Celecoxib for the treatment of musculoskeletal arthritis
Marco Krasselt and Christoph Baerwald

Division of Rheumatology, Medical Department III – Endocrinology, Nephrology and Rheumatology, Department of Internal Medicine, Neurology and Dermatology, University of Leipzig Medical Centre, Leipzig, Germany

Introduction: The cyclooxygenase (COX)-2 inhibitor celecoxib is an approved compound for rheuma- toid (RA) and osteoarthritis (OA), combining both anti-inflammatory and analgesic properties with a good gastrointestinal tolerability.
Areas covered: This article covers the pharmacological properties and clinical efficacy as well as the latest safety data available for celecoxib with emphasis on the treatment of RA and OA. It is based primarily on a current literature search on PubMed and Web of Science, but also on the professional rheumatological expertise of the authors.
Expert opinion: Celecoxib has been shown to be superior to placebo and equivalent to traditional non- steroidal anti-inflammatory drugs (tNSAIDs). Many studies have been published making celecoxib a good and safe treatment option in particular in moderate arthritis and patients without established cardiovascular (CV) disease. Moreover, older patients might gain significant benefits compared to tNSAIDs due to reduced gastrointestinal events even when having a history of ulcer bleedings. Nonetheless, there is still much to learn, especially regarding the prescription of celecoxib in patients with cardiovascular co-morbidities. While low doses seem to be safe according to present data, the knowledge on the more effective, higher doses >400 mg/day is still limited.
ARTICLE HISTORY Received 17 April 2019 Accepted 15 July 2019
Celecoxib; coxibs; arthritis; pain; NSAID

RA is an autoimmune disease and the most common kind of inflammatory arthropathy: the incidence is estimated to be 0.5% to 1% [1]. It appears to be rising with age and reaches a peak between 65 and 74 years with up to 89 per 100.000 people per year [2]. Studies measured the lifetime risk of ever developing RA to be 3.6% for women and 1.7% for men, respectively [3]. From a global perspective, RA was ranked as the 42nd highest contributor out of 291 conditions to disabil- ity, just below Malaria [4].
OA though affects 15% of the population and was ranked as the 11th highest contributor out of 291 conditions to global disability (knee and hip OA alone) [5,6]. The global prevalence of knee OA is estimated to be 3.8%, those of hip OA almost 1% [5]. Prevalence raises with age, reaching more than 33% in patients ≥65 years [7].
Since the first consultation of a physician usually is due to painful joints, the first goal for both, patient and attending physi- cian is rapid pain relief. The anti-inflammatory and analgesic properties of traditional (t) non-steroidal anti-inflammatory drugs (NSAID) are well known and approved for decades. Before usage of any other drugs, tNSAIDs are widely prescribed for symptomatic treatment of arthritis by physicians all over the world.
The article at hand reflects approx. 20 years of clinical experience with celecoxib, a commonly used cyclooxygenase (COX)-2-inhibitor, and presents most recent clinical trial data regarding efficacy as well as safety. Furthermore, it provides

important details on the drug itself including pharmacody- namics and pharmacokinetics. We will also discuss mechan- isms potentially being involved in the cardiovascular side effects of COX-2 inhibitors. Presently, celecoxib is probably one of the best investigated drugs; as of March 2019, the government webpage www.clinicaltrials.gov of the United States National Institutes of Health counts 354 clinical studies on the compound [8]. Celecoxib has – dose-dependent – a comparable effi cacy to tNSAIDs in the treatment of arthritis pain. Good tolerability, similar to tNSAID in combination with a proton-pump inhibitor (PPI), was shown for the upper gas- trointestinal (GI) tract [9]. Furthermore, a better tolerability of celecoxib was detected for the lower GI-tract [10]. Since lower GI-complications such as bleedings are associated with a higher mortality, this finding is of particular importance. A detailed view on the mechanism of action, clinical efficacy, side effects and recent clinical trials on celecoxib will be provided in the body of this review.
Using the term ‘celecoxib’ and either ‘rheumatoid arthritis’ or ‘osteoarthritis’, a literature search was performed in February and March 2019 in PubMed and Web of Science. The retrieved articles have been sorted by relevance with the focus being on clinical trials regarding RA and OA. Important studies on side effects, in particular addressing GI-complications and cardiovascular safety, have also been included by expanding the search terms using ‘gastrointestinal’, ‘ulcer’, ‘cardiovascular’ and ‘myocardial infarc- tion’. Investigations meeting the following criteria have been included: randomized controlled trials on celecoxib compared to

CONTACT Marco Krasselt [email protected] Division of Rheumatology, Medical Department III – Endocrinology, Nephrology and Rheumatology, Department of Internal Medicine, Neurology and Dermatology, University of Leipzig Medical Centre, Liebigstr. 20/22, Leipzig 04103, Germany © 2019 Informa UK Limited, trading as Taylor & Francis Group

