cox-2: separating myth from reality
TRANSCRIPT
Scand J Rheumatol 1999;28 Suppl 109:19–29
COX-2: Separating myth from reality
F. McKenna
Trafford General Hospital, Davyhulme, Manchester, UK
Several currently available nonsteroidal anti-inflammatory drugs (NSAIDs) have been evaluated for their relative selectivityin inhibiting the two cyclooxygenase (COX) isozymes, COX-1 and COX-2. Arguments have been made that more selectiveinhibitors of COX-2 will be safer than less selective ones. Rankings of the COX-2/COX-1 inhibition ratios of variousNSAIDs as they relate to the agents’ toxicities have been used as evidence that COX-2 selectivity is an important factorin the upper gastrointestinal (GI) safety of some NSAIDs. Unfortunately, none of these claims has been supported byendoscopy studies in treated patients. Since all NSAIDs inhibit COX-1, they all cause upper GI mucosal damage. What isneeded are specific COX-2 inhibitors that do not inhibit COX-1. Such agents are currently under development. Ongoingclinical trials will determine the potential role for specific COX-2 inhibitors in the treatment of arthritis and pain. If specificCOX-2 inhibitors are shown to be both safe and effective, the treatment of rheumatic diseases will be revolutionized.
Key words: cyclooxygenase, COX-1, COX-2, COX inhibition, NSAIDs
Aspirin and other nonsteroidal anti-inflammatorydrugs (NSAIDs) have been used for a century totreat rheumatic symptoms. However, their use isoften restricted by the risk of side effects, particu-larly in the upper gastrointestinal (GI) tract. Duringthe past two decades, investigators have recognisedthat NSAID-induced ulcers are present in up to 25%of treated patients at any one time (1). It is alsoclear that the risks of both NSAID-associated ulcersand their complications are greatest in the elderly(2), who have the most need for NSAID treatment.The morbidity and mortality from NSAID-inducedulcers and ulcer complications are considerable. Inthe United Kingdom alone, 2500–3000 deaths peryear may be attributed to perforation or haemor-rhage resulting from NSAID therapy (3).
In 1971, Vane (4) and Smith and Willis (5) sep-arately described the inhibition of the cyclooxyge-nase (COX) enzyme by aspirin, resulting in a re-duction in prostaglandin (PG) synthesis. This ob-servation led to the hypothesis that both the toxicityand efficacy of NSAIDs are mediated through theinhibition of PG synthesis. During the past decadeinvestigators have identified at least two COX en-zymes (COX-1 and COX-2) with different stimuliand different functions. Research has also estab-lished that the various NSAIDs have different in-hibitory effects on COX-1 and COX-2, and it hasbeen proposed that these differences determine thevarying GI toxicities of these agents. The presentpaper reviews the evidence for this hypothesis.
Correspondence: F. McKenna, Rheumatic Diseases Unit, TraffordGeneral Hospital, Davyhulme, Manchester M41 5SL, UK.
The discovery of different COX isoforms
PGs are short-lived substances that have importantlocal actions as part of normal physiology. Theyare also mediators of the inflammatory response.When arachidonic acid is liberated by phospholi-pase A2, the action of COX on the arachidonic acidproduces several PGs. Gastric mucosal integrityand renal function are maintained by some of theresulting PGs, such as prostacyclin, and platelet ag-gregation is aided by the production of thrombox-ane A2. However, PGE2 is detected principally ininflammatory conditions and mediates the swellingand pain associated with acute and chronic inflam-mation. NSAID-induced inhibition of COX there-fore leads to a reduction in the activity of thesemechanisms.
