Lund University Hospital, SE-221 85 Lund, Sweden
In 1992, I remember a board meeting at which Dr DeWitt from Michigan State University presented new in vitro data indicating predominant inhibition of cyclooxygenase-2 (Cox-2) by a non-steroidal anti-inflammatory drug (NSAID) which in clinical practice had shown good gastrointestinal tolerance [1]. The investigators used rodent enzymes, and unfortunately the data could not be reproduced when using human reagents. However, the search for real Cox-2 inhibitors was already in full swing and, as we all know, this has now resulted in the very successful marketing of two drugs of a new type of chemical, called coxibes [25]. The precise molecular characterization of two Cox isozymes, although not complete, is a fascinating story that has brought excitement into an area which until recently induced somnolence among the general rheumatologist. While it is still true that Cox-1 is expressed constitutionally in most cells and Cox-2 is induced in sites of inflammation and other pathology, recent careful work has clarified several physiological situations in which Cox-2 is up-regulated. The implications, if any, of this new knowledge for the use of Cox-2 inhibitors in the clinic are understood only partly at present. Generally speaking, it is possible that, without being aware of it, for many years we have suppressed important Cox-2 functions by the administration of non-selective NSAIDs.
The driving force behind the rapid and forceful cooperation between basic science and drug development was concern about the serious toxicities of conventional NSAIDs and aspirin, not least the increased fatalities resulting from gastrointestinal bleeding and ulcer perforation [6]. Those who are sceptical about extrapolation from databases such as ARAMIS are referred to a Finnish study that identified 30 fatalities from the use of NSAIDs in that country in a single year [7]. Cox-2 is up-regulated in the inflamed joint, and the hypothesis was that selective inhibition of the inducible Cox-2 isoenzyme would offer therapeutic efficacy without this severe toxicity. Endoscopic data from clinical trials support this hypothesis, but information about the risk of serious events, i.e. bleeding and perforation, is still not to hand. New insights into the biological functions of Cox-2 should caution us from the uncritical use of Cox-2 inhibitors. There is convincing evidence from published trials [24] that celecoxib is equivalent but not superior to conventional NSAIDs in the symptomatic control of osteoarthritis (OA) and rheumatoid arthritis (RA). Such evidence is also available for rofecoxib and OA [5]. However, long-term safety can be established only with time and, as with all new types of drugs, we should be vigilant in recognizing possible new types of problems. The questions that must still be addressed concern the ultimate consequences of selective inhibition of Cox-2 and its biological functions [8].
Cox-1 is the dominating isozyme in the upper gastrointestinal tract, where it probably serves a protective function. Animal data and endoscopic data in humans clearly indicate better tolerance for the Cox-2-selective drugs than for conventional NSAIDs [9]. It should be noted that patients with pre-existing ulcers were excluded from the endoscopic studies. However, both celecoxib and rofecoxib do cause dyspepsia in some patients, and the rate of drug discontinuation because of adverse gastrointestinal reactions was similar for coxibs and conventional NSAIDs in several trials [10]. Uncertainties also remain regarding higher doses of rofecoxib. For these reasons, and because of the lack of long-term safety data, labels for the new drugs still have warnings about upper gastrointestinal toxicity. Whereas Cox-2 inhibitors can be administered safely to rodents for long periods, other data indicate a role for Cox-2 in experimental ulcer healing. Rodents with a mutated Cox-1 gene do not develop spontaneous gastric ulceration [8]. In humans, large endoscopic studies in patients with RA and OA have convincingly shown less damage to the gastric mucosa than after exposure to conventional non-selective NSAIDs [2, 3, 911]. However, only post-marketing observations in larger groups, including patients who are at risk, will reveal how safe the Cox-2 inhibitors are in everyday use.
In experimental colitis, Cox-2, but not Cox-1, is up-regulated. Administration of a selective Cox-2 inhibitor caused exacerbation of the inflammation and perforation in a rat model of colitis [47]. This calls for caution when treating patients with inflammatory bowel disease.
