Do antirheumatic drugs have good side effects? TNF-a inhibitors Determination of the level of TNF and its significance.

For citation: Nasonov E.L. Efficacy and safety of tumor necrosis factor-a inhibitors in rheumatoid arthritis // RMJ. 2008. No. 24. S. 1602

Rheumatoid arthritis (RA) is the most common inflammatory disease of the joints, with a prevalence of about 1% in the population, and economic losses for society comparable to ischemic disease hearts. The study of RA is of general medical importance, since it creates the prerequisites for deciphering the fundamental mechanisms of development and improving the pharmacotherapy of other common human diseases (atherosclerosis, diabetes 2 types, osteoporosis, etc.), pathogenetically associated with chronic inflammation.

The treatment of RA remains one of the most difficult problems in clinical medicine. In many patients, even early initiation of mono- or combination therapy with traditional DMARDs does not always slow down the progression of joint destruction, even despite the positive dynamics of clinical indicators of inflammation activity. All this was a serious incentive to improve approaches to the pharmacotherapy of RA, based on modern medical technologies and deciphering the fundamental mechanisms of the development of rheumatoid inflammation.

Of particular importance in the pathogenesis of RA and other chronic inflammatory diseases a person is given tumor necrosis factor (TNF)-a - the most well-studied representative of the group of so-called "pro-inflammatory" cytokines. TNF-a exhibits numerous "pro-inflammatory" effects (Fig. 1), which are of fundamental importance in the immunopathogenesis of RA.

The progress of biology and medicine at the end of the 20th century expanded the possibilities of pharmacotherapy for RA. Fundamentally new anti-inflammatory drugs have been developed medicines(drugs), united under the general term "genetically engineered biological preparations" . These primarily include TNF-a inhibitors, which block biological activity of this cytokine in circulation and on cellular level: chimeric (infliximab - IFN) and human (adalimumab - ADA) monoclonal antibodies to TNF-a and etanercept (ETN) (Fig. 2), which are considered as one of the most effective drugs for the treatment of RA.

ETN is a hybrid molecule consisting of a TNF receptor (P) with a molecular weight of 75 kD, connected to the Fc fragment of Ig 1 human (Fig. 2). The dimeric structure of FNOR in the ETN molecule provides a higher affinity of the drug for TNF-a, which, in turn, determines a more pronounced competitive inhibition of TNF-a activity compared to the monomeric soluble FNOR present in biological fluids. The presence of an IgG fragment in the ETH Fc molecule contributes to a longer drug life in circulation than monomeric FNOR. ETN competitively inhibits the binding of TNF-a and TNF-b (lymphotoxin-a) to membrane FNOR, thereby abolishing the biological effect of TNF, and its effectiveness has been proven in various experimental models of inflammation, including arthritis resembling human RA.

The pharmacokinetics of ETN does not depend on the sex and age of patients, does not change during combination therapy with methotrexate (MT). There is no need for dose titration in case of kidney damage or liver failure. clinically significant drug interactions ETN with digoxin and warfarin was not observed.

The high efficacy and acceptable safety of ETN has been proven in a series of randomized placebo-controlled trials (RPCTs) and their open phase, in their meta-analysis and in the process of long-term use of the drug in real clinical practice (data from national registries). Let's consider the most important of them.

Important results were obtained in the TEMPO (Trial of Etanrecept and Methotrexate with radiological patients outcome) study, which included 682 patients with significant RA (mean duration of illness 6 years). The open phase of this study and the analysis of the results obtained are ongoing. In the controlled phase of the study, patients were randomized into 3 groups. Group 1 consisted of patients receiving ETN monotherapy, group 2 - patients receiving MT monotherapy (up to 20 mg per week), group 3 - patients receiving combination therapy of ETN and MT. It was found that the effectiveness of combination therapy (ACR, DAS, DAS28 and HAQ) and the frequency of remission was significantly higher than both ETN and MT monotherapy after 24, 52 and 100 weeks. therapy (p<0,01 во всех случаях) . Комбинированная терапия более эффективно, чем монотерапия, тормозила деструкцию суставов. Частота побочных эффектов, включая инфекционные осложнения, в сравниваемых группах больных не отличалась.

We recently analyzed the results of a 4-year follow-up of patients who continued to participate in the open-label phase of the TEMPO study, among which 55 patients added ETN to MTX, 76 patients added MTX to ETN, and 96 continued combination therapy with ETN and MTX. . At baseline, patients treated with MT or ETN monotherapy had moderate disease activity, while patients treated with combination therapy had low disease activity. By the end of the 4th year, the remission rate in patients of group 1 increased from 23.6 to 41.8% (p<0,01), у пациентов группы 2 - с 26,7 до 36,8% (p>0.05), and in patients of group 3 - from 37.6 to 50% (p<0,01).

These data convincingly indicate the high efficiency of the combination therapy of ETN and MT during long-term treatment in patients with RA, which persists and even increases by the end of the 4th year of continuous therapy. In addition, when MT is not effective enough, the addition of ETN allows to achieve a good clinical effect, which expands the therapeutic possibilities of RA pharmacotherapy in the long term.

Although MTX is regarded as the “gold standard” for RA treatment, many patients experience inadequate treatment, contraindications to treatment, or side effects that require MTX to be discontinued. In some patients, sulfasalazine (SULF), which is one of the most effective DMARDs, can be a good alternative to MT. This served as the basis for conducting an RCT ( The Etanercept Study 309 ), which included 254 patients randomized (2:1:2) into 3 groups: SULF monotherapy (n=50), ETN monotherapy (n=103) and combined ETN and SULF therapy (n=101) . Inclusion criteria for the study were high disease activity (≥6 painful and swollen joints, morning stiffness ≥45 min, ESR≥28 mm/h, CRP≥20 mg/L) despite SULF treatment. ETN monotherapy and combined ETN and SULF therapy were found to be significantly more effective than SULF monotherapy according to the ACR criteria (p<0,01). При этом различия в эффективности ЭТН и СУЛЬФ были достоверны уже через 2 нед. после начала терапии (p<0,01). Значение индекса DAS28 к 24 нед. в группе пациентов, получавших СУЛЬФ, уменьшилось на 19,6%, в то время как в группе, получавшей монотерапию ЭТН - на 48,2%, а комбинированную терапию - на 49,7%. Положительная динамика имела место и в отношении параметров качества жизни (p<0,01), причем эти различия были достоверны уже через 2 нед. лечения. Частота побочных эффектов, таких как головная боль, тошнота астения, была несколько выше в группе больных, получавших комбинированную терапию (p<0,05), в то время как инфекционных осложнений и инъекционных реакций - у пациентов, получавших монотерапию ЭТН (p<0,05).

In an open prospective study by O`Dell J.R. et al. evaluated the effectiveness of combination therapy for ETN with the most commonly used DMARDs, such as SULF (n=50), hydroxychloroquine (n=50), and intramuscular gold salts (n=19), in patients who failed monotherapy with these drugs. In all groups of patients, there was a significant decrease in clinical activity according to the ACR20, 50 and 70 criteria (by 24 and 48 weeks) without a significant difference between the groups. In general, a clinical response according to ACR20 was observed by 24 weeks. in 67%, and by 48 weeks. - in 54% of patients. The incidence of side effects was similar to those obtained in other studies, the rate of treatment interruption due to side effects was 9%.

Of undoubted interest are the data of Finckh A. et al. who performed a detailed analysis of a cohort of patients treated with TNF-a inhibitors and other DMARDs (Swiss Clinical Quality Management in Rheumatoid Arthritis database). A total of 1218 patients (out of 2097 included in the database) were included in the analysis, among whom 842 received TNF-α inhibitors in combination with MTX (31% ETN), 260 in combination with leflunomide (32% ETN) and 116 with other DMARDs (45% ETN). At the same time, there were no significant differences between the compared groups of patients both in terms of the duration of treatment, efficacy (clinical and radiological), and the frequency of side effects.

These data indicate the potential for monotherapy with ETN (when it is impossible to prescribe MTX) or combination therapy with MTX and other DMARDs.

Given the current concept of RA pharmacotherapy associated with early aggressive treatment of DMARDs, including biological agents, combined with careful evaluation of efficacy aimed at achieving remission, studies regarding the use of ETN in early RA are of particular interest (Table 1).

More recently, a multicenter international COMET (Combination of methotrexate and etanercept) study was completed, which included patients (n = 542), with early (duration 3 months - 2 years) active (DAS28> 3.2 and an increase in ESR> 28 mm/hour of RA or CRP>20 mg/l) who did not receive MTX. At the same time, 92% of patients had high disease activity (DAS28>5.1). Patients were randomized into 2 groups. The first included 274 patients who received ETN (50 mg/week) and MT, and the second included MT only. Depending on the effect (number of painful and swollen joints), the dose of MT was increased to 20 mg/week. within 8 weeks, starting with 7.5 mg / week. The duration of treatment was 52 weeks. The results obtained are summarized in Table 2. By the end of the study, remission occurred in 50% of patients receiving combined therapy with ETN and MTX and only in 28% of patients receiving MTX monotherapy (p<0,0001), а низкая активность - соответственно у 64 и 41% пациентов (p<0,001). Хороший/умеренный ответ по критериям EULAR отмечен у 94% получавших комбинированную терапию и у 80% пациентов, получавших монотерапию (p<0,001). При этом различия в эффективности лечения были высокодостоверны в течение всего периода наблюдения, начиная со 2 нед. Важно, что среди получавших комбинированную терапию и имевших хороший/умеренный ответ по критериям ЕULAR к 12-й неделе, у 94% пациентов эффект сохранялся до 24 нед. При этом среди пациентов, не отвечающих на комбинированную терапию к 12-й нед., у 54% развился хороший/умеренный эффект (EULAR) к 24 нед., а у 27% - клиническая ремиссия. У пациентов с высокой активностью отсутствие рентгенологического прогрессирования имело место у 80% в группе комбинированной терапии и у 59% получавших монотерапию МТ (p<0,0001). Комбинированная терапия существенно превосходила монотерапию по влиянию на параметры качества жизни (HAQ)

Despite the fact that RA most often affects middle-aged people, 10-33% of patients with RA are older than 65 years. However, data regarding the efficacy and safety of TNF-a inhibitors in older patients are limited, as these patients are generally not included in RCTs. Fleischman R.M. et al. retrospectively analyzed the results of several RCTs and open studies, which included 1128 patients, 197 (17%) of them over 65 years of age. There were no significant differences in the efficacy and toxicity of ETG therapy in the compared groups. Thus, after the first year of therapy, the ACR20 response occurred in 69% of patients under 65 years of age and in 66% of patients over 65 years of age, ACR50 - in 40% of patients in both groups, and ACR70 - in 17%. The frequency of side effects was similar. Thus, The efficacy and tolerability of ETN treatment in elderly patients was very good during 6 years of follow-up. .

In another study by the same group of authors, patients from the TEMPO study were also included in the analysis. As in the previous analysis, there were no differences in efficacy depending on the age of the patients. After 6 months the effect according to ACR20/50/70 was 70%, 45%/15% in patients older than 65 years, and 65%/39%/1% in patients younger than 65 years, and after 72 months. respectively 79%/47%/11% and 73%/53%/29%. The tolerability of therapy and the frequency of side effects in the elderly and young people were similar.

