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DO NONSTEROIDAL ANTI-INFLAMMATORY DRUGS HAVE A PATHOGENETIC
EFFECT?
Sobirjonov Islombek Tavakkaljon ugli
Andijan State Medical Institute
https://doi.org/10.5281/zenodo.14809570
Abstract.
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
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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
mg/ml) was statistically significant. Of course, it should be taken into account that this study
mainly included long-term ill patients (average duration of RA was 8 years) with high activity
of the process. However, the absence of significant improvement in inflammatory changes
against the background of taking NSAIDs is seen here quite clearly [3].
All the experience of modern rheumatology shows that in patients with RA who did not
receive adequate basic therapy, the disease has a higher rate of progression and is
significantly more severe than in those who received the correct treatment (i.e. based on the
active use of basic anti-inflammatory drugs - DMARDs). It is quite obvious that the majority of
patients with RA (and even more so patients who did not receive DMARDs) regularly used
NSAIDs as a pain reliever. It must be admitted that these drugs do not significantly affect the
course of the osteodestructive process and the development of systemic complications of RA.
Of course, to determine the true pathogenetic role of NSAIDs in RA, it would be interesting to
compare the course of the disease in patients who did not receive DMARDs, but regularly took
medium or high therapeutic doses of NSAIDs for a long time, and in patients who took NSAIDs
only “on demand” or did not use them at all. However, we were unable to find retrospective
studies in which such an analysis was carried out, and prospective studies of this kind are
impossible due to the obvious ethical aspect: according to modern concepts, all patients with
RA, if they are not in a state of stable remission, should receive DMARDs.
СОNСLUSIОN
Thus, there is sufficiently strong evidence that the use of NSAIDs in OA and AS allows for
not only symptomatic improvement, but also a slowdown in the progression of the underlying
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pathological process. The unity of theoretical concepts, experimental and clinical research
data confirming this effect is very important.
References:
1.
Karateev A.E., Karateev D.E., Luchikhina E.L. et al. Efficacy and safety of high-dose NSAID
monotherapy in early arthritis. RMZh 2016;16:24–9.
2.
Greenwald M., Peloso P., Mandel D. et al. Further assessment of the clinically effective
dose range of etoricoxib: a randomized, double-blinded, placebo-controlled trial in
rheumatoid arthritis. Curr Med Res Opin 2011;27(10):2033–42.
3.
Pincus T. Clinical evidence for osteoarthritis as an inflammatory disease. Curr Rheum
Rep 2016;3(6):524–34.
4.
Fernandes J., Martel-Pelletier J., Pelletier J. The role of cytokines in osteoarthritis
pathophysiology. Biorheology 2012;39(1–2):237–46.