Fetal silencing of the Cox-2 gene results in reduced fertility and offspring with severe renal pathology, effects that do not occur in Cox-1 knockout mice [14]. Cox-2 is involved in ovulation and egg implantation. For these reasons, it is possible that both NSAIDs and coxibs reduce fertility in humans, although no supporting data are available. Celecoxib in high doses is teratogenic in rabbits. The Cox-2 effect is mediated through prostacyclin and the peroxisome proliferator-activated receptor family, and ultimately results in angiogenesis. Teratogenicity should therefore not come as a great surprise. Cox-2 is also up-regulated in the vas deferens of adult male rats, and this is presumably androgen-driven [12]. It is thus evident that Cox-2 has several important functions in reproduction and that its inhibition should be avoided during pregnancy. It may not be generally appreciated that the same caution is warranted regarding conventional NSAIDs [13].
A hallmark of Cox-2 biology is that this isozyme is not active in platelets, and therefore selective Cox-2 inhibitors do not affect platelet function or thromboxane (Tx) synthesis. On the other hand, Cox-2 is expressed in endothelial cells and in macrophages. In contrast to ibuprofen, celecoxib given in doses up to 800 mg in humans did not inhibit platelet aggregation and it had only a marginal effect on circulating TxA and the urinary excretion of TxB, which in these experiments were markedly depressed by ibuprofen. Both drugs reduced circulating prostaglandin E (PGE) and the urinary excretion of stable prostacyclin (PGI) metabolites by 80% or more [15]. It follows that Cox-2-selective drugs should have advantages for pain therapy over conventional NSAIDs in patients with platelet dysfunction. But it also raises the question of whether they may be more dangerous in conditions associated with hypercoagulation. Anecdotal evidence of thrombotic complications in patients with systemic sclerosis and with antiphospholipid syndrome was presented at a meeting held only 7 months after the first US licensing of a Cox-2-selective drug [8].
As already mentioned, Cox-2 has an important function in renal embryonic development in the mouse [14]. Not only gene disruption, but also antenatal administration of selective Cox-2 inhibitors, resulted in impaired cortical development [16]. Administration of the Cox-2 inhibitor from day 0 to day 21 of the neonatal period resulted in severely reduced glomerular diameter. Administration of a Cox-1-selective inhibitor had no renal effects. Cox-2 expression in the macula densa is up-regulated in salt depletion and other situations that lead to renin production, and blockade of Cox-2, but not of Cox-1, inhibits renin production [17]. Whereas it is not entirely clear to what extent these animal data can be extrapolated to humans, sodium retention and oedema formation is well documented in the initial phase of Cox-2 inhibition [12]. On the other hand, only non-selective NSAIDs reduce the glomerular filtration rate [18]. Cox-2 is up-regulated in the kidney in mice with experimental lupus and Cox-2 inhibition prolongs the survival of such animals [8]. This observation indicates that Cox-2 may play a negative role in glomerulonephritis, and it has been reported to be up-regulated in patients with systemic lupus erythematosus [19]. It can be concluded that Cox-selective inhibitors have provided new tools to investigate renal physiology and that both Cox isozymes are expressed in the normal and diseased kidney. There is no evidence in support of increased renal safety of Cox-2 inhibitors compared with NSAIDs.
Prostanoids are involved in the regulation of circulation and bronchial secretion in the normal lung, and Cox-2 is up-regulated in macrophages, endothelial cells and smooth muscle cells in the bronchial epithelium [12, 20, 21]. Cox-2 may have more beneficial than adverse effects in the lung [8], and selective inhibitors probably have no advantage over conventional NSAIDs in patients with pulmonary sensitivity to NSAIDs.