Given the data on the high incidence of comorbidities in patients with RA, which can have a significant impact on the prognosis, the RPCT conducted by Weisman M.H. is of undoubted interest. et al. . This study (16 weeks) specifically examined the impact of comorbidities on the safety of ETN treatment. The study included 535 patients with at least one comorbid disease (diabetes mellitus, COPD, recent pneumonia or recurrent infections). It was found that in the group treated with ETN, there is a small statistically non-significant increase in the incidence of severe side effects (8.6% vs 5.9%) in patients with diabetes (RR=1.34) and COPD (RR=1.58) . The incidence of infectious complications was similar (43.4 on placebo vs 39.8% on ETN). Thus, the presence of comorbid diseases does not significantly affect the safety of ETN treatment and is not a contraindication for its use.

Recently, Klareskog L. et al. analyzed the results of long-term use of ETN in patients participating in the open phase studies of this drug in the United States and Europe. In total, the analysis included 2054 patients with early and advanced RA, refractory to DMARDs (9763 patient-years), who took ETN for 3-10 years. It has been established that the effectiveness of ETN is maintained for a long time: ACR20 - 70-76% of patients, ACR50 - 48-58% and ACR70 - 31-37%.

Treatment tactics

According to the recommendations, ETN should be prescribed at a dose of 25 mg 2 times a week, which ensures optimal pharmacokinetic characteristics of the drug. However, later it was shown that ETN can be used at a dose of 50 mg once a week. . With the ineffectiveness of ETN in a standard dose, increasing the dose (50 mg 2 times a week) does not lead to an increase in the effect.

In terms of optimizing RA therapy using ETN (including from the point of view of pharmacoeconomic prospects), the study of Kavanaugh A. et al. , which retrospectively analyzed the data of the TEMPO study in order to clarify the possible timing of the development of the effect during the treatment of ETN. According to the authors, during the treatment of ETN and MT, there is an increase in the number of "responders" to therapy by 24 weeks. compared with 12 weeks: 37.5% of patients on ACR20, 46.8% on ACR50 and 51.1% on ACR70. Thus, to make a decision on the tactics of treating ETN, it is advisable not earlier than after 24 weeks. therapy.

With the expansion of the use of TNF-a inhibitors in clinical practice, the question of the tactics of managing patients who “do not respond” to treatment with TNF-a inhibitors becomes more and more relevant. The materials of observational studies and national registries of genetically engineered biological products indicate that if INF is ineffective, switching to ETN (switch) allows obtaining a clinical effect in patients with primary and secondary inefficiency or avoiding the development of side effects in patients who have reason for discontinuation of treatment were toxic reactions.

However, according to a prospective study by Finckh A. et al., anti-B cell therapy (rituximab) is more effective than switching to another TNF-a inhibitor (including ETN), especially if this is due to ineffectiveness. TNF-a inhibitors. These data are in good agreement with RCTs that provide convincing evidence of high efficacy of rituximab in patients not responding to treatment with TNF-a inhibitors. Based on a detailed analysis of the totality of available evidence, the NICE panel currently does not recommend switching TNF-a inhibitors and favors rituximab.

Side effects

In general, ETN is well tolerated even with long-term use, and the frequency of treatment interruption due to side effects according to RCTs and open studies does not differ from comparison groups, with the exception of injection reactions, which develop more often during ETN treatment. They usually occur in the first months of therapy, last 3-5 days, but rarely cause interruption of treatment. Obviously, ETN does not cause infusion reactions, which is an advantage of this drug compared to INF, which is administered intravenously.

There was no increase in the frequency of side effects when prescribing ETN in the dose range from 10 mg and 25 mg 2 times a week. up to 50 mg 1 time per week. and duration of therapy (up to 9 years), which is similar to that in patients who received the drug for 1 year.

However, an analysis of the results of the use of ETN and other TNF-a inhibitors in real clinical practice drew attention to the problem of rare side effects, the main of which are an increase in the risk of infectious complications, including tuberculosis, and opportunistic infections, malignant neoplasms (lymphoma), autoimmune syndromes, demyelinating diseases of the nervous system, congestive heart failure and some others. They are considered class-specific side effects of all TNF-a inhibitors. However, the positive effects of TNF-a inhibitors significantly outweigh the disadvantages of therapy associated with toxicity. In addition, the severe course of RA, which is an indication for the appointment of TNF-a inhibitors, is associated with an unfavorable life prognosis, including due to an increased risk of infectious and cardiovascular complications. Traditional DMARDs can also cause adverse reactions with greater frequency and adverse effects than TNF-a inhibitors.

Infectious complications

Analysis of data from observational and post-registration studies indicates an increased risk of bacterial infections during treatment with TNF-a inhibitors (Table 3), especially during the first 6 months. treatment with these drugs. At the same time, according to a number of studies, the risk of developing infectious complications is higher during treatment with INF than with ETN.

From the point of view of the safety of treatment with TNF-a inhibitors, the development of tuberculosis is of particular clinical importance, which is primarily associated with the reactivation of latent tuberculosis infection. At the same time, it was found that the risk of developing tuberculosis infection during ETG treatment is significantly lower than that of INF and ADA.

For example, according to the British Biological Registry, which includes 9882 patients treated with TNF-a inhibitors (5265 patients - ETN, 3569 patients - INF and 2511 patients - ADA) and 2883 patients treated with standard DMARDs, TB infection was diagnosed in 29 patients ( all received TNF-a inhibitors). When compared with ETN (RR = 1.0), the risk of developing tuberculosis was 2.84 for INF and 3.53 for ADA. Disseminated tuberculosis developed in 1 patient treated with INF and 4 patients treated with ADA.

Similar results were obtained in a multicenter prospective 3-year study ( RATIO ) conducted in France, according to which the overall incidence of tuberculosis during treatment with TNF-a inhibitors was 39.3/100,000 patient-years, which was significantly higher than in the population - 8.7/100,000 patient-years. At the same time, during ETN treatment, the infection rate was only 6.6/100,000 patient-years, while with INF and ADA it was 71.5/100,000 patient-years. Preliminary analysis showed that risk factors for TB included age (RR=1.04), residence in endemic areas (RR=7.2), and use of INF and ADA compared to ETN (RR=10.05; p=0.006 and RR=8.63; p=0.02, respectively).

It is believed that the development of tuberculosis soon after the appointment of TNF-a inhibitors is associated with the reactivation of a latent infection, and at a later time - with the primary infection with mycobacterium. During treatment with INF, tuberculosis develops earlier (on average after 12-32 weeks) than ETN (on average after 18-79 weeks). In another study, it was shown that in patients treated with INF, 43% of cases of tuberculosis infection developed during the first 90 days of treatment, while only 10% of patients treated with ETN.

There are few studies on the effect of TNF-a inhibitors on the course of infection with hepatitis B and C virus. It is believed that TNF-α inhibitors can, on the one hand, slow down the clearance of the hepatitis B virus, but, on the other hand, suppress liver inflammation caused by the hepatitis C virus. There is evidence of a beneficial effect of ETN (in combination with interferon-a and ribavirin) on the course of hepatitis C virus infection. However, in HCV carriers treated with ETN (and other TNF-a inhibitors), liver enzyme levels should be monitored more closely.

Demyelinating diseases

An association between treatment with TNF-a inhibitors and the development of demyelinating diseases of the nervous system is highly probable, although not rigorously proven. Among 77,152 patients treated with ETN, 17 cases of demyelinating diseases were identified, which is 31 cases per 100,000 patient-years, while in the general population the incidence of this pathology is 4-6 cases per 100,000 patient-years. . Therefore, the appointment of TNF-a inhibitors in patients with a history of demyelinating diseases is not recommended.

The cardiovascular system

Given the fundamental role of TNF-a in the development of heart failure, 2 RCTs (RENAISSANCE and RECOVER studies) were conducted to evaluate the effectiveness of ETN in this pathology. Both studies showed a slight trend towards increased mortality in patients treated with ETN. However, when summarizing the results of these studies (the RENEWAL study), there was no association between ETN treatment, the risk of mortality and the development of decompensation. Thus, although the role of TNF inhibitors (with the exception of high-dose IFN) in the development of heart failure has not been proven, in patients with heart failure or a decrease in left ventricular ejection fraction, it is recommended to prescribe ETN with caution and avoid prescribing high doses of TNF-α inhibitors.

Another aspect of this problem is associated with a high risk of developing early atherosclerotic vascular disease and related complications (myocardial infarction and stroke) in RA. In this regard, attention is drawn to the data that against the background of treatment with TNF-a inhibitors (including ETN), there is a decrease in the risk of developing cardiovascular accidents, primarily in patients who “respond” to treatment with these drugs.

Hepatotoxicity

The risk of hepatoxic reactions during treatment with TNF-a inhibitors is minimal, with most cases described against the background of taking INF. According to the analysis of the CORDONA database, there was no association between ETN treatment and an increase in liver enzymes, while a 2.5-fold increase in the risk of this complication was noted with the use of INF and ADA.

cytopenia

The development of cytopenia is extremely rare, but is the basis for monitoring the number of leukocytes, especially in combination therapy with ETN and myelotoxic drugs.

Autoimmune reactions

Against the background of treatment with TNF-a inhibitors, the development of autoimmune serological reactions (ANF, anti-DNA, antibodies to cardiolipin, nucleosomes and histone), very rarely lupus-like syndromes, is observed. In general, autoimmune reactions are significantly more likely to occur during treatment with INF than with ETN.

Malignant neoplasms

Data regarding the risk of developing malignant neoplasms (primarily lymphomas) during treatment with TNF-a inhibitors are contradictory. This is due to several circumstances. First, in RA patients who are indicated for the appointment of TNF-a inhibitors, there is an increased risk of developing lymphomas. Secondly, some drugs used in combination with TNF-a inhibitors for the treatment of RA have the ability to increase the risk of developing lymphomas.

An analysis of data from observational studies suggests that treatment with TNF-a inhibitors is associated with a small increase in the risk of melanoma and other skin malignancies (RR = 2.2 and 1.5, respectively). Thus, the issue of prescribing ETN in patients at risk of developing malignant neoplasms should be decided individually. Combination therapy with ETN and cyclophosphamide is not recommended as it may increase the risk of tumor development.

