DO NONSTEROIDAL ANTI-INFLAMMATORY DRUGS HAVE A PATHOGENETIC EFFECT?

Аннотация

The information presented in the review can serve as a rationale for more active use of NSAIDs in cases where there are direct indications for their use. It is indicated that it is advisable to move from the tactics of purely symptomatic use of these drugs (“only when pain appears”) to the practice of regular use in a constant daily dose if pain in the joints and/or spine is present most of the time. Kеywоrds: pathogenetic action, osteoarthritis, ankylosing spondylitis. INTRОDUСTIОN If we consider the development of chronic inflammation in rheumatoid arthritis formally – as a unidirectional pathological process, then the therapeutic effect of NSAIDs occurs only at its very last stage. This is how we can evaluate the use of NSAIDs, for example, in rheumatoid arthritis (RA). The first stage of the pathogenesis of the disease should be considered the occurrence of a defect in the regulation of immunocompetent cells, the second – the appearance of immune complexes and the activation of lymphocytes and macrophages, the third – hyperproduction of cytokines (“cytokine cascade”), etc. The attack of inflammatory response cells on joint tissue, accompanied by a rapid increase in the amount of cyclooxygenase 2 (COX2) and, accordingly, active synthesis of prostaglandins (PG), is one of the last links in this process [1]. It turns out that NSAIDs, the main pharmacological action of which is associated with the blockade of COX-2, affect only the consequence, but not the cause of immune inflammation. Using NSAIDs in RA, it is possible to reduce pain and local manifestations of inflammation; but, since these drugs do not affect the first, “key” links of the autoimmune process, they cannot stop the destruction of the subchondral bone, cartilage and elements of the ligamentous apparatus of the joint. Here, an analogy with infectious inflammation suggests itself: NSAIDs are able to reduce its local and systemic manifestations, but not stop the development, since they do not have an antibacterial effect. MАTЕRIАLS АND MЕTHОDS However, unlike septic pathology, autoimmune inflammation has a self-sustaining, cyclical nature. Cell fragments and destroyed intercellular substance formed as a result of the inflammatory attack themselves become powerful stimulants of the immune system, thus closing the “vicious circle” of the autoimmune process [2]. NSAIDs, the main action of which is associated with the suppression of PG synthesis, are able to delay the development of inflammatory tissue damage. After all, PGs are not only pain mediators; these active substances have many biological effects that underlie the development of the inflammatory reaction. They cause chemotaxis of the main "aggressors" - neutrophils and macrophages, increase vascular permeability, stimulate mast cell degranulation, affect the blood coagulation system, stimulate the catabolism of cartilage and bone cells, etc. [3]. One of the most important biological phenomena that determine the chronicity of immune inflammation is neoangiogenesis - the process of active formation of new blood vessels "growing" into the 85 ` area affected by the pathological process. The development of granulation tissue, the persistence of chronic synovitis and the formation of pannus in RA, as well as tumor progression are unthinkable without angiogenesis. This is a COX2-associated process, therefore NSAIDs, which are COX2 inhibitors, are able to slow the development of newly formed vascular tissue [4]. This effect of NSAIDs, in addition to the influence on chronic immune inflammation, is largely associated with their antiproliferative effect, which determines the antitumor potential of these drugs [2]. RЕSULTS АND DISСUSSIОN But, unfortunately, the reduction of pain and local signs of inflammation is only a symptomatic effect. But there is no compelling evidence to support the ability of NSAIDs to inhibit the formation of bone erosions or significantly reduce systemic inflammatory activity in RA, i.e. to have a pathogenetic effect. An example is the results of a large-scale study that studied the therapeutic potential of etoricoxib. In this multicenter randomized clinical trial (RCT), 1,171 RA patients received etoricoxib 90 mg, naproxen 1000 mg/day, or placebo for 12 weeks. As in the VIGOR study, NSAIDs provided a significant improvement in the condition - a total of approximately 25% compared to the baseline level. The difference in the assessment of well-being in those receiving these drugs or placebo (although patients, of course, could use paracetamol “on demand” as an additional analgesic) was obvious [2]. However, the positive effect on the main manifestations of systemic inflammation in RA was not so brilliant. Thus, the number of inflamed joints, which averaged 19 in each group, decreased by only 1.43 and 1.39 while taking etoricoxib and naproxen; the average level of CRP increased slightly compared to the placebo group, and in those receiving etoricoxib this increase (by 1.11 m