Interleukin-1ß (IL-1ß) and PGE2 are known to inhibit insulin secretion. It is believed that exogenous IL-1ß acts via PGE2 [12]. It has now been shown that Cox-2 is the isozyme responsible [22]. The clinical effects of pharmacological Cox-2 inhibition for endocrine pancreas function need further investigation.
Both Cox isozymes are expressed in bone tissue and PGE and prostacyclin are involved in normal bone metabolism [12]. It is evident that up-regulation of Cox-2 by mechanical stimulation is one of the regulatory factors involved [23], and therefore adverse effects of Cox-2 inhibition on bone cannot be ruled out. This could be of particular importance in the healing of fractures. Bone morphogenic protein BMP-2, as well as IL-1, can induce both Cox-2 and osteoclast differentiation factor in human cell cultures [24]. Thus it is conceivable that inhibitors of Cox-2 can affect osteoclastogenesis and thereby normal bone remodelling.
As first shown by the editor of this journal more than a decade ago, a strong negative correlation exists between RA and Alzheimer's disease [25]. This effect is apparently related to the long-term pharmacological inhibition of Cox, but it is not entirely clear if one or both isozymes are involved [12]. Most but not all recent reports, however, favour the importance of Cox-2 [2629]. The implication of inflammation in the plaque lesions of Alzheimer's disease has motivated preliminary therapeutic trials with, for example, indometacin and other Cox inhibitors. These have not so far revealed a convincing benefit [30], but this does not exclude a putative preventive role for Cox-2 inhibitors.
In 1986, Finnish investigators reported that the nationwide mortality in gastrointestinal cancer among RA patients was only half of the expected rate [31]. This observation has been amply confirmed in several large studies and can be linked to long-term intake of aspirin [32] or NSAIDs [33] in a dose-related fashion. Later work showed Cox-2 expression in many, but not all, of the colon carcinomas that were examined [34], and some workers have even tried to correlate the occurrence of Cox-2 with survival and lymph node involvement [35, 36]. Other gastrointestinal malignancies, such as lung cancer, cancers of the prostate and urinary bladder and other forms of cancer, have been found to express Cox-2 [12, 3639]. The biological implications are not restricted to oncology but are of general interest. There is good evidence linking Cox-2 and perhaps Cox-1 to angiogenesis, an essential component of invasive cancer growth, but also of wound-healing and inflammation [40]. The therapeutic potential of Cox-1 or Cox-2 inhibition in preventing and treating malignancy [41] is beyond the scope of this article. There may be differences between drugs and there may be threshold dosages needed for efficacy. The NSAID clinoril has for some time been used in patients with the rare form of familial adenomatous polyposis (FAP) [4244]. Interestingly, the effect may rest in part on the induction of apoptosis [44, 45]. Another NSAID, nimesulide, was recently found to be ineffective in FAP [46]. In December 1999, the American FDA recommended celecoxib at the high dose of 400 mg twice daily in patients with FAP, on the basis of unpublished data showing regression of adenomas.
To my knowledge, no direct comparisons have been undertaken between the new drugs celecoxib and rofecoxib. Chemically, they differ from NSAIDs as they are non-acidic and thus lipophilic. Celecoxib is less water-soluble than rofecoxib, and it has a sulphonamide side-chain, whereas rofecoxib has a methylated sulphoxide in the corresponding side-chain. There may be differences in the degree of relative selectivity for Cox-2, although both are strictly Cox-2-selective at their recommended doses. Time will show if these two or any of the second- or third-generation coxibes have special advantages.
Returning to the provocative question posed in the title, this article is not intended to convey a negative message regarding the future of Cox-2 inhibition in rheumatic therapy. Improved gastrointestinal safety is a major advantage, although we do not yet know the extent of this improvement. But caution is still warranted when it comes to unexpected late risks, an attitude that seems reasonable when starting the wide use of a new pharmacological agent (Table 1). The impressive amount of new information regarding the regulatory functions of Cox-2 will have a major impact in several fields of medicine. The potential for use in high-risk patients and new indications holds considerable promise for the future.
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