Literature
1. Nasonov E.L. Rheumatoid arthritis as a general medical problem. Therapist. Archive 2004; 5:5-7
2. Sigidin Ya.A., Lukina G.V. Rheumatoid arthritis. Moscow, ANKO, 2001, 328 pages
3. Nasonov E.L. VN Treatment of rheumatoid arthritis. Clinical guidelines. Almaz Publishing House, Moscow, 2006, 118 pages
4. Brown AK, Quin MA, Karim Z, et al. Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatiic drug-induced remission: evidence from an imaging study may explain structural progression. Arthritis Rheum 2006; 54: 3761-3673
5. Ferinstein GS. Evolving concept of rheumatoid arthritis. Nature 2003; 423:356-360
6.Beayert R; Fiers W. Tumor necrosis factor and lymphotoxin. In: Mire-Sluis AR, Thorpe R., editors. Cytokines. 1st ed. London: Academic Pr; 1998.pp. 235-60.
7. Feldman M., Brennan F., Maini R.N. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 1996; 14:397-440.
8. Nasonov EL. Pharmacotherapy of rheumatoid arthritis in the era of genetically engineered biological drugs. Therapeutic Archive, 2007, 5, 5-8
9. Nasonov E.L. Pharmacotherapy of rheumatoid arthritis - a look into the 21st century. Wedge. medicine 2005; 6:8-12
10. Nasonov EL. Treatment of rheumatoid arthritis: the current state of the problem. RMJ 2006; 14 (8); 573-577
11. Kuek A, Hazleman BL, Ostor AJK. Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. Postgrad Med J 2007; 83:251-269
12. Nasonov E.L. Tumor necrosis factor-a is a new target for anti-inflammatory therapy in rheumatoid arthritis. Wedge. Pharmacol. Therapy 2001;1:64-70
13. Nasonov E.L. Prospects for pharmacotherapy of inflammatory rheumatic diseases: monoclonal antibodies to tumor necrosis factor. RMJ, 2001, 9, 7-9.
14. Tracey D, Klareskog L, Sasso EH, et al. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Therapeut 2008; 117:244-279
15. Mohler KM, Torrance DS, Smith CA, et al. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol. 1993;151:1548-61.
16. Dhillon S, Lyseng-Williamson KA, Scott LJ. Etanercept. A review of its use in the management of rheumatoid arthritis. Drugs 2007; 67:1211-1241.
17. Korth-Bradley JM, Rubin AS, Hanna RK, et al. The pharmacokinetics of etanercept in healthy volunteers. Ann Pharmacother. 2000;34:161-4.
18. Moreland LW, Schiff MH, Baumgartner SW et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 1999;130:478-486
19. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340:253-9.
20. Kremer JM, Weinblatt ME, Bankhurst AD et al. Etanercept added to background methotrexate therapy in patients with rheumatoid arthritis, continued observation. Arthritis Rheum 2003; 48: 1493-1499
21. Moreland LW, Cohen SB, Baumgartner SW, et al. Long term safety and efficact of etanercept in patients with rheumatoid arthritis. J Rheumatol 2001; 28:1238-1244
22. Klareskog L, van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomized controlled trial. Lancet. 2004;363:675-81.
23. van der Heijde D, Klareskog L, Rodrigiez-Valvelde V, et al. Comparison of etanercept and metoptrexate, alone and combined, in the treatment of rheumatoid arthritis. Two-year clinical and radiographic results from the TEMPO study, a doble-blind, randomized trial. Arthritis Rheum 2006; 54:1063-1074
24. van der Heijde D, Klareskog L, Landewe R, et a. Disease remission and sustained halting of radiographic progression with a combination of etanercept and methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 2007; 56: 3928-3939
25. Landewe R, van der Heijde D, Klareskog L, et al. Disconnect between inflammation and joint destruction after treatment with etanercept and methotrexate with radiographic and patients ourcomes. Arthritis Rheum 2006; 54: 3119-3125
26. van der Heijde D, Burmester G, Melo-Gomes J, et al. The safety and efficacy of adding etanercept to methotrexate or methotrexate to etanercept in moderately active rheumatoid arthritis patients previously treated with monotherapy. Ann Rheum Dis 2008; 67:182-188
27. Kameda H, Ueki Y, Saito K, et al. The comparison of effecacy and safety between etanercept (ETN) plus methotrexate (MT) combonation therapy and ETN monotherapy in MTX-refractory Japanese patients with rheumatoid arthritis; 24-week results frpm JESMR study. Ann Rheum Dis 2008; 67 (Suppl II): 184
28. Klareskog L, Gaubitz M, Rodriguez-Valverde V, et al. A long-term, open-label trial of the safety and efficacy of etanercept (Enbrel) in patients with rheumatoid arthritis not treated with other disease modifying antirheumatic drugs. Ann Rheum Dis 2006; 65: 1578-1584
29. van Riel PLC, Taggat AJ, Sany J, et al. Efficacy and safety of combination etanercept and methotrexate versus etanercept alone in patients with rheumatoid arthritis with inadequate response to methotrexate: the ADORE study. Ann Rheum Dis 2006; 65: 1478-1483
30. van Riel PLC, Freundlich B, MacPeek D, et al. Patient-reported outcome in a trial of etanercept monotherapy versus combination therapy with etanercept and methotrexate for rheumatoid arthritis: the ADORE trial. Ann Rheum Dis 2008; 67:1104-1110
31. Combe B, Codreanu C, Fiocco U, et al. Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double-blind comparison. Ann Rheum Dis 2006; 65:1357-1362.
32. O'Dell JR, Petersen K, Leff R, et al. Etanercept in combination with sulfasalazine, hydroxychloroquine, or gold in the treatment of rheumatoid arthritis. J Rheumatol 2006; 33:213-218.
33 Finckh A, Dehler S, Gabay C et al. The effectiveness of leflunomide as co-therapy of TNF inhibitors in rheumatoid arthritis. A population based study. Ann Rheum Dis 2008; January 29 online.
34. Ikeda K, Cox S, Emery P. Biological therapy in early arthritis - overtreatment or the way to go? Arthritis Res Therapy 2007; 9:211
35 Machold KP, Nell VPK, Stamm TA, Smolen JS. Traditional DMARD therapy: is it sufficient: Arthritis Res Ther 2006;8:21 on lone
36 Bathon JM, Martin RW, Fleischmann RM, et al. Comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343:1586-93.
37. Genovese MC, Bathon JM, Martin RW et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcome. Arthritis Rheum 2002; 46; 1443-1450
38. Genovese MC, Bathon JM, Fleishmann RM, et al. Long term safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis. J Rheumatol 2005; 32:1223-1242
39. Weinblatt ME, Genovese MC, Moreland LW, et al. Efficacy and safety of over 9 years of etanercept (Enbrel) therapy in North American patients with early and long-standing rheumatoid arthritis. Amer Coll Rheum. Annual Sci Meet 2006 Nov 11-15; Washington D.C. (abst)
40. Baumgartner SW, Fleischmann RM, Moreland LW, et al. Etanercept (Enbrel) in patients with rheumatoid arthritis with recent oncet versus established disease improvement in disability. J Rheumatol 2004; 31: 1532-1557
41. Emery P, Breedveld F.C., Hall S, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active early, moderate to severe rheumatoid arthritis (COMET): a randomized, double-blind, parallel treatment trial. Lancet 2008; July 16, online.
42. Moots R, Kekow J, Sato R, et al Assessment of early treatment with combination of etanercept and methotrexate on functional status among patients with active rheumatoid arthritis: the COMET trial. Ann Rheum Dis 2008; 67 (Suppl II):188
43. Breedveld F, Emery P, Ferraccioli G, et al. Clinical response and remission at 12, 24, and 52 weeks with the combination of etanercept and methotrexate in the treatment of active rheumatoid arthritis in the COMET trial. Ann Rheum Dis 2008; 67 (Suppl II): 320
44. Anis A, Zhang W, Emery P, et al. Work-related outcome in early active rheumatoid arthritis: results from the COMET trial. Ann Rheum Dis 2008; 67 (Suppl II): 79
45. Fleishman RM, Baumgartner SW, Tindall EA, et al. Response to etanercept (Enbrel) in eldery patients with rheumatoid arthritis: a retrospective analysis of clinical trial results. J Rheumatol 2003; 30:691-696.
46 Bathon JM, Fleischmann RM, van der Heijde DM, et al. Safety and efficacy of etanercept treatment in eldery subjects with rheumatoid arthritis. J Rheumatol 2006; 33:234-243.
47. Weisman MH, Paulus HE, Burch FX, et al. A placebo-controlled, randomized, double-blind study evaluating the safety of etanercept in patients with rheumatoid arthritis and concominant comorbid diseases. Rheumatology 2007; 46:1122-1125.
48. Baumgatner SW, Fleishman RM, Moreland LW et al. Etanercept (Enbrel in patients with rheumatoid arthritis with early onset versus established disease: improvement in disability. J Rheumat 2004; 31: 1532-1537
49. Keystone E, Freundlich B, Schiff M, et al. Patients with moderate rheumatoid arthritis achive better disease activity states with etanercept treatment than patients with severe rheumatoid arthritis. Ann Rheum Dis 2008; 67 (Suppl II): 186.
50. Klareskog L, Moreland LW, Cohen SB, et al. Safety and efficacy of over 10 years of continuous etanercept therapy in patients with rheumatoid arthritis in North America and Europe. Ann Rheum Dis 2008; 67 (Suppl II): 175
51. Chen Y-F, Jobanputra P, Barton P, et al. A systemic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and economic of their cost-effectiveness. Helth Technol Assess 2006; 10 (42)
52. Cartlehner G, Hansen RA, Jonas BL, et al. The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systemic review and metaanalysis. J Rheumatol 2006; 33: 2398-2408
53 Alonso-Ruiz A, Pijoan JI, Ansuategui E et al. Tumor necrosis factor alpha drugs in rheumatoid arthritis: a systemic review and metaanalysis of efficacy and safety. BMC musculoskeletal disorders 2008; 9:52
54. Donahue KE et al. Systemic review: comparative effectiveness and harm of disease-modifying medications for rheumatoid arthritis. Ann Intern Med 2008; 148:124-131
55. Nixon R, Bansback N, Brennan A. The efficacy of inhibiting tumor necrosis factor alpha and interleukin 1 in patients with rheumatoid arthritis: a meta-analysis and adjusted indferect comparisons. Rheumatology 2007, online
56. Zink A, Strangfeld A, Schneider M, et al. Effectiveness of tumor necrosis factor inhibitors in rheumatoid arthritis in an observation cohort study. Arthritis Rheum 2006; 54: 3399-3407
57. Hyrich KM, Symmons DPM, Watson KD, et al. Comparison of the response to infliximab or etanercept monotherapy with the response to cotherapy with methotrexate or another disease-modifying antirheumatic drug in patients with rheumatoid arthritis. Results from the BSBR. Arthritis Rheum 2006; 54: 1786-1794
58. Krisatensen LE, Saxne T, Geborek P. The LUNDEX, a new index of drug efficacy in clinical practice. Results of a five-years observational study of treatment with infliximab and etanercept among rheumatoid arthritis patients in Southern Sweden. Arthritis Rheum 2006; 54:600-606
59. Keystone EC, Schiff MH, Kremer JM, et al. Once-weekly administration of 50mg etanercept in patients with active rheumatoid arthritis: Results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;50:353-63.
60 Weinblatt ME, Schiff MH, Ruderman EM, et al. Efficacy and safety of etanercept 50 mg twice a week in patients with rheumatoid arthritis who had a suboptimal response to etanercept 50 mg once a week. Arthritis Rheum 2008; 58: 1921-1930.
61. Ariza-Ariza R, Navarro-Sarabia F, Hernandez-Cruz B, et al. Dose escalation of the anti-TNF-a agents in patients with rheumatoid arthritis. A systemic review. Rheumatology 2006
62 Kavanaugh A, Klareskog L, van der Heijde D, et al. Improvement in clinical response between 12 and 24 weeks in patients with rheumatoid arthritis on etanercept therapy with or without methotrexate. Ann Rheum Dis 5 June 2008. on line
63. Lutt JR, Deodhar A. Rheumatoid arthritis. Strategies in the management of patients showing an Inadequate response to TNFa antagonist. drug 2008; 68:591-606
64. Iannone F, Trotta F, Montecucco C, et al. Etanercept maintains the clinical benefit achieved by infliximab in patients with rheumatoid arthritis who discontinued infliximab because of side effect. Ann Rheum Dis 2007; 66:249-252
65. Cohen G, Courvoiser N, Cohen JD, et al. The efficiency of switching from infliximab to etanercept and vice-versa in patients with rheumatoid arthritis. Clin Exp Rheumatol 2005; 23:795-800
66. Di Poi E, Perrin A, Morassi MP, et al. Switching to etanercept in patients with rheumatoid arthritis with no response to infliximab. Clin Exp Rheumatol 2007; 25:85-87
67. Haraoui B, Keystone EC, Thorne JC, et al. Clinical outcome of patients with rheumatoid arthritis after swithing from infliximab to etanercept. J Rheumatol 2004; 31:2356-2359
68. Cantini F, Niccoli L, Porciello G, et al. Switching from ingliximab or adalimumab to etanercept 500 mg/once weekly in resistant or intolerant patients with rheumatoid arthritis. Arthritis Rheum 2005; 52 (Suppl 9): S384 (abst)
69. Buch MH, Bingham SJ, Bejarano V, et al. Therapy of patients with rheumatoid arthritis: outcome of infliximab failures switching to etanercept. Arthritis Rheum 2007; 57:448-453
70. Koike T, Harigai M, Inokuma S, et al. Safety and effectiveness of switching from infliximab to etanercept in patients with rheumatoid arthritis: results from a large Japanese post marketing surveillance. Ann Rheum Dis 2008; 67: (Suppl II):181
71 Finckh A, Ciurea A, Brulhart L, et al. B cell depletion may be more effective than switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis patients with inadequate response to anti-tumor necrosis factor agents. Arthritis Rheum 2007; 56: 1417-1423
72 Finckh A, Ciurea A, Brulhart L, et al. Which subgroup of rheumatoid arthritis patients benefit most from switching tp Rituximab versus alternative anti-TNF agents after previous failure to anti-TNF agents? Ann Rheum Dis 2008; 67 (Suppl II):
73. Cohen SB, Emery P, Greenwald MW, et al. Rituximab for theumatoid arthritis refractory to anti-tumor necrosis factor therapy. Results of multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006; 54: 2793-2806
74. Rheumatoid arthritis - adalimumab, etanercept and infliximab (sequential use). http;//www.nice.org.uk/guidance/index
75. Furst DE, Breedveld FC, Kalden JR, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2007. Ann Rheum Dis 2007; 66 (Suppl III): iii2-iii22
76. Stone JH. Tumor necrosis factor-alpha inhibitors: an overview of adverse effects. UpToDate 2008, May 31, version 16.2
77. Askling J, Dixon W. The safety of anti-tumor necrosis factor therapy in rheumatoid arthritis. Curr Opin Rheumatol 2008; 20:138-144
78. Solomon DH, Lunt M, Schneeweiss S. The risk of infection associated with tumor necrosis factor an antagonist. Making sense of epidemiologic evidence. Arthritis Rheum 2008; 58:919-928
79. Kozlov RS, Yakushin SB, Nasonov EL. Infectious complications of therapy with tumor necrosis factor blockers: forewarned is forearmed. Clinical Microbiology and Antimicrobial Chemotherapy, 2006, 8:314-324
80. Kim HA, Yoo CD, Baek HJ, et al. Mycobacterium tuberculosis infection in a corticosteroid-treated rheumatic disease patient population. Clin Exp Rheumatol 1998; 16:9-13.
81 Doran MF, Crowson CS, Pond GR, et al. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum 2002; 46:2287-2293.
82. Kroesen, S, Widmer, AF, Tyndall, A, Hasler, P. Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy. Rheumatology (Oxford) 2003; 42:617.
83. Crum, NF, Lederman, ER, Wallace, MR. Infections associated with tumor necrosis factor-alpha antagonists. Medicine (Baltimore) 2005; 84:291.
84. Gomez-Reino, JJ, Carmona, L, Valverde, VR, et al. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 2003; 48:2122.
85. Listing, J, Strangfeld, A, Kary, S, et al. Infections in patients with rheumatoid arthritis are treated with biologic agents. Arthritis Rheum 2005; 52:3403.
86. Curtis, JR, Patkar, N, Xie, A, et al. Risk of serious bacterial infections among rheumatoid arthritis patients exposed to tumor necrosis factor alpha antagonists. Arthritis Rheum 2007; 56:1125.
87. Curtis, JR, Xi, J, Patkar, N, et al. Drug-specific and time-dependent risks of bacterial infection among patients with rheumatoid arthritis who were exposed to tumor necrosis factor alpha antagonists. Arthritis Rheum 2007; 56:4226.
88. Dixon, WG, Watson, K, Lunt, M, et al. Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 2006; 54:2368.
89. Wolfe F, Caplan L, Michaud K. Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum 2006; 54:628-634
90 Askling J, Fored CM, Brandt L, et al. Time-dependent increase in risk of hospitalization with infection among Swedish RA patients treated with TNF antagonists. Ann Rheum Dis 2007; 66:1339-1344.
91 Dixon WG, Symmons DP, Lunt M, et al. Serious infection following antitumor necrosis factor alpha therapy in patients with rheumatoid arthritis: lessons from interpreting data from observational studies. Arthritis Rheum 2007; 56:2896-2904.
92. Keane, J, Gershon, S, Wise, RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345:1098.
93. Brassard, P, Kezouh, A, Suissa, S. Antirheumatic Drugs and the Risk of Tuberculosis. Clin Infect Dis 2006; 43:717.
94. Wallis, RS, Broder, MS, Wong, JY, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004; 38:1261.
95 Wolfe F, Michaud K, Anderson J, Urbansky K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum 2004;50:372-9.
96 Dixon WG, Hyrich KL, Watson KD, et al. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the BSP biologics register (BSRBR). Ann Rheum Dis 2008; 67: (Supp II) :178
97 Askling J, Fored CM, Brandt L, et al. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum 2005;52(7):1986-92.
98 Tubach F, Salmon D, Ravaud P, et al. The risk of tuberculosis with anti-TNF is higher with monoclonal antibodies than with the soluble receptor. Results of the French 3-year prospective ratio observation. Ann Rheum Dis 2008; 67: (Suppl II): 52
99. Guidotti, LG, Ishikawa, T, Hobbs, MV, et al. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity 1996; 4:25.
100. Guidotti, LG, Ando, ​​K, Hobbs, MV, et al. Cytotoxic T lymphocytes inhibit hepatitis B virus gene expression by a noncytolytic mechanism in transgenic mice. Proc Natl Acad Sci U S A 1994; 91:3764.
101. Nelson, DR, Lim, HL, Marousis, CG, et al. Activation of tumor necrosis factor-alpha system in chronic hepatitis C virus infection. Dig Dis Sci 1997; 42:2487.
102. Ferri C, Ferraccioli G, Ferrari D, et al. Safety of anti-tumor necrosis factor-a therapy in patients with rheumatoid arthritis and chronic hepatitis C virus infection. J Rheumatol 2008, Aug 1. online.
103. Marotte H, Fontanges E, Bailly F, et al. Etanercept treatment for three months is safe in patients with rheumatologic manifestations associated with hepatitis C virus. Rheumatology 2007; 46:97-99
104. Mohan, N, Edwards, ET, Cupps, TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001; 44:2862.
105. Nasonov E.L., Samsonov M.Yu. New aspects of the pathogenesis of heart failure: the role of tumor necrosis factor Heart failure, 2000; 1(4): 139-143
106. Mann, D, McMurray, J, Packer, M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the randomized etanercept worldwide evaluation (RENEWAL). Circulation 2004; 109:1594.
107. Anker, SD, Coats, AJ. How to RECOVER from RENAISSANCE? The significance of the results of RECOVER, RENAISSANCE, RENEWAL and ATTACH. Int J Cardiol 2002; 86:123.
108. Gabriel, SE. Tumor necrosis factor inhibition: a part of the solution or a part of the problem of heart failure in rheumatoid arthritis?. Arthritis Rheum 2008; 58:637.
109. Nasonov E.L. The problem of atherothrombosis in rheumatology. Bulletin of the Russian Academy of Medical Sciences, 2003; 7, 6-10
110. Nasonov E.L. Rheumatoid arthritis - model of atherothrombosis breast cancer 2005; 13:509-512
111. Jacobsson LTH, Turesson C, Culfe A, et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol 2005; 32:1213-1228
112. Jacobsson LTN, Turesson C, Nilsson J-A, et al. Treatment with TNF blockers and mortality risk in patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66:670-675
113. Dixon WG, Watson KD, Lunt M, et al. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor a therapy. Results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 2007; 56: 2905-2912
114. Furst DE, Sokolove J, Greenberg J, et al. Risk of elevated liver enzyme (LFTS) with THF inhibitors in rheumatoid arthritis: analysis in 6861 patients with 22552 visits. Ann Rheum Dis 2008; 67:52
115. Haraoui B, Keystone E. Musculoskeletal manifestations and autoimmune diseases related to new biologic agents. Curr Opin Rheumatol 2006; 18:96-100
116. Mongey A-B, Hess EV. Drug insight: autoimmune effects of medications - what's new? Nat Clin Pract Rheumatol 2008; 4: 136-144`
117. Georgescu, L, Quinn, GC, Schwartzman, S, Paget, SA. Lymphoma in patients with rheumatoid arthritis: association with the disease state or methotrexate treatment. Semin Arthritis Rheum 1997; 26:794.
118. Gridley, G, McLaughlin, JK, Ekbom, A, et al. Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst 1993; 85:307.
119. Ebeo, CT, Girish, MR, Byrd, RP, et al. Methotrexate-induced pulmonary lymphoma. Chest 2003; 123:2150.
120. Wolfe, W, Michaud, K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: Analyzes from a large US observational study. Arthritis Rheum 2007; 56:2886.
121. Stone, JH, Holbrook, JT, Marriott, MA, et al. Solid malignancies among patients in the Wegener's Granulomatosis Etanercept Trial. Arthritis Rheum 2006; 54:1608.