Box 1. Drug summary box

Drug name Celecoxib
Phase Launched
Indication Pain and Inflammation, in particular in osteoarthritis (OA) and rheumatoid arthritis (RA)
Mechanism of action Selective Inhibition of Cyclooxygenase (COX) 2
Route of administration Oral Chemical structure

Pivotal trial(s) [12,17,32,63]

Article highlights
● This article reflects approx. 20 years of clinical experience with celecoxib.
● Most recent clinical trial data regarding efficacy as well as safety are summarised and discussed.
● Important details on the drug itself including pharmacodynamics and pharmacokinetics are presented.
● Mechanisms potentially being involved in the cardiovascular side effects of COX-2 inhibitors are further described.
● An expert opinion based on the authors’ rheumatological expertise completes this article.
3. Introduction to the compound
Celecoxib (Celebrex®, Pfizer) was the first specific inhibitor of cyclooxygenase 2 (COX-2) and was approved by the US Food and Drug Administration (FDA) for adult patients with RA and OA on 31 December 1998 [11]. It demonstrated equipotency when being compared with tNSAIDs such as diclofenac or ibuprofen in terms of pain-management in RA and OA [12,13]. The recommended dose for RA is 100 to 200 mg bid, for OA 100 mg bid or 200 mg qd [14]. In Europe, contrary to the US, celecoxib is contraindicated in patients with estab- lished cardiovascular disease [15,16].

established NSAIDs in the treatment of adult patients with RA and OA. Studies regarding other indications (including spondyloarthri- tis), small studies (n < 50, not applicable for phase 2 trials), case reports, case series, non-randomized studies, results published only in abstract form and retrospective studies as well as articles in languages other than English have been excluded. As an excep- tion of that rule, retrospective cohort studies and meta-analyses of outstanding interest have been considered and discussed.

2.Overview of the market
Two main problems limit the use of tNSAIDs as analgesic and anti-inflammatory drugs in clinical practice: common conditions such as cardiovascular diseases and potential side effects like GI bleeding. Patients are at an increased risk for GI bleeding, if they have experienced one or more previous gastrointestinal ulcer(s) or are older than 60 years. Considering the fact that the average age in industrial countries is steadily increasing, the need for drugs with less side effects is essential. COX-2-inhibitors were developed with emphasis on decreasing adverse GI effects.
Besides celecoxib, the only remaining relevant oral coxib is etoricoxib. Both rofecoxib (Vioxx®) and valdecoxib have been withdrawn from the market (2004 and 2005) because of increased cardiovascular risks.

Celecoxib is a 4-[5-(4-methylphenyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl]benzenesulfonamide (molecular formula C17 H14F3N3O2S, see Box 1 for chemical 2D structure) [17]. The sulfonamide group seems to be essential for the COX-2 inhi- biting properties of the compound [17]. Its molecular weight is 381.37 g/mol.

Besides analgesic and anti-inflammatory effects, celecoxib also provides antipyretic potential. These effects are mediated by an inhibition of the enzyme COX-2, leading to an impaired biosynthesis of prostanoids. For details on the generation of prostanoids out of arachidonic acid with the two-stepped enzymatic help of cyclooxygenases (also known as prostaglan- din-endoperoxide synthases), see Figure 1.
Prostanoids, a subclass of eicosanoids, can be further divided into prostaglandins, thromboxanes, and prostacyclins. Their generation out of PGH2 (Figure 1) is catalyzed by tissue- specific isomerases [19]:

Figure 1. Mechanism of action of the isoenzymes of cyclooxygenase by metabolization of arachidonic acid (AA). Initially, AA is released from cell membranes with the help of lipases. Note that the process of generating PGH2 for further prostanoid synthesis requires two enzymatic steps, both provided by prostaglandin-endoperoxide synthase, commonly known as cyclooxygenase. NSAIDs as well as coxibs provide their effects by inhibition of the enzyme’s cyclooxygenase activity [18].
NSAIDs – non-steroidal anti-inflammatory drugs; PGE2 – Prostaglandin E2; PGG2 – Prostaglandin G2; PGH2 – Prostaglandin H2; PGI2 – Prostacyclin; TXA2 – Thromboxane A2

● Thromboxane synthase in platelets (TXA2)
for thromboxane A2
bleeding on the other hand [19]. Most likely, also topical effects not related to COX inhibition are involved into the

● Prostacyclin synthase in endothelium, vascular smooth muscle cells and renal cells for prostacyclin (PGI2)
● Prostaglandin E2 synthase in gastric mucosa and renal cells for prostaglandin E2 (PGE2)

