoreactive lymphocytes, was evaluated. The number of CD4 / CD25 T regulatory cells increased significantly, and their suppressor activity increased on the 30th and 90th days after treatment with rituximab. With ineffective rituximab therapy, the amount of CD4 / CD25 T-regulatory cells increased insignificantly, and their function remained unchanged. An increase in the level of BohRZ (a specific marker of T-regulatory cells) in patients who are in remission after treatment with rituximab has been noted. The development of remission was accompanied by a decrease in the activation of T-helpers and ANF titers. The achievement of partial remission of lupus nephritis developed against the background of suppression of cellular expression of CD40L on CD4 T-lymphocytes, expression of CD699 and HLA-DR. In patients with CNS lesion, a correlation was established between the onset of the clinical effect of rituximab and the suppression of CD40 and CD80 expression involved in the stimulation of T cells. Against the backdrop of treatment with rituximab, a decrease in the levels of antibodies (to nucleosomes and to DNA) that participate in immunopathogenesis of SLE is noted.

Pharmacokinetics

The pharmacokinetic parameters of rituximab (Cmax, AUC, T1 / 2, Tmax, clearance, volume of distribution in the stable state) did not depend on how the drug was administered alone or in combination with cyclophosphamide or methotrexate.

In men compared with women, the distribution is larger and the drug is excreted more quickly.

Against the background of the administration of rituximab at a dose of 1000 mg x 2, rapid, almost complete disappearance of B cells (CD191) was noted. In most patients, after my treatment with rituximab, the B-cell population started to recover after 6 months; the reduction in the number of peripheral B-cells assumed a protracted character only in a small part of patients (2 years after a single course of treatment the number of B-cells remained low). There is no direct relationship between the degree of depletion of the B-cell pool and the efficacy of treatment or exacerbation of the disease.

Rheumatoid arthritis and rituximab

The results of a study of the efficacy and safety of rituximab served as the basis for the registration of a drug for the treatment of rheumatoid arthritis in the United States, Western Europe and Russia.

It has been established that rituximab is effective in severe rheumatoid arthritis, both in monotherapy and in combination with methotrexate, which is resistant to standard HDL and inhibitors of TNF-a. The effectiveness of monotherapy is somewhat lower than that of combination therapy. With the appointment of rituximab, clinical improvement is rapidly different (within the first 3 weeks after the course of therapy), reaching a maximum and for 16 weeks and lasting 6-12 months.

According to X-ray data, combined therapy with rituximab and methotrexate suppresses the progression of joint destruction in patients with an inadequate response to standard BPVP and TNF inhibitors (according to the criteria of the American College of Rheumatology and the European Antirheumatic League). Slowing down the destruction of the joints does not depend on the clinical effect.

Data on the relationship between the efficacy of rituximab and seropositivity in the RF, as well as anti-CCPs are contradictory. Some studies have shown that rituximab is equally effective in both seropositive and seronegative for rheumatoid arthritis in the Russian Federation, while in others, the effect was noted predominantly in seropositive patients. However, in seronegative RF and / or anti-CCP patients who received rituximab, the effectiveness of treatment (good or moderate response according to the criteria of the European Antirheumatic League) was higher than in the group receiving the placebo.

The effectiveness of repeated courses of rituximab in patients who "responded" or "did not respond" to the first cycle of therapy, as well as the "predictors" of the response to the drug require further study. When deciding on the question of repeated courses of therapy (an average of 6 months), it is necessary to focus on the dynamics of clinical and laboratory manifestations of the disease. Data on the long-term use of rituximab (more than 5 years) indicate a high effectiveness of repeated courses (5 and more) in 80% of patients

In patients with ineffective TNF inhibitors, rituximab is more likely to suppress joint inflammation (decrease in DAS28) than replacing one TNF inhibitor with another (p = 0.01). The efficacy of rituximab in rheumatoid arthritis is higher in patients with an inadequate response to a single TNF inhibitor than several TNF inhibitors, so the earlier administration of rituximab is advisable.

Studies that examined how effective the repeated course of rituximab in patients with no or insufficient response to the first course of treatment was not conducted. It is not recommended to prescribe TNF-α inhibitors if rituximab therapy is ineffective, as this is associated with a high risk of infectious complications, especially when the level of B-cells in the peripheral blood decreases.

