Pro- and Anti-Inflammatory Cytokines in Rheumatoid Involvement of Internal Organs and Indications for Immunosuppressive Therapy Combined with Plasmapheresis

The dissertation is devoted to the study of the role of pro- and anti-inflammatory cytokines — tumor necrosis factor-α, interferon-γ, and interleukin-4 — in rheumatoid arthritis with extra-articular (in particular, visceral and vascular) manifestations. The work analyzes changes in the levels of these cytokines depending on the stage of osteochondral destruction, disease activity, the presence of the phenomenon of hormone dependence, and seropositivity for rheumatoid factor. A comparative study was conducted of cytokine dynamics under different treatment regimens: pulse therapy with glucocorticoids, the combination of plasmapheresis with pulse therapy with glucocorticoids, and the scheme "methotrexate + prednisolone", as well as with the isolated use of prednisolone. On the basis of the data obtained, differentiated indications were developed for immunosuppressive therapy combined with plasmapheresis in individual variants of rheumatoid involvement of internal organs.

Relevance of the problem

Rheumatoid arthritis (RA) is a common systemic autoimmune disease of unknown etiology, characterized by the development of chronic destructive polyarthritis and a wide range of extra-articular manifestations [Nasonov E.L., 2000].

In the vast majority of cases, the disease progresses steadily and leads to early loss of working capacity and a reduction in the life expectancy of patients [Pincus T. et al., 1984]. In some patients, a "malignant" variant of the course develops with multiple joint lesions and extra-articular involvement, refractoriness to ongoing therapy, and severe, potentially fatal disorders of internal organ function [Pincus T., 1994; Nasonov E.L., 2000].

The pathological activation of the immune system in rheumatoid arthritis is associated with an imbalance between pro-inflammatory (TNFα, IL-1, IL-8) and anti-inflammatory (IL-4, IL-10) cytokines, which leads to chronicity and progression of joint inflammation [Nasonov E.L., 2000; Feldman M. et al., 1996].

At present, the majority of researchers regard the cytokine interaction in rheumatic inflammatory diseases as a pyramid, at the apex of which is tumor necrosis factor-α (TNFα), which mediates the main manifestations of the pathological process. TNFα possesses numerous immunomodulatory and pro-inflammatory properties, the overwhelming majority of which may be of fundamental importance in the immunopathology of inflammatory rheumatic diseases, especially in rheumatoid arthritis [Nasonov E.L., 2001].

Interleukin-4 (IL-4), on the contrary, suppresses the release of TNFα from the membranes of rheumatoid synoviocytes; however, its production in RA may be reduced [Nasonov E.L., 2001].

A distinctive feature of interferon-γ (IFNγ) is the broad spectrum of its immunotropic action. The works of many authors have demonstrated the ability of IFNγ to stimulate the production of inflammatory cytokines. All types of interferons, especially IFNγ, enhance the formation of the cytokines TNFα, IL-1, IL-2, and IL-6 by monocytes. Possessing this capacity, IFNγ acts as a regulator of the interleukin cascade [Thomson A.W., 1994; Ershov F.I., 1996].

The pathogenetic target of the action of cytokines and immune factors in the rheumatoid process is, first of all, the vascular system of the internal organs [Polyanskaya I.P., Berestel T.I., 1988].

Of interest is the possibility of correcting the immune disorders that have arisen with the help of immunosuppressive agents. The anti-inflammatory and immunoregulatory effects of glucocorticoids (GCS) are largely determined by their action on the cytokine system [Soloviev S.K., 2001]. Methotrexate is currently the optimal drug in the treatment of RA [Nasonov E.L., 2000]. Further study of the indications for methotrexate in the treatment of RA, taking into account the level of pro- and anti-inflammatory cytokines, is, in our view, relevant and topical.

Plasmapheresis (PF) rapidly and substantially affects many links in the pathogenesis of RA by removing from the circulation enormous quantities of autoantibodies, immune complexes, cytokines, and mediators of inflammation. The anti-inflammatory and immunosuppressive effects of PF have been insufficiently studied [Sigidin Ya.A., 2000].

The development of principles for the regulation of immunocytokine relationships is pathogenetically substantiated. The use of effective immunocorrective agents and the principles of their combination with plasmapheresis in the treatment of rheumatoid vascular and internal organ involvement constitute an urgent task.

Aim of the study

To present the characteristics of the interrelationship of pro- and anti-inflammatory cytokines in rheumatoid arthritis and to develop the optimal combination of immunosuppression with methotrexate and pulse therapy with glucocorticoids together with plasmapheresis in individual variants of rheumatoid involvement of internal organs.

Objectives

1 To study the characteristics of changes in the levels of the pro-inflammatory cytokines tumor necrosis factor-α and interferon-γ in rheumatoid involvement of internal organs, at different stages of osteochondral destruction, and at different degrees of activity.

2 To study the nature of changes in the level of the anti-inflammatory cytokine interleukin-4 in rheumatoid involvement of internal organs, at different stages of osteochondral destruction, and at different degrees of activity.

3 To characterize the state of immunocytokine changes in patients with rheumatoid arthritis exhibiting the phenomenon of hormone dependence.