In the 1980s, studies by Needleman and col-leagues suggested that COX was not a single en-zyme (6–8). Until that time it was thought that therate-limiting factor for the formation of PGs wasthe availability of the arachidonic acid substrate.However, Needleman and associates discoveredthat both the cytokine interleukin-1 and bacteriallipopolysaccharide (endotoxin) increased the ac-tivity of COX without affecting the activity ofphospholipase A2. They subsequently demon-strated that the glucocorticoid dexamethasoneblocks lipopolysaccharide-induced prostanoid re-lease by inhibiting the induction of monocyte COXexpression without affecting basal PG production(9). Dexamethasone eliminated the enhanced PGproduction and COX expression stimulated by cy-tokines or endotoxin. Needleman and colleaguestheorized that part of the anti-inflammatory activity
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of glucocorticoids could be explained by down-regulation of COX expression, and since COX atthat time was not thought to be regulated, theyfurther postulated the existence of a second COXisozyme. Other researchers have subsequently con-firmed a second isoform from molecular cloning(10). One enzyme is involved in normal bodyhomeostasis, and the other is involved in the me-diation of inflammation. The two enzymes havebeen termed, respectively, COX-1 (the constitutiveenzyme) and COX-2 (the inducible enzyme).
Tissue expression of COX-1 and COX-2
COX-1 is present in the GI tract, in platelets and en-dothelial cells, and in the renal medullary collectingducts and interstitium (Table I). COX-1 synthesisesthe PGs that regulate the normal physiologic pro-cesses involved in protecting the GI mucosa andin maintaining renal function as well as vascularhomeostasis (through platelet aggregation). Thisrole of COX-1 has been referred to as a “house-keeping” function.
Table I: Comparison of COX-1 and COX-2 isoforms.
COX-1 COX-2
Constitutive Inducible
Present under basal conditionsin stomach, intestines, kidney,platelets, other tissues
Present under basal conditionsin brain, kidney, prostate, uterus
“Housekeeping” role Expression enhanced byendotoxin, cytokines
Regulates normal renal andgastric function and vascularhomeostasis
Up-regulated at inflammatorysites:— macrophages— synoviocytes
Inhibited by NSAIDs Inhibited by glucocorticoidsand NSAIDs
COX-2 is present under basal conditions inthe brain, renal cortex, uterus, and prostate gland(11–19) (Table I). The function of COX-2 at thesesites is not understood, although the enzyme ap-pears to have a role in the development of thebrain and kidney. Moreover, renal function maydepend at least in part on the ability of COX-2 togenerate PGs in response to certain stimuli (18),and the evidence from studies in COX-2 gene-destructed (“knock-out”) mice suggests a “house-keeping” role for COX-2 in certain visceral tissues(12). However, the major physiologic effects ofCOX-2 appear to result from its up-regulation dur-ing inflammation. Various inflammatory stimuli,
including growth factors, bacterial lipopolysaccha-rides, and mitogens, promote the expression ofCOX-2 in neutrophils, macrophages, endothelialcells, and fibroblasts (10,20–27).
COX-2 is intensely expressed in the synovial lin-ing layer in patients with rheumatoid arthritis (RA),and this has been shown to correlate with mononu-clear cell infiltration, which provides a measure ofsynovial inflammation (28). COX-2 is either un-detectable or detectable at low levels in synovialtissue from patients with osteoarthritis (OA) andfrom individuals with normal joints (28).
Efficacy of NSAIDs versussteroids in OA
Since the early 1970s, investigators have hypothe-sised that the mode of action of NSAIDs is throughthe inhibition of COX and inflammatory PGs (29).Bergstrom, Samuelsson, and Vane received the1982 Nobel Prize for Physiology or Medicine asa result of the work that led to this hypothesis (30).However, it has been difficult to reconcile certainclinical data with the NSAID hypothesis, partic-ularly with regard to the belief that NSAIDs arelargely equipotent despite considerable differencesin their ability to inhibit COX. The discovery oftwo isoforms of COX raised further doubts aboutthe NSAID hypothesis, especially as it relates tothe treatment of OA.
NSAIDs are effective in treating the signs andsymptoms of OA, but, as mentioned above, COX-2 may be undetectable in the synovial tissues ofOA patients. It could be argued that a variablepresence of COX-2 in synovial tissues in OA mayreflect differing clinical responses to NSAIDs inthis disease. A more difficult problem to reconcileis the lack of an effect of steroids in patients withOA.