For citation: Nasonov E.L. Tumor necrosis factor-a - a new target for anti-inflammatory therapy of rheumatoid arthritis // BC. 2000. No. 17. S. 718

MMA named after I.M. Sechenov

R Eumatoid arthritis (RA) is one of the most common chronic inflammatory diseases, the frequency of which reaches 1% in the population. Its main signs are almost constant pain in the joints and a progressive impairment of their functions, which, as a rule, leads to a decrease in the quality of life and early disability. In fact, 50% of RA patients become disabled within five years, and 10% within the first two years of the disease. A chronic inflammatory process that increases the risk of developing concomitant diseases (atherosclerotic vascular disease, hypersensitivity to intercurrent infections, osteoporotic skeletal fractures, etc.), toxic effects of non-steroidal anti-inflammatory drugs (gastrointestinal damage, impaired renal function, etc.) or complications of inadequate glucocorticoid ( GC) therapy - all these factors lead to a decrease in the life expectancy of patients suffering from this disease. Only 10% of patients have a benign monocyclic course of RA with rare episodes of exacerbations. In two-thirds of patients, the disease is characterized by a slow but steady progression with incomplete remissions and frequent exacerbations, while the rest develop a “malignant” variant of the course: with rapid multiple joint damage, resistance to ongoing therapy, and severe, potentially fatal, dysfunction of internal organs. . In many patients with RA, the life prognosis is as unfavorable as in insulin-dependent diabetes mellitus, stage IV lymphogranulomatosis, or three-vessel coronary artery disease. In general, the life expectancy of patients with RA is reduced by 5-10 years, and the standardized mortality rate is 2.26. All this allows us to consider RA as one of the most severe chronic diseases.

The pathogenesis of rheumatoid arthritis

RA is a multifactorial autoimmune disease of unknown etiology, the development of which involves many factors: environmental, immune, genetic, hormonal, etc. The essence of the pathological process in RA is a generalized immunologically conditioned (autoimmune) inflammation, leading to the development of a wide range of extra-articular (systemic) organ manifestations and catabolic disorders. However, with maximum intensity, inflammation affects the synovial membrane of the joints, leading to its hyperplasia and a rapid increase in the volume of synovial tissue (pannus), which destroys the articular cartilage and underlying subchondral bone. It is the progressive uncontrolled synovial inflammation, in the development of which resident synovial cells (fibroblasts, macrophages, dendritic cells, mast cells, endothelial cells, T- and B-lymphocytes) take part, that distinguishes RA from other inflammatory diseases of both rheumatic and non-rheumatic nature. .