4 To determine the features of the relationship of C-reactive protein and immunological indicators of rheumatoid inflammation activity with the level of blood cytokines.

5 To substantiate the effectiveness of the combined use of methotrexate, pulse therapy with glucocorticoids, and plasmapheresis at different stages of rheumatoid arthritis and in individual variants of internal organ involvement.

Scientific novelty

New data have been obtained that reveal the characteristics of the immunocytokine mechanism of rheumatoid arthritis. The basis for the manifestation of extra-articular lesions and the chronicity of rheumatoid inflammation is the activation of the immunocytokine system, characterized by an imbalance between pro-inflammatory (tumor necrosis factor-α, interferon-γ) and anti-inflammatory (interleukin-4) cytokines.

It has been shown for the first time that in rheumatoid arthritis the production of interleukin-4 by Th2 lymphocytes is reduced. It has been established that the disturbance of the ratio of pro- and anti-inflammatory cytokines reflects to a significant extent the severity of the general inflammatory activity of rheumatoid arthritis rather than the intensity of local joint inflammation. For the first time, an increase in the level of interleukin-4 has been noted in hormone-dependent patients with generalization of rheumatoid vasculitis and osteoporosis, which may serve as a predictor of the manifestation of vascular lesions. In rheumatoid processes that are seropositive for rheumatoid factor, the levels of pro- and anti-inflammatory cytokines are higher than in seronegative patients.

The use of methotrexate, pulse therapy with glucocorticoids in combination with plasmapheresis in rheumatoid arthritis and in individual variants of internal organ involvement is effective and can be recommended for the treatment of this pathology.

Practical significance of the work

In accordance with the clinical and immunocytokine characteristics of rheumatoid involvement of internal organs, principles have been developed for immunosuppressive therapy with methotrexate in combination with prednisolone, and for pulse therapy with glucocorticoids in combination with plasmapheresis. A differentiated approach to the combined treatment of extra-articular lesions in the rheumatoid process has been proposed.

Treatment according to the scheme "methotrexate + prednisolone" is optimal in rheumatoid vasculitis, in high activity of the rheumatoid process, and in refractoriness to steroidal and non-steroidal anti-inflammatory drugs.

Pulse therapy with glucocorticoids is effective predominantly in moderate activity of the rheumatoid process, while in high activity with extra-articular manifestations of vasculitis and nephropathy its effectiveness is reduced.

Treatment according to the scheme "plasmapheresis + pulse therapy with glucocorticoids" is more effective in extra-articular manifestations with a predominance of rheumatoid vasculitis, nephropathy, and polyserositis.

Implementation of research results into practice

The results of the present study have been implemented in the work of the therapeutic departments of Municipal Clinical Hospital No. 18 and Emergency Hospital No. 22 of the city of Ufa. The theoretical and practical recommendations of the dissertation are used in the process of student training at the Department of Hospital Therapy No. 2 of the State Educational Institution of Higher Professional Education "Bashkir State Medical University of the Federal Agency for Health Care and Social Development of the Russian Federation".

Main propositions submitted for defense

1 The cytokine defect in rheumatoid arthritis is characterized by an imbalance between pro-inflammatory (tumor necrosis factor-α, interferon-γ) and anti-inflammatory (interleukin-4) cytokines, which constitutes the basis for the manifestation of extra-articular lesions and the chronicity of joint inflammation.

Elevated levels of pro-inflammatory and anti-inflammatory cytokines are unfavorable with respect to the manifestation of vasculitis syndrome, the progression of osteochondral destruction, and systemic osteoporosis.

2 Joint involvement, without involvement of internal organs, is characterized by induction of the pro-inflammatory cytokines tumor necrosis factor-α and interferon-γ and by inhibition of the level of the anti-inflammatory cytokine interleukin-4.

3 Inhibition of the synthesis of pro-inflammatory cytokines (tumor necrosis factor-α, interferon-γ) by methotrexate in combination with prednisolone and according to the scheme "plasmapheresis + pulse therapy with glucocorticoids" promotes a reduction in the activity of rheumatoid inflammation.

Approbation of the work

The results of the study were reported at the Republican Conference of Young Scientists of the Republic of Bashkortostan "Medical Science - 2004" (Ufa, 2004), at the Interregional IV Conference of Immunologists of the Urals "Current Problems of Fundamental and Clinical Immunology and Allergology" (Ufa, 2005), and were discussed at a joint meeting of the Departments of Outpatient Therapy, Faculty Therapy, Hospital Therapy No. 2, and Propaedeutics of Internal Diseases with a course in physiotherapy of the State Educational Institution of Higher Professional Education "Bashkir State Medical University of the Federal Agency for Health Care and Social Development of the Russian Federation" (Protocol No. 7 of 31 October 2005).

Publications

On the topic of the dissertation, 5 scientific works have been published, including 2 in central press.

Volume and structure of the dissertation

The dissertation is presented on 129 pages, contains 10 tables and 15 figures. The work consists of an introduction, a review of the literature (two chapters), original studies (three chapters), a conclusion, conclusions, and practical recommendations. The bibliography includes 190 sources (86 domestic and 104 foreign).