Introduction
The introduction of genetically engineered biological drugs (GEBPs) into the treatment of rheumatoid arthritis (RA) has significantly improved results in patients who did not respond to traditional basic therapy.
However, the use of these drugs is associated with a significant increase in treatment costs. To date, the patents on most biologically active drugs used in rheumatology have expired, allowing these important drugs to be reproduced. The appearance of generic drugs on the market, as experience shows, leads to a significant reduction in treatment costs [1]. However, the reproduction of GIBP has a number of significant features. The reproduced low-molecular drug (generic) exactly repeats the chemical structure of the original. For protein molecules, such as GIBPs, the coincidence of the amino acid sequence does not guarantee the similarity of the three-dimensional structure of the protein, which determines its pharmacological properties. Therefore, when reproducing a biosimilar, a biosimilar is required not only to demonstrate the similarity of key chemical and physicochemical characteristics, but also to confirm therapeutic equivalence. To this end (as opposed to generics), putative biosimilars are studied in large phase III randomized clinical trials (RCTs) [1].
The first biosimilar for the treatment of RA (infliximab) was approved by the European Medicines Agency (EMA) in 2013 [2]. Since then, the number of biosimilar biosimilars has rapidly increased and they now play a significant role in the treatment of rheumatic diseases.
The drug rituximab, which is a chimeric monoclonal antibody against the surface molecule CD20 of B lymphocytes, was registered by the EMA for the treatment of RA in 2006. In 2021, the first Russian biosimilar of the drug Acellbia® was registered in the Russian Federation for the treatment of RA and ANCA-associated systemic vasculitis . The full development cycle of the drug, as well as its production, is carried out in the Russian Federation by BIOCAD. The large-scale 48-week phase III BIORA study did not reveal differences in the clinical efficacy and safety of the biosimilar Acellbiy® and the originator drug MabThera®, and revealed no effect of switching from one drug to another on the parameters of efficacy, safety and immunogenicity [3]. However, given the biological nature of the drugs, such differences are possible. Therefore, the accumulation of comparative data, especially in real practice, is of great interest.
Target
research: to evaluate the effectiveness and safety of switching from MabThera® (the original drug rituximab) to its biosimilar (Acellbia®) in patients with RA in real clinical practice.
Material and methods
Data from the Moscow Unified Register of Arthritis (MERA) was analyzed. The registry monitors patients receiving biologically active drugs or targeted synthetic anti-inflammatory drugs at the expense of budget funds, living in Moscow and giving informed consent to participate in the study.
The following patients were selected for analysis:
meeting the RA criteria of the American Rheumatism Association (ARA) 1987 or the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010;
who received at least one course of treatment with the original drug rituximab and subsequently switched to treatment with a biosimilar;
who made at least one visit during treatment with the original drug rituximab after at least 6 months. after it started;
who made at least one visit during treatment with a biosimilar after at least 6 months. after it started.
Rituximab was administered as one or two (2-week intervals) infusions with a single dose of 500–1000 mg and intravenous premedication with methylprednisolone (100–250 mg).
The effectiveness of the drugs was assessed based on the data from the last completed visit during treatment with the corresponding drug. At each visit, patients were asked using a questionnaire about all clinically significant events that had occurred since the previous visit. Data on adverse events (AEs) were analyzed for the entire period of use of the corresponding drug. Reports of acute respiratory illnesses were excluded from the analysis.
During the visits, all patients underwent a standard examination, which included, among other things, determination of the number of swollen joints and the number of painful joints (NBP), a study of erythrocyte sedimentation rate, and C-reactive protein. The effectiveness of treatment was assessed using the DAS28 composite index and indicators of the HAQ-DI (Health Assessment Questionnaire disability index), RAPID-3 (Routine Assessment of Patient Index Data 3) questionnaires.
Patients with missing data were excluded from the analysis. The IBM SPSS Statistic 22 (2013) program was used to process the data. To assess the significance of differences in quantitative indicators before and after the switch, the T-test for related samples was used. The significance of the dynamics of qualitative indicators was assessed using Fisher's exact test. The significance of changes in drug dose was assessed using the nonparametric Pearson correlation method.
results
The study included 46 outpatients who were prescribed the original drug rituximab at the beginning of treatment, and then the patients were switched to a biosimilar. The average duration of therapy on the original drug rituximab before switching was 36.8±26.8 months. The average follow-up period for patients on biosimilar therapy was 12.2±6.18 months. The follow-up period for treatment with the original drug rituximab and the biosimilar was 141 and 46 patient-years, respectively (total volume - 187 patient-years). 20 patients (43.5%) had previously reported ineffectiveness or intolerance to other GEBDs .