The COX-2 isoform was first detected as a resultof the observation that dexamethasone had no ef-fect on basal PG production but eliminated the PGproduction and COX expression stimulated by cy-tokines and endotoxin. Corticosteroids are knownto be effective inhibitors of COX-2. Therefore, ifthe mode of action of NSAIDs is through the in-hibition of COX-2, corticosteroids should be as ef-fective as NSAIDs in the same clinical situations.However, except for intra-articular treatment, cor-ticosteroids do not have any proven efficacy in pa-tients with OA. This may be a dose effect, althoughintra-articular steroids are usually beneficial only inpatients with demonstrable inflammation (31). Itis also possible that NSAIDs are effective in OA
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COX-2: Separating myth from reality
through their ability to inhibit the basal expressionof COX-2 in the central nervous system, which maynot occur with the usual therapeutic doses of oralcorticosteroids. Nevertheless, the differing thera-peutic effects of NSAIDs and corticosteroids in OAneed to be explained, since these observations makeit difficult to support the argument that the anti-inflammatory efficacy of NSAIDs is mediated onlythrough the inhibition of COX-2.
Differential inhibition of COX-1and COX-2 by NSAIDs
In view of the discovery of the two COX isoforms,investigators currently hypothesise that the efficacyof NSAIDs is mediated by their ability to inhibitCOX-2 and that the toxicity of NSAIDs is mediatedby their ability to inhibit COX-1. NSAIDs inhibitthe two COX isoforms to varying degrees. Pairetand Engelhardt have proposed that the differenttoxicities of the currently available NSAIDs canbe explained by each drug’s differential inhibitionof COX-1 and COX-2 (32). They have also arguedthat newer drugs will be safer in the upper GI tract
if they preferentially inhibit COX-2 over COX-1.This argument is outlined below.
The ratio of inhibition of COX-1 to COX-2 hasbeen evaluated in different enzyme systems formost currently available NSAIDs. The degree ofCOX inhibition and the COX-2/COX-1 inhibitionratio vary depending on the assay used. Never-theless, different NSAIDs have been ranked in theorder of their COX-2/COX-1 inhibition ratios, andthis ranking has been used to draw comparisonsamong NSAIDs in some published studies. TheGI toxicity of diclofenac, naproxen, ibuprofen, in-domethacin, and piroxicam has been evaluated intwo different studies using different assay methods(33,34). In a report by Langman and colleagues(33), 1144 NSAID users aged > 60 years admittedto hospital with bleeding peptic ulcer were com-pared with 1126 hospital controls and 989 com-munity controls matched for age and sex. In addi-tion, Garcıa Rodrıguez and Jick evaluated exposureto NSAIDs in 1457 cases of bleeding or perfora-tion from a peptic ulcer (34). Cases of bleedingor perforation were identified from general practi-tioners’ computerised records in the United King-dom and were compared with the records of 10000
Figure 1: Comparison of GI toxicity odds ratios of NSAIDs in two case-control studies (33,34).
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control subjects from the same source. The tox-icity ratios (odds ratios) for some NSAIDs weresimilar in the two studies, whereas the toxicity ra-tios of other NSAIDs were different. For example,the toxicity ratios for diclofenac were 3.9 and 4.2in the two reports, respectively, whereas the ra-tios for naproxen were 3.1 and 9.1 and the ratiosfor indomethacin were 6.3 and 11.3. The toxicityratios for piroxicam were 18.0 and 13.7. Never-theless, the rank orders of these five widely pre-scribed NSAIDs were similar in the two studies,supporting the view that real differences in toxic-ity exist among these agents (Fig. 1). Moreover,the rank orders of COX-2/COX-1 inhibition ratioswere similar to the toxicity ratios in the two studies,supporting the clinical relevance of COX-2/COX-1ratios as indicators of NSAID-associated GI toxic-ity (32) (Table II).
However, this argument has serious flaws. Di-rectly comparing each NSAID, rather than usingan artificial “rank order”, appears to provide lessconvincing data (Fig. 2). The major problem liesin the methods used to assess COX-2/COX-1 inhi-bition ratios and to determine the toxicity of dif-
Table II: Comparison of rank orders of COX-2/COX-1inhibition ratios from Langman et al. (33)and Garcıa Rodrıguez and Jick (34).
