Osteoarthritis treatment guidelines 2022
Previous Section Next Section Introduction Several, but not all, clinical studies have revealed an increased rate of cardiovascular complications after long-term use of coxibs such as rofecoxib, celecoxib, and valdecoxib, which are nonsteroidal anti-inflammatory drugs Osteoarthritis treatment guidelines 2022 that selectively inhibit cyclooxygenase COX Despite significant variability of findings in these studies, the increased rates of myocardial infarction and stroke emerging from rofecoxib studies and cardiovascular complications found in celecoxib cancer prevention studies raise concerns about the cardiovascular safety of long-term treatment with coxibs, as well as traditional NSAIDs that inhibit both COX-1 and COX-2 [ 1 — 5 ].
Cyclooxygenase COX -2 expression is elevated at sites of inflammation such as in synovial tissues in rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis [ 6 ]. However, they can induce hemorrhage and severe gastrointestinal complications because they also inhibit COX-1, which has major roles in hemostasis and gastrointestinal cytoprotection [ 7 ].
Clinical trials have shown that coxibs have analgesic profiles similar to traditional NSAIDs, but are significantly less toxic to the gastrointestinal system. They therefore widely replaced non-selective NSAIDs for treatment of inflammatory joint diseases and other painful inflammatory conditions [ 89 ].
The primary goal of this review is to elucidate the pathophysiology and molecular pathology of cardiovascular complications of NSAIDs, especially COXselective inhibitors such as coxibs.
A second goal is to ízületi fájdalom hastánc clinical factors and laboratory tests that may identify patients with increased risk of cardiovascular complications when using NSAIDs.
A final goal is to identify potential pharmacological and other strategies for cardiovascular risk reduction. The COX-2 isoform plays a major role in initiation of inflammatory alterations in response to injury. In addition, during later stages it may aid in repair and resolution of inflammation.
It is inducible by inflammatory stimuli osteoarthritis treatment guidelines 2022 as cytokines, growth factors, and bacterial endotoxin and is expressed in atherosclerotic lesions and in a variety of tumors.
COX-1 is constitutively expressed in most tissues where it regulates synthesis of physiological levels of prostaglandins. COX-2 is expressed in various normal tissues where its expression may be important for physiological functions such as cardioprotection associated with high-density lipoprotein and apolipoprotein E apoE [ 12 ] see below. Interpretation of experimental and clinical findings is complicated further by dissimilar tissue distribution and altered expression of COX-1 and COX-2 in diseased tissues and by the observation that COX expression differs in different species [ 13 ].
Because COX-1 and COX-2 have some adaptable overlapping functions, effects of their inhibition on the cardiovascular system remain complex and sometimes contentious [ 14 ]. Also important osteoarthritis treatment guidelines 2022 interpretation of effects of NSAID inhibition, when immunohistochemistry is employed to determine COXprotein expression in normal, inflamed, or neoplastic tissues, is the fact that the results may depend on the antibody used [ 17 ].
COX-2 is induced in atherosclerotic plaques, during angiogenesis, and during wound healing [ 918 ]. In a vállízület fájó karja nem emelkedik fel, experimental balloon injury and stent implantation induce expression of COX-2 in areas with atherosclerotic lesions.
Normally, arteries at these anatomic locations express only COX-1 [ 19 ]. In addition, COX-2 is constitutively expressed in the macula densa and renal medullary interstitial cells [ 20 ]. Hyperkalemia can induce cardiac arrhythmia [ 21 ].
Moreover, COX-2 inhibition can increase kidney water retention, and induce peripheral edema and osteoarthritis treatment guidelines 2022 gain. In animal models, selective inhibition of COX-2 promotes hypertension, atherogenesis, and formation of thrombi, all risk factors for acute myocardial infarction.
Nevertheless, the exact pathogenesis of the increased rates of cardiovascular complications caused by coxibs is unclear at this point [ 24 ]. Smoking increases COX-2 expression that induces inflammation [ 25 ]. Chronic inflammatory processes play a major role in carcinogenesis and atherogenesis.
The latter is a major risk factor for myocardial infarction [ 2627 ]. Inflammation plays a role in all stages of atherogenesis, from fatty streak development to plaque formation and plaque rupture [ 28 ]. The inflammatory features resemble the inflammatory alterations osteoarthritis treatment guidelines 2022 in rheumatoid arthritis and osteoarthritis.