Two closely interrelated processes are of primary importance in the pathogenesis of RA: antigen-specific activation of CD4 + T-lymphocytes by Th1 type, characterized by excessive synthesis of interleukin (IL)-2, interferon (IFN) g and IL-17, IL-18, and an imbalance between hyperproduction of pro-inflammatory cytokines of a predominantly macrophage nature, such as factor tumor necrosis-a, IL-1, IL-6, IL-8, etc. and anti-inflammatory cytokines (IL-10, soluble IL-1 antagonist, soluble TNF receptors, IL-4), with a predominance of the production of the former over the latter.

Tumor necrosis factor-a

In recent years, the pro-inflammatory cytokine, tumor necrosis factor-a (TNF-a), has been of particular importance in the immunopathogenesis of RA. This cytokine is considered as a prototype of a family of molecules that, on the one hand, play an important role in the regulation of normal differentiation, growth, and metabolism of various cells, and, on the other hand, act as mediators of pathological immunoinflammatory processes in various human diseases. The biological activity of TNF-a is mediated by binding to specific membrane receptors with a molecular weight of 55 Kd (type I or CD120a) and 75 Kd (type II or CD120b). The latter belong to type I transmembrane receptors and are expressed on many cells, including polymorphonuclear leukocytes, endothelial cells (EC), fibroblasts, keratinocytes, etc. Binding of TNF-a to the corresponding receptors leads to activation of transcription factors NF-kB, AP-1 , which, in turn, regulate the activity of several genes encoding the synthesis of pro-inflammatory cytokines and other inflammatory mediators and induce programmed cell death (apoptosis) .

Clinical signs of inflammation (pain, fever, loss of muscle and bone mass);

Induces the expression of adhesion molecules, which determines the transendothelial migration of leukocytes towards the joint cavity;

Stimulates the synthesis of pro-inflammatory mediators, such as prostaglandins, platelet activating factor, superoxide radicals of metalloproteinases (collagenase, gelatinase, stromelysin), which cause bone and cartilage damage;

Induces the synthesis of pro-inflammatory cytokines (IL-1, IL-6, GM-GFR) and chemokines (IL-8, RANTES, monocytic chemoattractant protein-1, macrophage inflammatory protein-1a),

Stimulates the growth of new vessels (neoangiogenesis) and the proliferation of fibroblasts, which play an important role in the formation of rheumatoid panus.

According to experimental studies, suppression of TNF-a synthesis is associated with a decrease in signs of inflammation in various forms of experimental arthritis. Transgenic mice carrying a modified human TNF-a transgene that overexpress TNF-a spontaneously develop erosive inflammatory arthritis, the progression of which is effectively controlled by blockade of TNF-a synthesis.

Clinical studies have shown that in the synovial tissue, fluid and serum of patients with RA, an increase in the concentration of TNF and soluble TNF receptors was noted, which correlates with clinical signs of the activity of the rheumatoid process. Blocking the synthesis of TNF with monoclonal antibodies leads to the suppression of the synthesis of IL-1 and other pro-inflammatory mediators, including GM-CSF, IL-6 and IL-8 in the culture of synoviocytes from RA patients.

All this suggests that it is TNF-a that is the key mediator of the immune-inflammatory process in RA, and, consequently, the most important target for anti-inflammatory therapy.

Monoclonal antibodies to TNF-a in the treatment of RA

Currently, almost the entire arsenal of anti-inflammatory and immunoactive drugs existing in medicine is used for the treatment of RA, along with mono- or combination therapy with basic anti-inflammatory drugs (methotrexate, sulfasalazine, gold salts, cyclosporine, etc.) and glucocorticoids (GCs). Very important, significant factors limiting the possibilities of RA therapy include the development of adverse reactions or resistance to previously effective drugs, which often occurs during their long-term use. For example, there is evidence that no more than 60% of RA patients can take methotrexate (MT) for 5 years or more, and for most other basic anti-inflammatory drugs, this figure does not exceed 25%. Thus, in the process of treating patients with RA, the doctor is faced with several closely related intractable problems, such as primary inefficiency, secondary resistance, and the development of side effects requiring interruption of treatment. All this required the development of new methods for the treatment of RA, in which the main attention is paid to the study of the clinical efficacy of new biological drugs that specifically inhibit the synthesis of TNF-a.

The first drug of this group introduced into clinical practice, approved by the US Pharmacological Committee for the treatment of RA, are monoclonal antibodies (mAb) to TNF-a: infliximab (Remicade ), which were previously referred to as cA2. They are chimeric antibodies consisting of the variable (Fv) region of a high affinity neutralizing mouse anti-TNF-a monoclonal antibody (A2) coupled to a fragment of the human IgG1k molecule, occupying a total of two-thirds of the antibody molecule. The drug has a very high affinity for trimeric TNF-a K d - 100pM and in vitro effectively inhibits the activity of secreted and membrane-associated TNF-a.

pharmachologic effect

The most obvious mechanism of action of mAbs is the binding and inhibition of the synthesis of pro-inflammatory mediators. Indeed, during treatment, there is a decrease in the concentration of IL-6 and IL-1, which correlates with a decrease in the level of acute phase proteins and clinical manifestations of disease activity, other inflammatory mediators (IL-8, raIL-1, pCD14, monocytic chemoattractant protein-1, nitric oxide , collagenase, stromelysin), which play a role in the development of inflammation and tissue destruction in RA, as well as the level of soluble forms of adhesion molecules ICAM-1 and E-selectin, reflecting the activation of the vascular endothelium. It is noteworthy that the decrease in the level of soluble adhesion molecules correlated well with the clinical efficacy of therapy. According to the immunomorphological studies of synovial biopsy specimens, during treatment, there is a decrease in the expression of E-selectin and vascular adhesion molecule-1 (VCAM-1) on the cells of the inflammatory infiltrate, the number of T-lymphocytes, and the entry of neutrophils into the joint cavity. Since the TNF-TNF-R interaction regulates cellular apoptosis, it is also assumed that inhibition of TNF-α synthesis can modulate synovial cell apoptosis and thus inhibit the development of synovial hyperplasia. The role of another mechanism associated with an increase in the synthesis of IL-10 or modulation of the expression of cells with the Th1 and Th2 phenotype is not excluded.

Clinical effect

Already in the course of the first open trial, it was shown that, in general, in the group of patients with RA who received an intravenous infusion of Remicade, there is pronounced positive (more than 50%) dynamics of individual indicators, reflecting the activity of the articular syndrome, such as the number of inflamed joints, pain count, ESR, CRP. The duration of the effect after a single administration of Remicade ranged from 8 to 25 weeks. Subsequently, several double-blind, placebo-controlled studies were conducted, confirming preliminary conclusions about the high efficacy of mAbs in RA (Table 2).

An analysis of the results of these studies showed that the average duration of the clinical effect after a single administration of Remicade is 3 weeks with the introduction of 1 mg / kg, 6 weeks - 3 mg / kg and 8 weeks - 10 mg / kg of the drug . Based on these data, and on the assumption that the clinical effect of Remicade can be prolonged with the help of basic antirheumatic drugs, several placebo-controlled studies have been conducted to evaluate the possibilities of combination therapy of Remicade with methotrexate (MT), which is currently being considered, as the most effective ("gold standard") basic antirheumatic drug used for the treatment of RA. These trials included patients with persistent disease activity despite the use of high (10 mg/week or more) doses of MT. The first 12-week study included 28 patients treated with MTX (for at least 3 months at a stable dose of 10 mg/week for at least 4 weeks) and continuing to take the drug at a stable dose of 10 mg/week, who received Remicade at a dose of 0 , 5, 10 and 20 mg/kg or placebo. The clinical effect, according to the criteria of the American College of Rheumatology (ACR), was achieved significantly more often in patients treated with Remicade (81% - in 12 of 21 patients) than placebo (14% - in 1 of 7 patients). Another study showed that Remicade treatment resulted in a marked improvement in articular syndrome (mean number of inflamed joints decreased from 30.1 to 13.0) and CRP concentration from 3.0 to 1.1 by 12 weeks of treatment. The duration of the clinical effect depended on the dose: 12 weeks in 33% of patients who received 5 mg / kg Remicade, and in 64% of patients who received Remicade at a dose of 10-20 mg / kg. All patients were given Remicade (10 mg/kg) repeatedly (3 times at 8-week intervals). Two-thirds remained in remission during the next 40 weeks of treatment. Another study evaluated the efficacy of 3 doses of Remicade (1, 3, and 10 mg/kg) in 101 patients with active RA who received MTX (7.5 mg/week) or placebo. The clinical effect (20% according to the ACR criteria) was achieved in 60% of patients, and combined treatment with MT made it possible to enhance and prolong the clinical effect of Remicade. This was especially noticeable when Remicade was used at low doses. Thus, for example, the clinical effect with the introduction of 1 mg/kg Remicade was maintained with the combined use of MT for more than 16 weeks compared with 3-4 weeks without MT. In patients treated with high doses of Remicade in combination with MT, the clinical effect was achieved in more than 80% of patients and persisted for more than 26 weeks in 60%. According to the Paulus criteria, a 50% improvement with 10 mg/kg Remicade persisted for more than 13 weeks in patients treated with MTX, and only 6 weeks in patients treated with placebo. It is noteworthy that, according to pharmacological studies, during treatment with MT, a higher level of the drug in the blood of patients remained, especially noticeable in patients receiving low doses of Remicade. All this points to the synergism of the anti-inflammatory activity of Remicade and MT.

More recently, preliminary results of Remicade in 428 patients with active RA refractory to high (greater than 12.5 mg/kg per week) doses of MT have been presented. Patients received Remicade (3 and 10 mg/kg) or placebo every 4 and 8 weeks for 30 weeks. While in the placebo group, the clinical effect (20% according to ACR criteria) was achieved in only 20% of patients, with Remicade treatment, the effect was achieved in 52% of cases. It is noteworthy that the effectiveness of treatment did not directly correlate with the dose of the drug and the frequency of administration. Similar regularities were also obtained when using more “rigid” criteria for evaluating efficiency. Thus, 50% improvement, according to ACR criteria, occurred in 28% of patients treated with Remicade, and only 5% treated with placebo, and 70% improvement in 12% of patients treated with the drug, and none treated with placebo.

A group of leading rheumatologists who took part in an international symposium on the use of anti-TNF therapy in RA developed preliminary indications and contraindications for Remicade therapy in RA (Table 3).

Side effect

Given the important physiological role of TNF-a in immunoregulation, the analysis of side effects of specific inhibition of TNF-a synthesis by mAbs, such as increased sensitivity to certain infections and the development of malignant neoplasms, is of particular importance from the point of view of the introduction of this treatment method into wide clinical practice. At the same time, it should be emphasized that in patients with RA (especially those who have a severe, rapidly progressive course of the disease with high inflammatory activity), there are such disorders in the immune system that lead to an increase in sensitivity to infections and increase the risk of developing certain malignant neoplasms. . It is these patients who are the most likely candidates for anti-TNF-a mAb therapy. An analysis of the results of clinical trials of Remicade showed that in treated patients there is no increase in the incidence of infections, compared with the group of patients taking placebo. The same has been demonstrated for malignant neoplasms. However, given the fact that the treatment was carried out in a relatively small group of patients and for a short time, the true frequency and risk of these complications require further study.