Langman et al. Garcıa Rodrıguezand Jick
Diclofenac 3.9 4.2
Naproxen 3.1 9.1
Ibuprofen 6.5 2.0
Indomethacin 6.3 11.3
Piroxicam 10.8 13.7
ferent NSAIDs. Any attempt to “rank” the dif-ferent NSAIDs according to their COX-2/COX-1 inhibition ratios depends on the assay methodused. Some systems employ animal cells, whereasothers use human platelets and lipopolysaccharide-stimulated human monocytes. Some models consistof whole-cell cultures, and others use homogenisedcells. It is impossible to predict the results thatwill be achieved with any individual assay model.For example, Mitchell and colleagues demonstrated
Figure 2: Comparison between the toxicity odds ratios of five NSAIDs in Langman et al. (33) and the COX-2/COX-1inhibition ratios of the same NSAIDs in Vane and Botting (29). IC50 = concentration required to inhibit enzymeactivity by 50%.
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COX-2: Separating myth from reality
that aspirin and nonsalicylate NSAIDs have vary-ing COX-2/COX-1 inhibition ratios depending onwhether the assays were done with broken cells,purified enzyme, or intact cells (35). Overall, theresults of different assay systems are discordant,and standardisation is urgently needed (Fig. 3).
It is also difficult to reach a consensus regardingthe toxicity ratios of NSAIDs based on the clinicaldata. Although the results of the case-control stud-ies reported by Langman and colleagues (33) and
by Garcıa Rodrıguez and Jick (34) show some con-cordance, data from other studies do not. Geis andcoworkers published the largest endoscopic studyof the prevalence of NSAID-induced upper GI mu-cosal damage (1). A screening of more than 1800patients treated with different NSAIDs showed thatthe prevalence of gastric or duodenal ulceration orerosions was not significantly different among thevarious agents. For example, the prevalence of mu-cosal damage by ibuprofen was similar to that byindomethacin or piroxicam. The rank order of toxi-
Figure 3: Variability in laboratory assessments of COX-2/COX-1 inhibition ratios using four different assaymethods (35,39,43,47).
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city derived from the ARAMIS (Arthritis, Rheuma-tism, and Aging Medical Information System) database (36), which comprises information from morethan 23000 patients, also gives a different rankingof NSAIDs compared with those in the studies byLangman (33) and by Garcıa Rodrıguez and Jick(34). The ARAMIS programme included data onthe outcome of approximately 3000 patients withRA who were followed prospectively for an aver-age of > 9 years (36). Both this study and theone by Geis and colleagues (1) do not support therank order of toxicity described by Langman andby Garcıa Rodrıguez and Jick (Fig. 4). It is ap-parent, therefore, that by choosing a certain animalmodel and a specific toxicity index, one may sup-port virtually any argument (Fig. 5).
Are conventional NSAIDsCOX-2 selective?
On the basis of in vitro data, some NSAIDs havebeen promoted as being less likely to cause GIdamage by virtue of their ability to preferentiallyinhibit COX-2 rather than COX-1. The evidenceto support these claims is discussed below.
Meloxicam
Meloxicam is in the enolic class of NSAIDs, whichincludes piroxicam and tenoxicam. It has a shorterhalf-life (approximately 20 hours) than the otherenolic drugs. In most biologic models, meloxi-cam has demonstrated markedly preferential inhi-bition of COX-2 over COX-1, conferring an ap-parently improved therapeutic ratio. For example,Englehardt (37) reported a COX-2/COX-1 inhibi-tion ratio of 0.33 for meloxicam compared with2.2 for diclofenac, 16 for tenoxicam, 30 for in-domethacin, 33 for piroxicam, and 317 for ibupro-fen. Meloxicam has been shown to be an effectiveanti-inflammatory drug in animal models, and inclinical studies it has demonstrated efficacy sim-ilar to that of other NSAIDs when prescribed at15 mg/d, although 7.5 mg/d appears to be lesseffective than 100 mg/d of diclofenac (38). Theuse of meloxicam, however, is still associated withupper GI side effects. In a 4-week comparisonof meloxicam 7.5 mg/d and diclofenac 100 mg/din more than 9000 patients with OA, GI adverseevents were reported in 13% of the patients givenmeloxicam versus 19% of those given diclofenac(39). Five patients taking meloxicam had serious
Figure 4: Toxicity of five NSAIDs at endoscopy in Geis et al. (1) and in the ARAMIS study (36).