Contraindications

• Hypersensitivity to the drug or mouse proteins.
• Acute severe infections.
• Heart failure (IV NYHA).

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

Side effects

Treatment with rituximab is well tolerated and rarely leads to the development of side effects that require discontinuation of therapy.

A common side effect is infusion reactions (30-35% after the first infusion with glucocorticosteroids as a premedication). The frequency of this complication is significantly reduced when using the infusomat and repeated administration of the drug. The intensity of infusion reactions is moderate, only sometimes additional therapeutic interventions are required (prescription of antihistamines, bronchodilators, GK). Severe reactions develop extremely rarely and, as a rule, do not require interruption of treatment. Since rituximab is a chimeric antibody, its infusion results in the synthesis of anti-chimeric antibodies (about 10%). The production of anti-chimeric antibodies can increase the risk of allergic reactions and reduce the effectiveness of depletion of the B-cell pool.

The risk of infectious complications in patients receiving rituximab is slightly higher than that of patients receiving placebo. Increased risk of opportunistic infections (including tuberculosis), reactivation of viral infections, as well as the onset of cancer were not noted.

Analysis of the results of long-term use of rituximab (up to 7 repeated courses) indicates a high safety of therapy with this drug.

There was a reduction in the overall incidence of side effects and infusion reactions. Although the frequency of infectious complications increased slightly (which correlated to a certain degree with a decrease in the concentration of IgG and IgM immunoglobulins), the incidence of serious infections did not increase.

The safety of rituximab in patients with rheumatoid arthritis carriers of hepatitis B and C viruses is not known. Rituximab has been successfully used in carriers of hepatitis C virus - patients with lymphoma without antiviral prophylaxis and hepatitis B against lamivudine. However, hepatitis B carriers receiving rituximab described the development of fulminant hepatitis. There was no increase in the risk of infectious complications in HIV-infected patients with lymphomas. In patients receiving rituximab, the effectiveness of vaccination is less, so it must be done before rituximab is administered.

Evaluation of treatment effectiveness

The effectiveness of treatment is assessed using standardized criteria (DAS index). Treatment is considered effective with a decrease in DAS 28 of more than 1.2 from the baseline and reaching a DAS 28 of less than 3.2.

[14], [15], [16], [17], [18], [19], [20], [21], [22],

Systemic lupus erythematosus

To date, rituximab has been used in more than 200 patients with SLE (both in adults and children). The overwhelming majority of patients had a severe course of the disease (half of them had proliferative lupus nephritis) refractory to standard therapy. About half of the patients received rituximab according to a protocol developed for the treatment of lymphomas (4 infusions and 1 week to a dose of 375 mg / m ² ), 30% of rituximab patients were administered in combination with cyclophosphamide. The duration of observation ranged from 3 to 46 (mean 12 months). More than 80% of patients receiving rituximab showed a significant decrease in the activity of the disease. According to repeated biopsies, a year after the therapy with rituximib, positive dynamics of morphological changes in the glomeruli of the kidney was noted. Along with suppression of lupus nephritis, positive dynamics of extrarenal manifestations of SLE (skin lesions and CNS, arthritis, thrombocytopenia, hemolytic anemia) was noted. Rituximab was used for life indications in patients with severe CNS damage (loss of consciousness, convulsions, disorientation, ataxia, sensory neuropathy) and with a cytopenic crisis (anemia, thrombocytopenia, leukopenia). In all cases, the appointment of rituximab led to a rapid improvement, frolicking within a few days from the start of treatment. The increase in positive dynamics, which turns into a stable improvement, was observed for 6-7 months.

All patients during this period of time managed to significantly reduce the dose of prednisolone. Rituximab is also effective in catastrophic APS.

All this testifies to the prospects of using rituximab in the development of critical states of SLE threatening the lives of patients.

Repeated courses of treatment with rituximab are highly effective (7 patients - a total of 18 courses, an average of 3 courses per patient) in maintaining a remission from 6 to 12 months.

