Intensification of Treatment for Rheumatoid Arthritis (a Clinical and Immunological Study)

The dissertation is devoted to a clinical and immunological study of the intensification of treatment for rheumatoid arthritis. The work aims at a comparative evaluation of two therapeutic approaches: pulse therapy with cyclophosphamide combined with methylprednisolone, and the combined use of infliximab with methotrexate. The study covers an analysis of the influence of these regimens on the clinical and laboratory indicators of disease activity, the dynamics of the levels of pro-inflammatory cytokines (IL-6, IL-8, TNF-α) in peripheral blood, the state of the joint syndrome, the frequency of side effects, and the formation of antibodies to infliximab. On the basis of the data obtained, the indications for the administration of infliximab are refined and the choice of tactics for intensifying treatment in patients with rheumatoid arthritis is substantiated.

Relevance of the topic

Rheumatoid arthritis (RA) is an important medical and social problem. It occurs in persons of working age and leads to rapid disability and a reduction in the life expectancy of patients [14, 17].

The treatment of RA is based on the use of disease-modifying anti-inflammatory drugs, the action of which is aimed at suppressing the immune-inflammatory process and preventing joint destruction. However, in a number of cases these drugs are of low efficacy, cause intolerance, or give rise to the development of side effects. This situation provides a reason for further search for new methods and principles of treatment of rheumatoid arthritis [12, 13, 17].

The principles of intensification of RA treatment using pulse therapy with cytostatic drugs and glucocorticosteroids have been insufficiently developed. In 30% of RA patients a significant reduction in disease activity cannot be achieved [12, 18, 60].

In recent years, monoclonal antibodies against tumor necrosis factor-α have come to be used in the treatment of RA [22]. The introduction of these agents into clinical practice has made it possible to reformulate the standards of pharmacotherapy of RA. At the same time, data on the indications for and the duration of this therapy, as well as on the development of resistance to this group of drugs, remain quite contradictory [19, 42].

Reports in the literature on a comparative analysis of the influence of pulse therapy and biological agents on the course of RA are scarce. The considerations set forth above indicate the need for further research on the choice of tactics for the management of RA patients using programs of intensification of treatment and monoclonal antibodies, as well as on the prediction of side effects during their use.

Aim of the study

To investigate the influence of pulse therapy with cyclophosphamide in combination with methylprednisolone and of infliximab in combination with methotrexate on clinical and immunological parameters in patients with rheumatoid arthritis.

Objectives:

1. To study the influence of standard disease-modifying therapy with methotrexate on clinical and immunological parameters in RA patients.

2. To evaluate the influence of pulse therapy with cyclophosphamide in combination with methylprednisolone on clinical and immunological parameters in RA patients.

3. To investigate the influence of infliximab in combination with methotrexate on clinical and immunological parameters in RA patients.

4. To carry out a comparative analysis of the influence of pulse therapy with cyclophosphamide in combination with methylprednisolone and of infliximab in combination with methotrexate on clinical and immunological parameters in RA patients.

5. To determine the frequency of side effects of pulse therapy with cyclophosphamide in combination with methylprednisolone and of infliximab in combination with methotrexate.

6. To develop indications for the administration of infliximab to RA patients.

Statements put forward for defense:

1. Pulse therapy with cyclophosphamide in combination with methylprednisolone and infliximab in combination with methotrexate reduce the clinical and laboratory indicators of RA activity.

2. Pulse therapy with cyclophosphamide and methylprednisolone reduces the levels of pro-inflammatory cytokines, which is accompanied by an improvement in the indicators of joint syndrome and the course of the disease (according to the criteria of the American College of Rheumatology) 2 months after the start of therapy. By 3 months of observation an increase in disease activity was noted, which was accompanied by an elevation of cytokine levels in peripheral blood (IL-6, IL-8, TNF-α) and a worsening of the indicators of joint syndrome.