During treatment with Remicade, a peculiar side effect was registered associated with an increase in the level of antibodies to DNA (anti-DNA) in the sera of patients, observed in approximately 10% of patients. However, the development of classic clinical signs of systemic lupus erythematosus during treatment with Remicade has not been registered, and the clinical significance of this side effect is not yet clear. Generally, analysis of the results of 10 controlled antibody studies did not reveal a significant increase in the incidence of complications (sudden death, autoimmune disease and malignancy) in patients treated with Remicade compared with patients treated with placebo during 3 years of follow-up.

Certain problems may arise in connection with the immunogenicity of monoclonal antibodies that induce the synthesis of antibodies against administered monoclonal antibodies. Obviously, the synthesis of these antibodies can lead to a decrease in the effectiveness of treatment, induce the formation of immune complexes or allergic reactions. According to a number of authors, the synthesis of antibodies against occurs in 0-25% of patients treated with Remicade, less often when using high rather than low doses of the drug. The frequency of detection of antibodies is especially high in patients receiving repeated infusions of Remicade, which reaches 50%. It is noteworthy that the combined use of MT can reduce the immunogenicity of Remicade. Against the background of Remicade monotherapy, antibodies were detected in 53% of patients who received the drug at a dose of 1 mg/kg, in 21% - 3 mg/kg, and only in 7% - 10 mg/kg, and against the background of the combined use of MT - in 17, 7 and 0% of cases, respectively. Thus, modification of the dose of the drug and the combined use of MT can significantly reduce the immunogenicity of Remicade and, consequently, improve the results of treatment, both in terms of efficacy and the frequency of side effects.

Conclusion

The introduction of anti-TNF-a mAbs into clinical practice has been one of the most significant advances in the treatment of RA in the last decade. Against the background of the use of Remicade, it is possible to achieve a pronounced clinical improvement even in patients resistant to other basic antirheumatic drugs, and to slow down the radiographic progression of articular destruction. Particularly promising is the combined treatment with Remicade in combination with MT, and possibly with other chemical (cyclosporine A) or biological drugs.

E.L. Nasonov
GU Institute of Rheumatology RAMS

Autoimmune diseases include more than 80 nosological forms, are among the most common and severe human diseases. The frequency of autoimmune diseases in the population reaches 8%. Autoimmunity forms the basis of a wide range of rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic scleroderma, systemic vasculitis, etc. A wide range of drugs with anti-inflammatory ( glucocorticoids - GC), cytotoxic or immunosuppressive (at low doses) activity, most of which were created for the treatment of malignant neoplasms or the suppression of transplant rejection. The rational use of these drugs in combination with extracorporeal methods of blood purification during the period of exacerbation has significantly improved the immediate and long-term prognosis, but in many cases it does not allow to control the progression of the disease, the development of life-threatening complications or is associated with severe side effects.

Rheumatoid arthritis (RA) is the most common autoimmune rheumatic disease, the prevalence of which in the population reaches 1.0%, and the economic losses for society are comparable to coronary heart disease. Although significant progress was made in the treatment of RA at the end of the 20th century, the pharmacotherapy of this disease still remains one of the most difficult problems in clinical medicine.

Currently, the "gold" standard of pharmacotherapy for RA is methotrexate (MT) and leflunomide, the efficacy and safety of which meet the modern criteria of "evidence-based medicine". However, therapy with "standard" DMARDs (primarily MT) at the most effective and tolerable doses, starting from the earliest period of the disease, really improved the immediate (suppression of pain and inflammation of the joints) and even long-term (reduced risk of disability) prognosis in many patients. However, in general, the results of RA treatment until recently did not inspire optimism. Approximately half of the patients with DMARDs do not effectively control the clinical manifestations of RA and the progression of the destructive process in the joints, often causing adverse reactions that limit the possibility of using these drugs at doses necessary to achieve a stable clinical effect.

The rapid progress of biology and medicine at the end of the 20th century found its bright practical reflection in the expansion of the possibilities of pharmacotherapy for RA and other inflammatory rheumatic diseases. With the help of biotechnology methods, fundamentally new anti-inflammatory drugs were created, united under the general term "genetically engineered biological agents" ("bio-logics"), the use of which, due to the decoding of the key mechanisms of the immunopathogenesis of this disease, is theoretically well substantiated and has significantly increased the effectiveness of RA pharmacotherapy. . Among a wide range of "pro-inflammatory" mediators involved in the development of RA, special attention is drawn to tumor necrosis factor (TNF)-a, which is considered as the main cytokine that determines the development of synovial inflammation and osteoclast-mediated bone destruction in arthritis. Not surprisingly, TNF-a is currently the most important "target" for the so-called "anti-cytokine" therapy for RA and other inflammatory joint diseases, such as ankylosing spondylitis and psoriatic arthritis. This served as the basis for the development of a group of drugs - the so-called TNF-a inhibitors, blocking the biological activity of this cytokine in circulation and at the cellular level.

The most significant clinical experience has been with Infliximab (Remicade), a chimeric monoclonal antibody to TNF-a. Another representative of the class of TNF-a inhibitors is adalimumab (Humira), the first and so far the only drug that is a fully human recombinant monoclonal antibody to TNF-a. The results of the analysis, which meet the criteria of "evidence-based medicine", indicate that infliximab and adalimumab are effective drugs for the treatment of RA resistant to "standard" DMARDs, including MT (Fig. 1). Considering the modern concept of RA pharmacotherapy based on the need for early aggressive therapy, the analysis of the results of using infliximab and adalimumab as the "first" DMARDs (in combination with MT) in "early" RA is of particular interest. It has been established that in patients with "early" RA on the background of combined therapy with infliximab and MT or adalimumab and MT, a greater number of patients can achieve a state of "remission" and achieve a significant slowdown in the progression of joint destruction than against the background of MT monotherapy.

Rice. 1.

However, despite the fact that TNF inhibitors have demonstrated extremely high efficacy in RA in the process of controlled trials, in real clinical practice, about 30-40% of patients are "refractory" to therapy with these drugs, less than half achieve complete or partial remission. , and about a third are forced to stop treatment due to the development of secondary inefficiency or side effects after 2-3 years of therapy (Fig. 2). It should be taken into account that treatment with TNF inhibitors may be accompanied by the development of infectious complications, primarily tuberculosis infection (Fig. 3).

Among the various immune disorders underlying the development of autoimmune diseases, the study of defects in B-cell regulation is of particular interest, including from the point of view of developing new pathogenetically substantiated approaches to treatment (Fig. 4). Recall that B lymphocytes are cells of the immune system involved in the development and maintenance of adaptive immunity, are formed from hematopoietic precursors in the bone marrow throughout a person’s life, and are involved in maintaining immunological tolerance to self antigens (autoantigens). Defect B in cellular tolerance leads to the synthesis of autoantibodies, which, by activating the effector links of the immune response, induce the development of inflammation and tissue destruction in the human body. However, the significance of B cells in the development of autoimmune diseases is not limited to the synthesis of "pathogenic" autoantibodies. It has been established that disturbances in B cell costimulation of T lymphocytes play a fundamental role in the development of autoimmune pathological reactions and can develop at the earliest stages of the pathological process before the clinical manifestation of the disease (Fig. 5). Data from experimental studies indicate the fundamental role of B-lymphocytes in the immunopathogenesis of RA (Figs. 6 and 7). In a study of experimental arthritis in mice with severe combined immunodeficiency (NOD-SCID), which develops as a result of synovial tissue transfer from patients with active RA, it was shown that B lymphocytes are involved in the activation of Th1 type CD4+ T cells in inflamed synovial tissue, performing function of specific antigen-presenting cells. B-cells synthesizing RF have a unique ability to interact with immune complexes and "present" a wide range of autoantigens, and activated B-cells express co-stimulatory molecules (B7 and CD40) necessary for the full activation of T-cells. The effector role of B cells in the development of articular destruction in RA is also discussed, which is realized through the synthesis of "pro-inflammatory" cytokines (TNF, IL-1 and lymphotoxin), as well as IL-6 and IL-10, which have an additional stimulating effect on B -lymphocytes. In addition, according to clinical and epidemiological studies, patients with autoimmune rheumatic diseases have an increased risk of developing non-Hodgkin's B cell lymphomas. All this taken together makes B cells promising therapeutic "targets" in autoimmune diseases.

Rice. 4. In lymphocyte

Rice. 5. Role of B cells in the development of autoimmunity

T Cell Activation in Rheumatoid Synovium Is B Cell Dependent Seisuke Takemura, Piotr A. Klimiuk, Andrea Braun, Jörg J. Goronzy, and Cornelia M. Weyand J Immunol 2001 167: 4710-4718.
Antigen-Specific B Cells Are Required as APCs and Autoantibody-Producing Cells for Induction of Severe Autoimmune Arthritis Shannon K. O'Neill, Mark J. Shlomchik, Tibor T. Glant, Yanxia Cao, Paul D. Doodes, and Alison Finnegan J Immunol 2005 174: 3781-3788.

Rice. 7. T cell activation in rheumatoid synovial tissue depends on B cells

The first and so far the only anti-B cell drug approved for use in clinical practice is rituximab (Rituximab, MabThera F. Hoffmann-La Roche Ltd.), a chimeric monoclonal antibody to the CD20 antigen of B cells (Fig. 8). The drug has been used in medicine since 1997 for the treatment of B cell non-Hodgkin's lymphomas, and in recent years for a wide range of autoimmune diseases.

Rice. 8. Rituximab (Rituximab, MabThera, Roche)

The choice of the CD20 molecule as a target for monoclonal antibodies is associated with the differentiation of B cells, which, in the process of maturation from stem cells to plasma cells, go through several successive stages, each of which is characterized by the expression of certain membrane molecules (Fig. 9). Expression of CD20 is observed on the membrane of "early" and mature B-lymphocytes, but not stem, "early" pre-B, dendritic and plasma cells. therefore, their depletion does not cancel the regeneration of the B-lymphocyte pool and does not affect the synthesis of "normal" antibodies by plasma cells. In addition, CD20 is not released from the membrane of B lymphocytes and is not present in a circulating (soluble) form that 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. The mechanisms that determine the high efficacy of rituximab in RA and other autoimmune diseases are summarized in Fig. 10.

Rice. 9. CD20: an ideal target for pharmacological intervention.

Rice. 10. Proposed mechanism of action of rituximab in autoimmune diseases.

• Weakening of antigen-presenting function of B cells in relation to the induction of proliferation and cytokine synthesis by CD4+ T cells
• Destruction of aberrant germ centers: decreased production of autoantigen-specific B memory cells, plasma cells, and antibody synthesis
• Depletion of plasma cell precursors: inhibition of antibody synthesis and immune complex formation
• Modulation of the activity of other autoreactive cells by disrupting T cell function
• Activation of T regulatory cells (CD4+ CD25+)

Currently, the possibility of effective control of autoimmune pathological conditions by depletion (and / or modulation of function) of B cells has been proven in clinical studies. This is evidenced by the high efficacy of rituximab in RA, which served as the basis for registration of the drug for the treatment of this disease. At present, studies have been conducted and are continuing to confirm the high efficacy of rituximab in RA in both patients resistant to therapy with "standard" DMARDs and TNF-a inhibitors (Fig. 11-13), which allows us to consider rituximab as a highly effective basic anti-inflammatory genetically engineered biological drug (Fig. 14) At the same time, repeated courses of rituximab therapy are as effective as the first one (Fig. 16-20), and the therapeutic effect of the first course lasts an average of 40-50 weeks (Fig. 21). These data indicate that the use of rituximab makes it possible to maximally individualize the treatment of RA and thereby increase the efficacy and safety of pharmacotherapy in general. Against the background of repeated courses of rituximab, there was no increase in the frequency of side effects (Fig. 22), including infectious complications (Fig. 23 and 24), and the frequency (and intensity) of infusion reactions significantly decreased (Fig. 25).