Idiopathic inflammatory myopathies

The treatment of polymyositis and dermatomyositis is more empirical and usually consists of a combination of HA and immunosuppressants. For many patients, this therapy is not effective enough, therefore, the use of rituximab in IWM is of undoubted interest. A study was made of the efficacy of rituximab in seven patients with dermatomyositis (six of them were resistant to a number of immunosuppressive drugs). Patients received one infusion of rituximab per week for a month without further treatment with this drug. The observation was carried out for 1 year. As a result, clinical and laboratory improvement was noted in all patients. The maximum effect was achieved 12 weeks after the first injection and correlated with a decrease in CD20 B cells. Later on, four patients developed an exacerbation of the disease (before the end of the 52-week observation), which coincided with an increase in the number of CD20 B-cells in the blood. A decrease in such manifestations of the disease as a skin rash, alopecia, an increase in the forced vital capacity of the lungs was noted. The tolerability of the drug was good. Other authors used rituximab (2 infusions of 1000 mg twice every 14 days) in three patients with refractory dermatomyositis. Against the background of treatment, normalization of CK was observed (an average of 4.6 months), an increase in muscle strength; as a result of therapy, it was possible to reduce the dose of HA and methotrexate. According to clinical data, rituximab was successfully used in patients with antisynthesis syndrome, with interstitial pulmonary fibrosis. On the background of treatment with rituximab (375 mg / m ², four injections per month) there was an improvement in the diffusivity of the lungs (4 months after the start of treatment), which reduced the dose of glucocorticosteroids.

Systemic vasculitis

Currently, three pilot prospective studies have been conducted (total of 28 patients) and four retrospective observations (35 patients), indicating the effectiveness of rituximab in systemic vasculitis associated with antibodies to the neutrophil cytoplasm (ANCA). The effectiveness of rituximab is high and reaches 90%. In 83% of patients, complete remission was achieved, which was preserved in the absence of therapy or against the background of taking small doses of glucocorticosteroids. In 14 patients, an exacerbation (9-21 months), successfully suppressed by the repeated administration of rituximab, developed. Treatment with rituximab was performed both against the background of cytotoxic therapy, and in the form of monotherapy (in combination with small doses of glucocorticosteroids). It should be emphasized that a potential limitation for the use of rituximab in the form of monotherapy is the development of a complete clinical response at 3 months after completion of treatment, which is unacceptable for patients with rapid progression of internal organ damage.

Sjogren's Syndrome

Preliminary results of studies on the use of rituximab in the early manifestations of primary Sjögren's syndrome and Sjögren's syndrome associated with MALT (mucosa-associated lymphoid tissue) lymphoma (37 patients in total) indicate high efficacy of the drug for systemic manifestations of the disease. There was also a marked reduction in symptoms of dryness and improvement in salivary gland function. These data allowed to formulate an indication for the appointment of rituximab in Sjogren's syndrome. These include arthritis, peripheral neuropathy, glomerulonephritis, cryoglobulinemic vasculitis, refractory scleritis, severe cytopenia, B-cell lymphomas. It should be noted that in patients with Sjogren's syndrome the frequency of infusion reactions (associated with the synthesis of anti-chimeric antibodies) is higher than in other diseases. In Sjogren's syndrome, rituximab is preferred not as a monotherapy, but in combination with glucocorticosteroids and other immunosuppressive drugs.

Thus, rituximab is an effective and relatively safe drug for the treatment of rheumatoid arthritis and other severe autoimmune rheumatic diseases, its introduction into clinical practice can rightly be considered a major achievement of rheumatology of the beginning of the XXI century. At present, the study of the place of rituximab in the treatment of rheumatoid arthritis is just beginning. In the near future, it is necessary to optimize the treatment tactics (determine the minimum effective dose, the optimal time for repeated courses, the possibility of combination therapy with other DMARDs and biological agents), determine the predictors of effectiveness and resistance to therapy (including secondary inefficiency), the possibility of rituximab with early rheumatoid arthritis and as the first biological preparation. There is no complete answer to the questions about the risk of developing side effects (infectious complications, malignant neoplasms, etc.) against the background of a prolonged depletion of the B-cell pool, the optimal vaccination strategy, the safe use of rituximb in combination with other biological agents, the possibility of rituximab at women during pregnancy and a lactemia, and also at patients with malignant neoplasms in the anamnesis.