3. Therapy with infliximab in combination with methotrexate leads to a more pronounced and sustained reduction of the clinical and laboratory indicators of RA activity compared with pulse therapy with cyclophosphamide and methylprednisolone, which is manifested by an improvement in the indicators of joint syndrome and by a decrease in the levels of pro-inflammatory cytokines (IL-6, IL-8, TNF-α) in peripheral blood over 6 months of observation.

4. The frequency of development of side effects in patients receiving pulse therapy with cyclophosphamide and methylprednisolone is higher than in patients receiving infliximab in combination with methotrexate.

Scientific novelty

For the first time, a comparative study has been carried out to evaluate the influence of pulse therapy with cyclophosphamide combined with methylprednisolone and of infliximab in combination with methotrexate on clinical and immunological parameters in RA patients.

It has been shown that after 6 months of treatment with infliximab in combination with methotrexate a more significant and sustained reduction of the indicators of the immune-inflammatory process was observed, which was expressed in a decrease in the levels of pro-inflammatory cytokines (IL-6, IL-8, TNF-α) in peripheral blood, in an improvement in the indicators of joint syndrome and in the course of the disease compared with pulse therapy with cyclophosphamide and methylprednisolone.

For the first time it has been shown that in RA patients receiving infliximab in combination with methotrexate, by the 6th month of treatment a decrease in the efficacy of therapy was observed, which was accompanied by the detection of high titers of antibodies to infliximab.

Practical significance of the work

It has been established that infliximab in combination with methotrexate suppresses the immune-inflammatory process and improves the functional capacity of the joints in RA patients more markedly and for longer than pulse therapy with cyclophosphamide and methylprednisolone. Side effects in patients receiving pulse therapy with cyclophosphamide and methylprednisolone occur more often than in patients receiving infliximab in combination with methotrexate. The appearance of antibodies to infliximab in peripheral blood is accompanied by a worsening of the course of RA and by the development of resistance to the therapy being administered. The indications for the administration of infliximab to RA patients have been refined.

The author's contribution to the research carried out

The author personally participated in obtaining the scientific results presented in the dissertation, selected, followed up, and examined RA patients, participated in carrying out immunological investigations, and performed the scientific and statistical analysis of the results.

Implementation of the results of the study

The results of the study have been used in the practical work of the Rheumatology and Therapeutic Departments of the SEI APE "Saint Petersburg Medical Academy of Postgraduate Education of the Federal Agency for Health Care and Social Development" and of the Rheumatology Department of the FI "North-Western District Medical Center of Roszdrav", and have also been introduced into the teaching and research processes of the Department of Therapy No. 1 with a course in rheumatology named after E.E. Eikhval'd of SPbMAPO.

Approval and practical implementation of the work

The materials of the dissertation were reported and discussed at the IV Congress of Rheumatologists of Russia (Kazan, 2005), at the IX All-Russian Scientific Forum named after Acad. V.I. Ioffe "Days of Immunology in Saint Petersburg", 2005, at the V Northwestern Conference on Rheumatology (Saint Petersburg, 2005), at the VI Northwestern Conference on Rheumatology (Petrozavodsk, 2006), at the scientific and practical conference on rheumatology of the Institute of Rheumatology of the RAMS (Moscow, 2006), at the XI All-Russian Scientific Forum named after Acad. V.I. Ioffe "Days of Immunology in Saint Petersburg", 2007, and at the Presidium of the Session of the RAMS (Moscow, 2008).

Publications

Twelve works have been published on the topic of the dissertation.

Scope and structure of the dissertation

The dissertation is set out on 120 pages of typewritten text and consists of an introduction, a review of the literature, chapters presenting the clinical characteristics of the patients, the methods of investigation used, the results of the investigation and their discussion, conclusions, practical recommendations, and a list of references containing 200 sources, of which 165 are foreign. The dissertation is illustrated with 16 tables and 14 figures.