Rice. 11. Rituximab Research Program in RA

Rice. 12.

Rice. 13. Efficacy of rituximab in RA according to randomized controlled trials

Rice. 14. Rituximab Meets Criteria for Genetically Engineered Biological DMARD

Rice. 15. Repeat courses of rituximab (September 2006)

Rice. 16. Duration of rituximab use

Rice. 17. Dynamics of disease activity in patients with ineffectiveness of TNF inhibitors

Rice. 18. Patients (n=96) with TNF inhibitor failure: ACR (24 weeks)

Rice. 19. Patients (n=97) with TNF inhibitor failure: EULAR (24 weeks)

Rice. 20. Patients (n=57) with DMARD failure: EULAR (24 weeks)

Rice. 21. Average time between courses

Rice. 22. Side effects

Rice. 23. Infectious complications

Rice. 24. Frequency of infectious complications

• 702 patients (67%) had episodes of >1 infection
• Most common URT including pharyngitis (32%) and urinary infection (11%)
• No opportunistic infections, viral reactivation, or tuberculosis

Rice. 25. Frequency of acute infusion reactions

Recently, a group of reputable European and American rheumatologists have developed recommendations for the use of rituximab in RA (Fig. 26), which emphasize that the main indication for prescribing at present is the ineffectiveness of TNF-a inhibitors. In addition, rituximab can be prescribed to patients who have contraindications for treatment with TNF-α inhibitors, especially in the presence of a history of lymphoproliferative tumors, as well as in rheumatoid vasculitis (Fig. 27). In patients with TNF-a inhibitor failure, rituximab suppresses joint inflammation activity (decrease in DAS28) to a greater extent than switching from one TNF inhibitor to another (Figures 28 and 29). A preliminary analysis of the results of the use of rituximab in patients with the ineffectiveness of one TNF-a inhibitor indicates not only clinical, but also significant pharmacoeconomic advantages of treatment with rituximab compared to the appointment of another TNF-a inhibitor.

Rice. 27. Place of rituximab in the treatment of rheumatoid arthritis

Rice. 29. Dynamics of disease activity during treatment with rituximab compared with TNF inhibitors

On fig. 30 summarizes the main data regarding the effectiveness of the drug in this disease, from the perspective of evidence-based medicine.

Rice. 30. Efficacy of rituximab in RA
Key points

• Monotherapy (Evidence level lb)
• Combination Therapy (Level of Evidence 1a)
• The effectiveness and duration of the effect of combination therapy is higher than monotherapy (Evidence level lb)
• In “responders”, the duration of the effect after one course of rituximab lasts more than 6 months (Evidence level III)
• In patients with insufficient effect of DMARDs and TNF inhibitors, treatment with rituximab slows the progression of joint destruction (Evidence level lb)

In recent years, clinical experience with the use of rituximab for the treatment of other human autoimmune diseases, including SLE, Sjögren's disease, systemic vasculitis, idiopathic inflammatory myopathies, catastrophic antiphospholipid syndrome, etc., has been rapidly accumulating (Fig. 31). It should be emphasized that in most cases rituximab was successfully used in patients with very severe disease who were resistant to standard glucocorticoid and cytotoxic therapy, intravenous immunoglobulin, extracorporeal methods of blood purification, often for health reasons.

Rice. 31. Diseases for which Rituximab has been shown to be effective

There is no doubt that rituximab is an extremely effective and relatively safe drug for the treatment of RA and other severe autoimmune diseases. Its introduction into clinical practice can rightfully be considered a major achievement in medicine at the beginning of the 21st century, which has not only important clinical but also theoretical significance, since it contributes to the deciphering of the fundamental links in the pathogenesis of human autoimmune diseases. In fact, rituximab is the founder of a new direction in the treatment of human autoimmune diseases, which is based on the modulation of the B cellular link of immunity.

Thus, the beginning of the 21st century was marked by rapid progress in the treatment of autoimmune rheumatic diseases, primarily RA. The introduction of genetically engineered biological agents allows us to hope that in the near future a cure or, at least, the achievement of a long-term remission in patients suffering from these diseases will become a reality.

LITERATURE
1. Nasonov E.L. Pharmacotherapy of rheumatoid arthritis - a look into the 21st century. Wedge. medicine 2005; 6:8-12
2. Nasonov E.L. The use of infliximab (monoclonal antibodies to tumor necrosis factor) in rheumatology: new data. RMJ 2004; 20:1123-1127
3. Nasonov E.L. The use of infliximab (monoclonal antibodies to tumor necrosis factor) in rheumatology: new data. RMJ 2004; 20:1123-1127
4. Nasonov E.L. Prospects for the use of fully human monoclonal antibodies to tumor necrosis factor (Adalimumab -Humira) in rheumatoid arthritis. Klin Pharmacol. Pharmacotherapy 2007; 1:71-74
5. Furst DE, Breedveld FC, Kalden JR, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2007; Ann Rheum Dis 2007; 66:2-22
6. Nasonov EL. Prospects for the use of monoclonal antibodies to B-lymphocytes (rituximab) in rheumatoid arthritis. Wedge. Pharmacol. therapy 2006; 1-5:55-58
7. Nasonov E.L. New directions in the treatment of rheumatoid arthritis: prospects for the use of monoclonal antibodies to B-lymphocytes (rituximab). RMJ 2006; 25: 1778-1782
8. Smolen JS, Betteridge N, Breedveld FC, et al. Consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66:143-150.
9 Finckh A, Ciurea A, Brulhart L, et al. B cell depletion may be more effective than switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis patients with inadequate response to anti-tumor necrosis factor agents. Arthritis Rheum 2007; 56: 1417-1423
10. Soloviev S.K., Kotovskaya M.A., Nasonov E.L. Rituximab in the treatment of systemic lupus erythematosus. RMJ 2005; 13:1731-1735
11. Nasonov E.L. Prospects for the use of rituximab in human autoimmune diseases. RMJ, 2007; 15(26):1958-1963

Immunotherapeutic agents currently represented by four groups of drugs. Immunosuppressants. Anti-TNF drugs. Immunoglobulins for intravenous administration (IGIV). IFN

IMMUNODEPRESSANTS

The choice of immunosuppression protocol (dose, combination of drugs, duration of therapy) depends on the disease, the type of transplantation, and the degree of histocompatibility between the donor and the recipient.

Indications to the use of immunosuppressants: . treatment of autoimmune diseases. prevention and treatment of graft-versus-host disease after bone marrow transplantation. prevention and treatment of transplant rejection.

GC have systemic anti-inflammatory and immunosuppressive activity.

The mechanism of action and changes in the immune system. After passive diffusion through the cytoplasmic membrane, they bind to an intracellular receptor. During the translocation of the resulting complex in the cell nucleus, it interacts with specific DNA sequences ( GREs, from. English glucocorticoid responsive elements) and gene transcription factors... For example, HAs activate the gene I kappa B alpha factor that negatively regulates NF-k B (from the English. nuclear factor k B is the nuclear factor k B). NF-k B is a transcription factor for granulocyte-monocyte colony-stimulating factor (GM-CSF) genes. ), IL-2, IL-6, IL-8. Thus, steroid-induced suppression of NF-kB causes a decrease in the secretion of these cytokines ... In addition, GCs inhibit the expression of IL-1, IL-3, IL-4, TNF genes and neutrophil secretion products: collagenases, elastase and plasminogen activator .. GCs reduce the number of all circulating leukocytes except for neutrophils. However, due to a decrease in adhesion to endothelial cells, neutrophils lose their ability to leave the bloodstream and penetrate into infected and damaged areas. The bactericidal activity of neutrophils and monocytes is also suppressed. The immunosuppressive effect depends on the dose of HA. At low or medium doses (<2 мг/кг/сут эквивалентной дозы преднизона для детей и <40 мг/сут для взрослых) наблюдают кожную анергию. Умеренно снижается количество циркулирующих Т-лимфоцитов, причём CD4 + -клеток в большей степени, чем CD8+-клеток. Дозы преднизона >2 mg/kg/day in children and >40 mg/day in adults inhibit lymphocyte activation and AT production.

The risk of infectious complications of glucocorticoid therapy is significantly increased at a dose of prednisone >10 mg/day. The relative risk of opportunistic infections (pneumocystis pneumonia) is significantly higher than typical viral (herpesviruses), bacterial ( Staphylococcus aureus etc.) and fungal ( Candida) infections. Protozoal infections and helminthiases are uncommon except for endemic pathogens (eg, Plasmodium falciparum).

Some properties of commonly used glucocorticoids. elimination half-life 1-2 h, relative glucocorticoid activity 1, relative mineralocorticoid activity 2.. Methylprednisolone: ​​half-life 2-3 h, relative glucocorticoid activity 5, relative mineralocorticoid activity 0.. activity 4, relative mineralocorticoid activity 1.. Prednisone: half-life 1.7-3 h, relative glucocorticoid activity 3.5, relative mineralocorticoid activity 1.. Triamcinolone: ​​half-life 2-3 h, relative glucocorticoid activity 5, relative mineralocorticoid activity 0

Methotrexate inhibits dihydrofolate reductase, inhibiting the synthesis of thymidine and some amino acids, and slows down cell division. At a dose of >20 mg/kg used for the treatment of cancer, the drug suppresses the primary and secondary cellular and humoral immune response and can cause bone marrow depression, hemorrhage and sepsis. In the basic therapy of rheumatoid arthritis and other rheumatoid diseases (1/5-1/10 of the immunosuppressive dose - 7.5-15 mg / week once orally, intramuscularly, intravenously), methotrexate has an anti-inflammatory effect by inhibiting the expression of adhesion molecules and cytokines. At a dose of 10-25 mg/week, methotrexate is used once for the treatment of psoriasis.

Mycophenolate mofetil— a new effective immunosuppressant for the prevention of kidney transplant rejection. The drug is in the phase of clinical trials in the treatment of rheumatoid arthritis and SLE.

After oral administration, mycophenolate mofetil undergoes hydrolysis to form the active component, mycophenolic acid, which is excreted primarily in the urine. The half-life is 6 hours.

Mycophenolic acid reversibly inhibits the enzyme inosine monophosphate dehydrogenase, thereby inhibiting de novo biosynthesis of purines. Lymphocytes are highly dependent on purine synthesis de novo and to a lesser extent from the hypoxanthine-guanine phosphoribosyl transferase-mediated purine biosynthetic pathway. Therefore, the drug acts mainly on lymphocytes, in which the concentration of guanine nucleotides is significantly reduced, which limits the synthesis of DNA and RNA and inhibits proliferation.

Mycophenolic acid inhibits: .. AT production.. cytotoxic T-lymphocytes.. NK cell activity.. production of cytokines IL-1a, IL-1b, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IFN-g, IFN-a, TNF-b, GM-CSF .. expression of selectins by lymphocytes and monocytes.. recruitment of neutrophils, lymphocytes and monocytes.

Dosage: 1 g 2 r / day inside.

Side effects: fever, headache, infections, hypertension, skin rash, insomnia, anemia, thrombocytopenia, leukopenia, dyslipidemia, hyperglycemia, electrolyte disturbances.

Leflunomide is an isoxazole derivative with an antiproliferative effect.

The drug is used to prevent transplant rejection. Leflunomide is also approved for the treatment of rheumatoid arthritis as monotherapy or in combination with methotrexate.