Rheumatoid arthritis is associated with accelerated atherosclerosis, anyagcsere-fokozók a fogyáshoz cardiac mortality, and shortened life expectancy. As inhibition of COX-2 reduces inflammation, it was hoped that COXselective inhibitors, when used to reduce pain and inflammation in joint disease, might also inhibit atherogenesis and reduce the rates of myocardial infarction [ 29 ].
For reasons not entirely agreed upon, the opposite was observed in several, but not all, clinical studies associated with use of coxib inhibitors, particularly after long-term use, and in a few clinical studies on the use of traditional NSAIDs such as aspirin and naproxen. Are cardiovascular complications caused by alterations in eicosanoid synthesis?
Are they due to interference with mitochondrial function? Are both mechanisms involved? What is the effect of polymorphism of genes involved in eicosanoid synthesis on responses to NSAID therapy? Cyclooxygenase is rate-limiting for conversion of arachidonic acid to prostaglandin PG H2, which is converted to the important vasoactive eicosanoids thromboxane TXA2 and prostacyclin PGI2 by thromboxane osteoarthritis treatment guidelines 2022 prostacyclin synthase respectively Fig.
The latter plays a key role in carrageenan-induced inflammation [ 30 ]. View larger version: In a new window Fig. Less arachidonic acid AA is consumed. Mitochondrial dysfunction lowers cardiac contractility and is atherogenic. Some important NSAID effects are cyclooxygenase independent, such as celecoxib regulation of expression of monocyte chemoattractive protein-1 MCP-1 that regulates monocyte chemotaxis 8.
Polymorphism of CYP2C9 affects the rate of celecoxib degradation 9.
Az osteoarthritis egy krónikus ízületi patológia, amelyet az ízületi porc pusztulása és potenciális elvesztése jellemez, más csuklócsere-változásokkal, beleértve a csont-hipertrófiát oszteophyta-képződés. Osteoarthritis is a very common condition which can affect any joint in the body.
For details see text. Cyclooxygenase contains 2 active sites. The peroxidase activity is independent of the osteoarthritis treatment guidelines 2022 activity. Furthermore, in addition to PGG2, the peroxidase site can use hydroperoxides such as H2O2 as substrate and generate reactive oxygen species ROS [ 31 ]. NSAIDs can induce secondary effects by altering the size of the arachidonic acid pool, which depends on a dynamic balance between supply and consumption.
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Supply is determined by cytosolic c and soluble s phospholipase A2 PLA2which catalyse cleavage of fatty acids from membrane phospholipids [ 32 ]. Selective inhibition of COX-2 by coxibs, or selective inhibition of COX-1 by tenoxicam, increases the cellular arachidonic acid pool, which stimulates leukotriene synthesis by lipoxygenase LO. Furthermore, some NSAIDs also exert functions that are independent of osteoarthritis treatment guidelines 2022 inhibition, for example, many NSAIDs affect mitochondrial function, expression of cytokines, and growth factors [ 33 — 35 ].
By comparison, valdecoxib 4-[5-methylphenyl-isoxazolyl]-benzene-sulfonamide [ 38 ], meloxicam 4-hydroxymethyl-N-[5-methylthiazolyl] -2H-1,2-benzothiazinecarboxamide-1,1 dioxideibuprofen 2- 4-isobtyl-phenyl -propionic acidnaproxen Dmethoxy-α-methylnaphthaleneacetic acidor diclofenac 2-[ 2,6-dichlorophenyl -amino-benzene-acetic acid exhibit no significant effect on LDL oxidation [ 3439 ].
Many, but not all, clinical studies show that aspirin significantly reduces the risks of MI and stroke. Aspirin lowers cardiovascular risk by osteoarthritis treatment guidelines 2022 platelet thromboxane synthesis and platelet aggregation. Aspirin lowers the serum levels of C-reactive protein CRP [ 41 ] and lipoprotein L a Lp a [ 42 ], which are both independent risk factors for atherosclerosis and myocardial infarction. Aspirin inhibits platelet COX-1 irreversibly, and since platelets lack nuclear DNA, neither additional COX-1 osteoarthritis treatment guidelines 2022 further thromboxane can be synthesized by affected platelets.