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Figure 5: Comparison of the toxicity of five NSAIDs at endoscopy in Geis et al. (1) with the COX-2/COX-1inhibition ratios of the same NSAIDs in Vane and Botting (29).
GI complications (defined as perforation, ulcera-tion, or haemorrhage) compared with 7 patientstaking diclofenac. Fewer side effects were reportedwith meloxicam, but there was no statistical differ-ence between the rates of serious GI complicationswith the two agents.
To date, no endoscopy studies of arthritis patientstreated with meloxicam have been published. Asmall endoscopy study in healthy volunteers com-pared meloxicam 15 mg/d with piroxicam 20 mg/d(40). After 4 weeks of treatment, the patients givenmeloxicam had a mean endoscopic damage scoreof 2.5 compared with a mean score of 4.4 in thosegiven piroxicam (Fig. 6). This difference was notstatistically significant.
From the published data, it may be concludedthat although meloxicam is a selective COX-2 in-hibitor, it still causes dyspepsia and upper GI mu-cosal damage. In low doses, meloxicam may besafer than 100 mg of diclofenac, but in equipotentdoses its toxicity profile may not be much betterthan that of other NSAIDs. The reason for this isperhaps explained by some of the published data.In recommended clinical doses, meloxicam can be
expected to achieve a plasma concentration that ex-ceeds the IC50 for the inhibition of COX-1 (41)(Table III). Other drugs may exceed the IC50 forCOX-1 inhibition by a greater degree, but if thereis any inhibition of COX-1, then it is likely thatupper GI mucosal damage will occur.
Nabumetone
Nabumetone is a pro-drug that is metabolised in theliver to its active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA). In vitro findings suggestedthat 6-MNA is a selective inhibitor of COX-2 (42),although this was not confirmed by other reports(43,44).
Postmarketing surveillance studies of nabume-tone as well as prescription monitoring of 2000 pa-tients in the United Kingdom have indicated thatthe GI safety of nabumetone is similar to thatof other currently available NSAIDs (45). Anendoscopy study of 171 OA patients aged > 60years found more ulceration by ibuprofen than bynabumetone, and the incidence of GI mucosal dam-age by nabumetone 1000 mg/d was similar to thatof ibuprofen co-prescribed with misoprostol (46).
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Table III: Relationship between in vivo drug concentration and COX inhibition. Data from Churchill et al. (41).
In vivo plasmaconcentration (ÿmol/L)
In vitro COX-1 IC50(ÿmol/L)
In vitro COX-2 IC50(ÿmol/L)
Ratio of COX-1 vsCOX-2 selectivity
Piroxicam 60.0 2.03 0.98 2.1
Naproxen 238.0 0.33 7.08 0.1
Diclofenac 0.9 0.0026 0.001 2.6
Ibuprofen 243.0 2.26 15.72 0.1
Indomethacin 28.0 0.02 0.03 0.7
Nimesulide 16.0 1.61 0.36 4.5
Meloxicam 6.0 2.24 0.166 14.0
These results are interesting, but it could be ar-gued that the dose of nabumetone used in thesestudies was subtherapeutic and may therefore havebeen expected to cause less upper GI mucosal dam-age. Moreover, since the COX-2 selectivity ofnabumetone is debatable and since the postmarket-ing surveillance data have associated nabumetonewith upper GI side effects (47), the clinical find-ings do not support an advantage of nabumetonethrough COX-2 selectivity.