The mechanism of action. The active metabolite of leflunomide, A77 1726, has a half-life of more than 2 weeks and is excreted in the urine and feces. The antiproliferative effect of A77 1726 in lymphocytes is realized through two mechanisms: de novo biosynthesis of pyrimidines in phase G 1 of the cell cycle ... at high concentrations of A77 1726 inhibits IL-2-induced phosphorylation of Jak1 and Jak3 kinases and the b-chain of the receptor for IL-2 .. Leflunomide also inhibits the humoral response, tk. inhibits the proliferation of B-lymphocytes in the S-phase of the cell cycle, as well as the adhesion of peripheral blood mononuclear cells and synovial fluid.

Dosage: on days 1-3, 100 mg orally in a single dose, then 10-20 mg orally in a single dose.

Side effects: gastrointestinal disorders, infections of the respiratory and urinary systems, arterial hypertension, headache, baldness, skin rash, hypokalemia, diabetes, dyslipidemia, anemia, leukopenia, thrombocytopenia.

Cyclosporine- a cyclic peptide consisting of 11 amino acid residues, produced by a fungus Tolypocladium inflatum.

The drug is used in organ transplantation and autoimmune diseases.

Mechanism of action. Cyclosporine binds to the cytoplasmic receptor protein cyclophyllin. The resulting complex inhibits calcium-dependent calcineurin phosphatase, which is responsible for the activation of the transcription factor NF-AT (from the English. nuclear factor of activated T cells- nuclear factor of activated T cells). This molecule is necessary for the transcription of genes for a number of cytokines (GM-CSF, IL-2, IL-3, IL-4, IL-5, IL-8, IL-13, TNF, TNF g) and the membrane molecule CD40L (CD40 ligand) .. In addition, cyclosporine inhibits the activation of TCR-dependent (TCR - T-lymphocyte receptor, from the English. T cell receptor) signaling pathway in T-lymphocytes and Ag-presenting function of monocytes/macrophages. Thus, the drug predominantly suppresses cellular immunity; however, its action is not associated with significant lymphopenia or leukopenia.

Dosage: maintain a therapeutic serum concentration of 100-300 mcg/l; dynamic control of the serum level of cyclosporine is shown.

Side effects: nephrotoxicity, arterial hypertension, electrolyte disturbances, hepatotoxicity, hirsutism, acne, viral, bacterial pneumonia, fungal sepsis.

Sirolimus- a macrolide of fungal origin, forms a complex with FK-binding proteins from the cyclophyllin family, other than cyclosporin-binding cyclophyllins. The drug is used to prevent transplant rejection. Sirolimus does not inhibit calcineurin. Mechanism of action.. Sirolimus binds to a specific cytosolic protein - immunophilin (FK-binding protein-12), the FKPB-12-sirolimus complex inhibits the activation of the kinase "mammalian target of rapamycin" (from the English mTOR - mammalian target of rapamycin), which performs a major role in the cell cycle. Inhibition of mTOR leads to the blockade of several specific signal transduction pathways and, ultimately, to the suppression of lymphocyte activation and a decrease in immune forces. Dosage: initial dose of 6 mg, then 2 mg orally 1 r / day or under the control of serum concentration (therapeutic concentration of 4-12 ng / ml in combination with cyclosporine for the first 2-3 months, after the abolition of cyclosporine - 12-20 ng / ml).

ANTI-TNF DRUGS

Tumor necrosis factor a (TNF a) is a pro-inflammatory cytokine that plays an important role in the pathogenesis of rheumatic and inflammatory diseases. New data on the importance of TNF-a in the pathophysiology of rheumatoid arthritis and Crohn's disease have led to the development of a new class of anti-TNF-a drugs.

Infliximab (a humanized monoclonal antibody against TNF-a) is approved for the treatment of rheumatoid arthritis and active Crohn's disease. Dosage: 5 mg/kg over 2 hours IV. Side effects: viral infections, bronchitis, pneumonia, sinusitis, urinary system infections, vomiting, diarrhea, headache, dizziness, arterial hypertension. Contraindications: sepsis, overt infection, abscess, pregnancy, age under 17 years.

IMMUNOGLOBULINS FOR INTRAVENOUS ADMINISTRATION

Immunoglobulins for intravenous administration (IGIV) are the standard of care for humoral and combined immunodeficiencies, as well as a number of autoimmune diseases.

Manufacturing method. All IVIGs are prepared by cold precipitation with ethanol. The sera of several thousand donors after screening for infectious pathogens are mixed to produce a single batch. IVIG contains antibodies against the most common native viral and bacterial antigens, as well as antigen vaccines. Pasteurization or detergent treatment is used to reduce the risk of pathogen transmission. The final product usually contains more than 99% IgG in terms of protein. Up to 10% of IgG molecules form polymeric complexes. The half-life in serum ranges from 15 to 30 days. The content of IgA and complement components varies depending on the manufacturer.

Mechanisms of action of IVIG: .. blockade and modulation of the expression of Fc g receptors .. suppression of the proliferative response of lymphocytes .. modulation of the production and secretion of cytokines (IL-1, IL-1ra [IL-1 receptor antagonist], TNF a, TGF-b 1 [from English. transforming growth factor b - transforming growth factor b ], IL-2, IL-10) .. inhibition of the damaging effects of complement .. suppression of endothelial cell proliferation .. stimulation of catabolism of IgG class autoantibodies .. suppression of Fas-mediated apoptosis (Fas is one of the cell membrane glycoproteins ) .. regulation of idiotype-anti-idiotypic interactions.

Indications.. FDA approved indications: ... X-linked agammaglobulinemia... Hyper-IgM syndrome... Transient neonatal hypogammaglobulinemia... IgG subclass deficiency... AT deficiency syndrome... Severe combined immunodeficiency ... Common variable immunodeficiency... DiGeorge syndrome... Wiskott-Aldrich syndrome... Ataxia-telangiectasia... Chediak-Higashi syndrome... X-linked lymphoproliferative syndrome... Hyper-IgE syndrome... Chronic lymphocytic leukemia with hypogammaglobulinemia ... Immunoprophylaxis ( varicella) ... Kawasaki disease ... Recurrent infections in bone marrow transplantation ... Idiopathic thrombocytopenic purpura ... HIV infection in children.. Indications based on results of controlled clinical trials: ... Prevention of RSV and CMV infections ... Guillain-Barré syndrome... Chronic inflammatory demyelinating polyneuropathy.

Conditions in which the effectiveness of IVIG is being studied: .. autoimmune neutropenia.. autoimmune hemolytic anemia.. bronchial asthma.. atopic dermatitis.. chronic urticaria.. lupus nephritis.. Wegener's granulomatosis.. autoimmune thyroiditis.. glomerulonephritis.. Lyell's syndrome.. secondary immunodeficiencies.

Dosing. The serum IgG concentration in patients with hypogammaglobulinemia should be above 500 mg%. The dose of IVIG required to achieve and maintain this level depends on the initial concentration of IgG, the frequency of administration of the drug and the intensity of immunoglobulin catabolism in an individual patient. For most patients, a dose of 300 mg/kg once every 3 weeks or 400 mg/kg once every 4 weeks is sufficient.

Side effects. From 5 to 15% of patients experience adverse reactions to IVIG: facial flushing, back pain, nausea, chills. Symptoms may disappear with a decrease in the rate of infusion. The first dose of the drug must be administered at a rate of 30 ml / h in adults and 10-15 ml / h in children. With good tolerance, subsequent infusions begin at a rate of 40 ml / h and increase the rate by 25% every 30 minutes. Other side effects may include acute renal failure, thrombosis, migraine, aseptic meningitis, hemolytic anemia.

INTERFERONS

Pharmacological effects: antiviral, antiproliferative, immunomodulatory.

Indications: chronic viral hepatitis, various acute viral infections, multiple sclerosis, chronic granulomatosis.

Side effects: fever, sweating, fatigue, arthralgia, myalgia, arrhythmia, depression, tremor, paresthesia, gastrointestinal disturbances, hair loss, exanthema, itching.

Contraindications: heart disease, central nervous system disease, renal failure, liver failure, bone marrow depression.

Abbreviations. NF- k B - nuclear factor k B (from the English. nuclear factor k B), GM-CSF - granulocyte-monocyte colony stimulating factor (from the English. granulocyte-macrophage colony-stimulating factor), IVIG - immunoglobulins for intravenous administration.

Note. FDA - US Federal Agency that controls the production, storage and sale of food, drugs and cosmetics ( The Food and Drug Administration).

TNF-α (tumor necrosis factor alpha) plays a key role in starting and maintaining the inflammatory process in rheumatoid arthritis (RA). Suppression of TNF activity leads to a decrease in the synthesis of inflammatory mediators in the body, due to which the necessary therapeutic effect in the treatment of the disease is achieved.

One of the disadvantages of therapy with TNF-α inhibitors is the high cost. However, this method of treatment also has significant advantages: proven effectiveness; safety; persistence of the achieved remission.

Consider use of TNF-α inhibitors in clinical practice on the example of a drug widely used over the past 10 years in the United States, Canada and European countries called etanercept. This TNF inhibitor is designed for subcutaneous administration, which allows patients with RA to avoid costly and lengthy hospitalizations.

Etanercept is used in the treatment of rheumatoid arthritis with moderate to high inflammatory activity. The drug has a stimulating effect on the TNF-α receptors present in the patient's body. As a result, receptors more actively capture excess TNF-α, thereby reducing its concentration, which leads to a decrease in the inflammatory process.

Like other TNF-α inhibitor drugs, etanercept differs significantly in its pharmacological action from the immunosuppressants also used in some RA treatment regimens. Immunosuppressants affect almost the entire immune system, while TNF-α inhibitors are active against specific targets, which are specific sites in the pathogenesis of rheumatoid arthritis.

The results of etanercept studies have shown that a new drug, a TNF inhibitor, leads to a significant reduction in the severity of symptoms of the disease, the achievement of stable and long-term remissions. Etanercept can be used both as monotherapy for RA (treatment with this drug alone) and as part of complex treatment. TNF inhibitors can be combined with non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressants (methotrexate), glucocorticoids (GCs), and pain medications.

Etanercept is given by injection under the skin. "Injections" are performed twice a week. Possible injection zones: under the skin of the shoulder, anterior abdominal wall or thigh. Hospitalization of patients for treatment with a TNF inhibitor is not required; injections can be made by a nurse in the treatment room of a polyclinic or at home.

It should be noted that the use of TNF inhibitors may be accompanied by certain undesirable effects: fever, diarrhea, abdominal pain, leukopenia (decrease in the number of leukocytes), headache, dizziness, respiratory disorders. In addition, local reactions sometimes occur at the injection site (skin itching, and rashes).

It has not been established with certainty what effect TNF-α inhibitors have on the protective function of the immune system. Therefore, patients receiving etanercept should be warned that the use of the drug can potentially provoke infection with various infections. Etanercept should not be used in patients with weakened immune systems as in this case, patients may develop serious infectious diseases that are fraught with sepsis and death. Etanercept is also contraindicated in patients with certain heart conditions (the drug can lead to severe cardiovascular failure). TNF-α inhibitors are not intended for the treatment of RA without the participation of a physician.

The introduction of TNF-α inhibitors into wide clinical practice can be considered one of the greatest advances in medicine in the treatment of RA in recent decades. The use of this group of drugs makes it possible to achieve remission of the disease or a significant decrease in the activity of the inflammatory process, even in patients who were resistant (not sensitive) to other types of basic antirheumatic therapy. The use of TNF-α inhibitors for the treatment of RA significantly slows down the progression of the destruction (destruction) of the affected joints, which is confirmed by x-ray methods.