Cardiovascular patients who are resistant to aspirin therapy have more than twice the rate of cardiovascular events, compared to aspirin-sensitive patients [ 45 ].
Cardiovascular Complications of Non-Steroidal Anti-Inflammatory Drugs
The altered hemostasis induced by aspirin and other traditional NSAIDs increases the risk of gastrointestinal hemorrhage, intestinal perforation [ 3 ], and excessive perioperative bleeding. Moreover, the inhibition of COX-1 lowers gastrointestinal synthesis of cytoprotective prostaglandins.
Surprisingly, in a clinical study designed to evaluate valdecoxib compared to aspirin, diclofenac, ibuprofen, and placebo, aspirin was associated with a higher risk of thrombotic events than placebo [ 50 ]. However, no increased risk of myocardial infarction was caused by simultaneous use of aspirin and ibuprofen [ 51 ].
In experimental models coxibs cause significantly fewer gastrointestinal complications than traditional NSAIDs [ 52 ]. Rofecoxib, celecoxib, and valdecoxib [ 553 ] oral medication, injectable counterpart: parecoxib differ considerably in their COXselectivity. The exact degree of inhibition of COX-2 versus inhibition of COX-1 varies in different publications, and the following values are representative examples: rofecoxibetodolacmeloxicamand celecoxib 9-fold [ 54 ].
Other investigators found that in a whole blood assay rofecoxib exhibited a fold preference for COX-2 compared with COX-1; the corresponding values for celecoxib, diclofenac, meloxicam, and indomethacin térdízület tünetei a ragasztások gyulladása acid [ 3455 ] were 6. Importantly, in vitro selectivity values are method-dependent, and may not accurately predict selectivity in clinical applications.
Note that some reported selectivity values for meloxicam and indomethacin differ somewhat from those indicated in this gradation list. Rofecoxib is a compound with high analgesic and antiphlogistic efficacy in carrageenan- induced inflammation in rodents. It has demonstrated analgesic potency similar to ibuprofen. However, unlike ibuprofen rofecoxib does not inhibit thromboxane synthesis [ 3757 ].
A study by the rofecoxib manufacturer of a group of patients treated with different NSAIDs for osteoarthritis found no difference in cardiovascular thrombotic events between users of rofecoxib, celecoxib, or non-selective NSAIDs such as ibuprofen, nabumetone 4-[6-methoxynaphthalenyl]butan-one [ 34 ], and diclofenac [ 58 ].
A Canadian study supported this interpretation; it reported no increased risk of myocardial infarction in rofecoxib users [ 59 ]. Additionally, an osteoarthritis treatment guidelines 2022 review of data from multiple rofecoxib studies affirmed that osteoarthritis treatment guidelines 2022 was no solid evidence for increased cardiovascular risk in patients using rofecoxib [ 60 ].
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This point of view was corroborated by other experts [ 61 ]. In a gastrointestinal outcomes research study of rofecoxib, which included patients with rheumatoid arthritis treated either with rofecoxib or naproxen a non-selective cyclooxygenase inhibitorpatients in the rofecoxib treatment group had significantly fewer gastrointestinal complications than those in the naproxen-treated group [ 56 ].
However, the study showed an increased incidence of myocardial infarction and other thrombotic complications in the group of patients treated with rofecoxib. The rates of myocardial infarction were 0.
Several clinical studies have shown that naproxen [ 62 ] may be cardioprotective [44,60,63, 64]. These findings led to a suggestion that the interpretation of an increased rate of myocardial infarction in rofecoxib users was biased because of the cardioprotective effects of naproxen. However, other studies corroborated that rofecoxib therapy in patients with rheumatoid arthritis is associated with increased risk of myocardial infarction [ 6566 ].
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Also, in a group of patients over 65 years of age, use of rofecoxib was associated with increased risk of myocardial infarction compared to use of celecoxib or other NSAIDs. The reports of such diverse clinical findings have led to controversy, dispute, and uncertainty.
Ethical stances emerged about perceived undue delay in issuing warnings about cardiovascular complications [ 68 ]. Public controversy over rofecoxib findings and the final decision to withdraw the drug from the market drew attention to other COXselective inhibitors, eg, celecoxib [ 7374 ] and valdecoxib [ 5 ].
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