NimesulideNimesulide is a weakly acidic sulphonanilidederivative. In some in vitro studies, this agentpreferentially inhibited COX-2 over COX-1, withan inhibition ratio of 0.1 (29). Epidemiologic dataindicate that nimesulide may be associated with areduced incidence of GI side effects compared withother NSAIDs (48). In a small endoscopy studyof patients with dyspepsia, the endoscopic findingswere largely unchanged after 1 week of treatmentwith nimesulide 100 or 200 mg/d and were nodifferent than those of placebo (49). Moreover,in another small endoscopy study in patients withOA, the incidence of gastric and duodenal musocaldamage after 1 month of treatment with nimesulide100 mg BID was similar to that of diclofenac 50mg TID (50). Although nimesulide is an interestingagent, the clinical data are insufficient to supportan improved GI safety profile compared with other,less preferential or less selective COX-2 inhibitors.
EtodolacEtodolac is a pyranocarboxylic acid that was re-ported to preferentially inhibit COX-2 over COX-1,with an inhibition ratio of 10:1 (51). This find-ing, however, was not confirmed by Laneuvilleand colleagues, who found the COX-2/COX-1 in-hibition ratio of etodolac to be only 1.24 (43).
Figure 6: Mean endoscopic scores in volunteers takingmeloxicam 15 mg/d or piroxicam 20 mg/d. Data fromPatoia et al. (40).
A 1-week, placebo-controlled endoscopy studyin healthy male volunteers reported better gastricscores with etodolac 600 or 1000 mg/d comparedwith indomethacin 200 mg/d, ibuprofen 2400 mg/d,and naproxen 1000 mg/d (52). The long-term GIside effects of etodolac also appeared to be lesssevere than those of ibuprofen in a randomisedparallel-group study of 1446 patients with RA(53). In that trial, patients received either etodolac(150 or 500 mg BID) or ibuprofen (600 mg QID)for up to 3 years. Ibuprofen caused a significantlyhigher incidence of GI ulceration and haemorrhagecompared with both doses of etodolac (p = 0.005).Nevertheless, an endoscopy evaluation by Geis andcolleagues found a 36% incidence of GI mucosal
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damage by etodolac, which was similar to that ofother NSAIDs (1). In a review of the clinical datarelated to etodolac, the Food and Drug Adminis-tration (FDA) in the United States concluded thatthe spectrum of adverse events associated with thisagent does not appear to differ from that of othercurrently available NSAIDs (54).
Specific COX-2 inhibitors
Although some NSAIDs inhibit COX-2 more thanCOX-1, it is apparent from the clinical data thatall currently available NSAIDs inhibit COX-1 tosome degree and are likely to cause upper GI mu-cosal damage, with the consequent risk of signifi-cant morbidity and mortality. Rather than preferen-tial or selective inhibitors of COX-2, what is neededare specific inhibitors of COX-2 — drugs that willinhibit this enzyme without inhibiting COX-1. The-oretically, such agents should be free of the riskof upper GI mucosal damage associated with con-ventional NSAIDs. What is unknown, however, iswhether they would be as effective as the currentlyavailable anti-inflammatory agents.
In vitro studies of several drugs currently un-der development have indicated COX-2 inhibitionwithout significant COX-1 inhibition. Celecoxib(SC-58635), which is at the most advanced stageof clinical development of the specific COX-2 in-hibitors, inhibits COX-2 more than COX-1 by afactor of 375 (compared with a factor of 14 formeloxicam). Other drugs at earlier stages of de-velopment have COX-2/COX-1 inhibition ratios ofup to 5000:1 (CGP-28238). Celecoxib has beenshown to inhibit COX-2 without inhibiting COX-1,and studies in adjuvant models of arthritis indicateanti-inflammatory activity comparable with that ofindomethacin (55). Moreover, early results fromclinical trials suggest that this compound is effec-tive in relieving the symptoms of RA (56) and isan effective analgesic in patients with OA or den-tal pain (57).
If confirmed, these data are extremely importantfor the therapy of rheumatic diseases. It is likelythat, with the new millennium, we will witness arevolution in the treatment of rheumatic pain andthat most, if not all, currently available NSAIDswill become redundant.
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