The proportion of patients receiving concomitant glucocorticoid therapy was 19.6% (9 patients), 43.5% (20 patients) received methotrexate in various dosages. The clinical characteristics of the patients are shown in Table 1. The dose of rituximab changed during treatment: it was reduced in the case of sustained low disease activity or remission and could be increased in the case of an increase in the level of disease activity above the target during treatment. Table 1 shows the doses of rituximab at the time of the last completed visit at which the clinical effectiveness of treatment was assessed. There was a statistically significant reduction in the dose of rituximab after switching (p=0.002).
When assessing the dynamics of DAS28, HAQ-DI and RAPID3 indicators, it was found that switching from the original drug rituximab to a biosimilar was not accompanied by a decrease in the effectiveness of treatment (Table 2). Moreover, the numerically average values of these activity and functional capacity indices were slightly lower during ongoing biosimilar therapy. However, no significant differences were recorded. There was a statistically significant increase in the number of patients with low disease activity (DAS28 <3.2) and remission (DAS28 <2.6). The proportion of people with low disease activity after switching increased from 39.1% to 52.2%, and the percentage of patients in remission - from 17.4% to 23.9% (see Table 2). The increase in the rate of positive response to treatment is apparently associated with the duration of use of rituximab in general, and not with switching from one drug to another.
No patient had a biosimilar discontinued due to lack of efficacy.
A brief description of the observed AEs is given in Table 3. During the period of use of the original drug rituximab, 13 AEs were recorded in the analyzed patients (incidence - 9.22 per 100 patient-years) in 5 patients (10.9%), of which 2 were regarded as serious. During treatment with the biosimilar, 5 AEs (10.9 per 100 patient-years) were observed in 4 patients (8.7%), none of which were considered serious. There were no significant infusion reactions, AEs requiring treatment discontinuation, or deaths.
Causes of development of ankylosing spondylitis
The exact causes of the development of ankylosing spondylitis are still unknown. As with other rheumatic diseases, the underlying cause is a malfunction of the immune system. The body's protective functions are directed against the cells and tissues of the body and thus cause inflammatory reactions. Ankylosing spondylitis is one of the autoimmune diseases.
Experts associate it in specific cases with genetic inheritance. Hereditary predisposition underlies the occurrence of ankylosing spondylitis. If one of the parents has ankylosing spondylitis, the risk of the child's disease is estimated at 4 to 15%.
Factors provoking spondyloarthritis
Risk factors contributing to the development of spondyloarthritis:
- frequent hypothermia;
- infectious diseases;
- hormonal disorders;
- chronic intestinal inflammation;
- inflammatory disease of the genitourinary organs.
The cause may also be injury to the hip or spinal column.
Discussion
In the present study, based on the analysis of data from the registry of patients with RA, the preservation of the clinical effect was demonstrated after switching patients from therapy with the original drug rituximab to a biosimilar. Disease activity and functional capacity scores at least did not worsen after the switch.
Moreover, the proportion of patients achieving low disease activity and remission according to the DAS28 criterion has increased. Such dynamics cannot be considered as the superiority of the biosimilar over the original drug rituximab. It should be borne in mind that in all cases the biosimilar was used after the original drug. Across different cohorts, there was a decrease in disease activity and an increase in the proportion of patients achieving target activity over follow-up [3]. Such changes were observed previously in the MERA registry as a whole [4].
To assess the safety of a drug, real-world studies are the most valuable source. On the one hand, they tend to be longer and, as a result, may have a larger follow-up and may detect complications, the frequency of which increases with long-term treatment. Thus, in our study, the total observation volume was 187 patient-years (in the phase III RCT BIORA it was about 148 patient-years) [5]. On the other hand, RCTs typically have strict selection criteria that exclude patients at increased risk of AEs. Therefore, the safety profile in real practice may differ slightly from that in RCTs. The safety analysis did not reveal significant differences between the study drugs. The overall incidence of AEs was almost comparable.
Variants of spondyloarthropathies
Taking into account the localization and manifestation of the clinical picture, the following variants of the disease are distinguished:
- Central. In 50% of cases, the spine is affected (the sacroiliac joints are most often affected; the lumbar, thoracic and cervical spine are also affected).
- Peripheral. Develops at a young age up to 40 years. Joints
- can shoot out after an infection, the so-called Reiter's disease. Disease
- affects not only the spinal column, but also the knees, ankles, hip joints (the joints of the lower extremities are most often affected) and elbow joints (it can occur without the spine at all).
Additional studies identified extraskeletal manifestations separately. This is a complication of a long course of the disease without proper treatment. The process most often involves the kidneys, and IgA vasculitis develops.