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 resistant to standard therapy.

B-lymphocytes are cells of the immune system that participate in the development and maintenance of adaptive immunity. They are formed from hematopoietic progenitor cells in the bone marrow throughout a person’s life. B-lymphocytes express membrane receptors, including autoreactive ones, and participate in the maintenance of immunological tolerance to their own antigens (autoantigens). Defects in B-cell tolerance, manifested, in particular, in the disruption of the repertoire of autoreactive B-cells, lead to the synthesis of autoantibodies. However, the significance of B-cells in the development of autoimmune diseases is not limited to the synthesis of autoantibodies. It has been established that B-cells (like T-cells) participate in the regulation of the immune response both normally and against the background of the development of immune-inflammatory 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 associated with the peculiarities of B-cell differentiation. In the process of maturation of stem cells into plasma cells, B-lymphocytes undergo several successive stages. Each stage of B-cell differentiation is characterized by the presence of certain membrane molecules. 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 cells. In addition, CD20 is not released from the B-lymphocyte membrane and is absent in the circulating (soluble) form, which could potentially interfere with the interaction of anti-CD20 antibodies with B-cells. The ability of rituximab to eliminate B cells is believed to be mediated by several mechanisms, including complement-dependent and antibody-dependent cellular cytotoxicity, as well as induction of apoptosis.

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Indications for use and dosage

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

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

According to Edwards, who has extensive experience with long-term use of rituximab, indications for repeated administration of the drug so far include pronounced signs of exacerbation or an increased concentration of CRP by 50% of the initial level (as well as IgM RF titers) plus increased intensity of morning stiffness and joint pain.

Indications for repeated courses of rituximab therapy:

• residual activity: DAS 28 greater than 3.2;
• reactivation of the disease at low activity; increase in DAS 28 to 3.2.

Mechanism of action of rituximab

In patients with rheumatoid arthritis, rituximab administration results in almost complete (over 97%) depletion of the B-cell pool (CD19) in the bloodstream within a few days. This effect persists in the vast majority of patients for at least 6 months. Along with a decrease in the number of synovial B cells, a decrease in synovial membrane infiltration by T cells (CD3) and monocytes/fibroblasts (CD68) was noted. However, no clear relationship was found between the number of B cells and the efficacy of rituximab therapy. 80% of rituximab-resistant B cells are CD27-positive, which is typical of memory B cells. Regeneration of CD27 B lymphocytes is slow, and the number of these cells does not reach 50% of the initial level for more than 2 years after drug infusion. Repeated courses of rituximab treatment result in a progressive decrease in the number of CD27 B cells. Since the concentrations of "pathogenic" autoantibodies (RF, anti-cyclic citrullinated peptide (anti-CCP) are significantly reduced, it is assumed 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 the function of monocytes/macrophages: a decrease in the synthesis of TNF-a and an increase in the production of IL-10, which has anti-inflammatory activity. The effectiveness of rituximab in rheumatoid arthritis correlates with a decrease in the concentration of biological markers reflecting the severity of autoimmune reactions and inflammation (titers of RF 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 of procollagen type 1 and osteocalcin).

In the pathogenesis of SLE, the violation of the mechanisms of suppression of the autoimmune response is of particular importance. Against the background of treatment with rituximab, the change in the number of CD4 / CD25 T-regulatory cells and their suppressor function, capable of suppressing the proliferation of autoreactive lymphocytes, was assessed. The number of CD4 / CD25 T regulatory cells significantly increased, and their suppressor activity increased on the 30th and 90th days after treatment with rituximab. With ineffective therapy with rituximab, the number of CD4 / CD25 T-regulatory cells slightly increased, and their function remained unchanged. An increase in the level of BoxR3 (a specific marker of T-regulatory cells) was noted in patients in remission after treatment with rituximab. The development of remission was accompanied by a decrease in the activation of T-helpers and ANF titers. 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 damage, a correlation was established between the onset of the clinical effect of rituximab and suppression of expression of CD40 and CD80, involved in costimulation of T-cells. Against the background of treatment with rituximab, a decrease in the levels of antibodies (to nucleosomes and to DNA), involved in the immunopathogenesis of SLE, was noted.

Pharmacokinetics

The pharmacokinetic parameters of rituximab (Cmax, AUC, T1/2, Tmax, clearance, volume of distribution at steady state) were independent of whether the drug was administered alone or in combination with cyclophosphamide or methotrexate.

In men, the volume of distribution is larger than in women and the drug is eliminated faster.

Rapid, almost complete depletion of B cells (CD191) was observed with rituximab 1000 mg x 2. In most patients, the B cell population began to recover 6 months after rituximab treatment; only in a small proportion of patients did the decrease in the number of peripheral B cells become protracted (2 years after a single course of treatment, the number of B cells remained low). No direct relationship was established between the degree of depletion of the B cell pool and the effectiveness of treatment or exacerbation of the disease.

Rheumatoid arthritis and rituximab

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

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

According to radiographic data, combination therapy with rituximab and methotrexate suppresses the progression of joint destruction in patients with inadequate response to standard DMARDs and TNF-a inhibitors (according to the criteria of the American College of Rheumatology and the European League Against Rheumatism). Slowing down of joint destruction does not depend on the clinical effect.

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

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

In patients with ineffective TNF-a inhibitors, rituximab suppresses joint inflammation activity to a greater extent (reduction 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 one TNF inhibitor than to several TNF inhibitors, so earlier administration of rituximab is advisable.

There are no studies examining the effectiveness of repeated rituximab treatment in patients with no or insufficient response to the first course of treatment. Prescribing TNF-a inhibitors is not recommended if rituximab therapy is ineffective, as this is associated with a high risk of infectious complications, especially with a decrease in the level of B cells in the peripheral blood.

Contraindications

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

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Side effects

Treatment with rituximab is well tolerated and rarely results in the development of side effects requiring interruption of therapy.

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

The risk of infectious complications in patients receiving rituximab was slightly higher than in patients receiving placebo. No increase in the risk of opportunistic infections (including tuberculosis), reactivation of viral infections, or the occurrence of cancer was observed.

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

A reduction in the overall incidence of adverse events and infusion reactions was noted. Although the incidence of infectious complications increased somewhat (which correlated to a certain extent with the decrease in the concentration of immunoglobulins IgG and IgM), the incidence of serious infections did not increase.

The safety of rituximab in patients with rheumatoid arthritis who are carriers of hepatitis B and C viruses is unknown. Rituximab has been successfully used in hepatitis C virus carriers - patients with lymphoma without antiviral prophylaxis and hepatitis B with lamivudine. However, fulminant hepatitis has been reported in hepatitis B carriers receiving rituximab. No increased risk of infectious complications has been observed in HIV-infected patients with lymphomas. Vaccination is less effective in patients receiving rituximab, so it should be administered before rituximab is prescribed.

Evaluation of treatment effectiveness

The effectiveness of treatment is assessed using standardized criteria (DAS index). Treatment is considered effective when DAS 28 decreases by more than 1.2 from the initial value and DAS 28 reaches less than 3.2.

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Systemic lupus erythematosus

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

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

All this indicates the prospects for the use of rituximab in the development of critical conditions of SLE that threaten the lives of patients.

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

Idiopathic inflammatory myopathies

Treatment of polymyositis and dermatomyositis is largely empirical and usually consists of a combination of GC and immunosuppressants. For many patients, this therapy is not effective enough, so the use of rituximab in IMM is of undoubted interest. A study of the efficacy of rituximab was conducted in seven patients with dermatomyositis (six of whom were resistant to a number of immunosuppressive drugs). Patients received one rituximab infusion per week for a month without further treatment with this drug. Observation was carried out for 1 year. As a result, all patients showed clinical and laboratory improvement. The maximum effect was achieved 12 weeks after the first injection and correlated with a decrease in CD20 B cells. Subsequently, 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 skin rash, alopecia, and an increase in forced vital capacity were noted. The drug was well tolerated. Other authors used rituximab (2 infusions of 1000 mg twice with an interval of 14 days) in three patients with refractory dermatomyositis. During the treatment, normalization of CPK (on average after 4.6 months) and an increase in muscle strength were observed; as a result of the therapy, it was possible to reduce the dose of glucocorticosteroids and methotrexate. According to clinical observations, rituximab was successfully used in patients with antisynthetase syndrome and interstitial pulmonary fibrosis. During treatment with rituximab (375 mg/m2 ^, four injections per month), an improvement in the diffusion capacity of the lungs was noted (4 months after the start of treatment), which made it possible to reduce the dose of glucocorticosteroids.

Systemic vasculitis

Currently, three pilot prospective studies (a total of 28 patients) and four retrospective observations (35 patients) have been conducted, indicating the efficacy of rituximab in systemic vasculitis associated with antibodies to neutrophil cytoplasm (ANCA). The efficacy of rituximab is high and reaches 90%. Complete remission was achieved in 83% of patients, which was maintained in the absence of therapy or against the background of taking small doses of glucocorticosteroids. Exacerbation developed in 14 patients (after 9-21 months), successfully stopped by repeated administration of rituximab. Rituximab treatment was carried out both against the background of cytotoxic therapy and as monotherapy (in combination with small doses of glucocorticosteroids). It should be emphasized that a potential limitation for the use of rituximab as monotherapy is the development of a complete clinical response 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 early manifestations of primary Sjogren's syndrome and Sjogren's syndrome associated with MALT (mucosa-associated lymphoid tissue) lymphoma (a total of 37 patients) indicate high efficacy of the drug against systemic manifestations of the disease. A subjective decrease in symptoms of dryness and improvement in the function of the salivary glands were also noted. These data allowed us to formulate indications for the use 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 antichimeric antibodies) is higher than in other diseases. In Sjogren's syndrome, rituximab is preferably prescribed not as 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 rightfully be considered a major achievement in rheumatology at the beginning of the 21st century. At present, the place of rituximab in the treatment of rheumatoid arthritis is only just beginning to be studied. In the near future, it is necessary to optimize treatment tactics (to determine the minimum effective dose, the optimal time for repeated courses, the possibility of combination therapy with other DMARDs and biological agents), to determine the "predictors" of effectiveness and resistance to therapy (including secondary ineffectiveness), the possibility of using rituximab in early rheumatoid arthritis and as the first biological drug. There is no complete answer to questions about the risk of developing side effects (infectious complications, malignant neoplasms, etc.) against the background of long-term depletion of the B-cell pool, about the optimal vaccination strategy, about the safe use of rituximab in combination with other biological agents, about the possibility of using rituximab in women during pregnancy and lactation, as well as in patients with a history of malignant neoplasms.