Since all of those prostanoids have different functions, inhi- bition of their synthesis leads to very different effects. Properties of the clinically most important prostanoids in the physiological state can be obtained from Table 1. To date, we know of at least two isoforms of COX. Of extraordi- narily clinical importance, there is one crucial difference between COX-1 and COX-2: while COX-1 is expressed consti- tutively in most cells, COX-2 levels significantly raise in states of inflammation via cytokines, growth factor and shear in endothelial cells, monocytes, tumor cells, and plaque- associated cells [19,20]. Under basal conditions, COX-2 expression is thought to be minimal [19]. A selective inhibi- tion of COX-2 by celecoxib therefore leads to different effects, than a simultaneous inhibition of COX-1 and 2 by tNSAIDs.
COX-1 inhibition is hypothesized to be responsible for the cardioprotective effects of aspirin via reduced TXA2 expres- sion on one hand, while it also interferes with gastric mucosa protection via PGE2/PGI2, leading to upper GI ulcers and GI
negative impact of tNSAIDs on the gastric mucosa (e.g. uncoupling of the oxidative phosphorylation, leading to impaired function of the GI barrier) [22]. The anti- inflammatory and analgesic properties though are assigned to inhibition of COX-2 [19]. It is further thought that while reducing pain and inflammation, a selective COX-2 inhibition also blocks the vasodilatory and antiplatelet effects provided by PGI2 among endothelial cells [23]. Indeed, a mouse model showed that deletion of the COX-2 encoding gene in vascular smooth muscle cells and endothelial cells leads to a reduction of both, urinary excretion of PGI2 metabolite as well as NO release and predisposed for thrombosis and hypertension [23,24]. While this could explain at least partly the increased cardiovascular risk that leads to the withdrawal of some of the coxibs, this hypothesis is not undisputed. Some researches argue that PGI2 synthesis is actually mediated by COX-1 in healthy blood vessels [19].
Early investigations using in vitro-assays of inhibition of recombinant human COX-1 and COX-2 for celecoxib esti- mated the doses to achieve a 50% inhibition of the distinct isoenzyme (IC50) are 15 ± 1 μg/l for COX-1 and 0.04 ± 0.01 μg/l for COX-2, respectively. This lead to the assumption of a theoretical COX-2/COX-1 selectivity ratio of 375 [13,17]. Importantly, later publications using different test system reported a lower in-vitro selectivity ratio of 30 that is, sur- prisingly, comparable to diclofenac [25–27]. Since the COX

Table 1. Physiological effects of the clinically most relevant prostanoids. Prostanoid Physiological effect(s) Reference
selectivity also depends on the given dose and the adminis- tration frequency, the results of in vitro-assays may be diffi-

TXA2 ● Platelet aggregation, vasoconstriction [19,21] cult to interpret [26,28]. Therefore, the postulated COX-2

● Inhibition of platelet aggregation, endothelial function, vasodilatation (nitric oxide generation), hyperalgesia
selectivity should be considered rather continuous than simply dichotomous [28].

PGE2 ● Inflammation, vascular leakage, fever, hyperalgesia [19,21,29]

● Mucus secretion, bicarbonate release, mucosal blood flow – mucosal integrity in the gastroin- testinal tract

PGI2, Prostacyclin; PGE2, Prostaglandin E2; TXA2, Thromboxane A2.
6.Pharmacokinetics and metabolism
Celecoxib is applicated orally and the following capsule doses are usually used: 100 and 200 mg. After applying

200 mg orally, the mean maximum plasma concentration (Cmax) is reached after 2 to 4 h [13]. The compound is meta- bolized primarily via the cytochrome P450 (CYP) isoenzyme 2C9 with an elimination half-life of approx. 11 hours in healthy individuals [13]. A steady state is achieved after 5 days of multiple dosing [29]. Elimination of celecoxib is pre- dominantly hepatic with less than 2% being excreted unchanged through urine and 2.6% in feces [13,29,30]. In line with tNSAIDs, protein binding is high with >97% of celecoxib being mostly bound to albumin, resulting in a distribution volume of approx. 400 l [13,31].

7.Clinical efficacy and safety in rheumatoid and osteoarthritis
7.1.Clinical efficacy
The efficacy of celecoxib was established in multiple studies (Table 2). Most of these trials compared several doses with either placebo and/or tNSAIDs to prove not merely efficacy but also equipotency of celecoxib. The majority of tNSAIDs used as a comparator have been naproxen and diclofenac.
The first randomized phase 2 trials showing the clinical effi- cacy of celecoxib were published in 1998 by Simon et al. in one single article [32] and investigated its use in RA as well as OA. Furthermore, GI safety and the effect on platelet aggregation have been examined in healthy volunteers. All celecoxib doses except 40 mg bid showed a significant reduction in OA pain as measured using the visual analogue scale (VAS). In patients with RA, a significant reduction of patients’ global assessment was achieved with all celecoxib doses. The reduction in tender joints was limited to doses above 40 mg bid [32]. Contrary to aspirin, celecoxib did not have any effect on the platelet function [32]. In 1999, the same lead authors published a phase 3 trial investigat- ing the efficacy and GI safety of celecoxib exclusively in a cohort of n = 1149 symptomatic RA patients. Celecoxib was tested double blind in different dosages against naproxen and placebo over 12 weeks [12]. As the main result, all celecoxib doses showed equipotency when being compared to 500 mg of naproxen in terms of reducing tender and swollen joints. Both celecoxib and naproxen were superior to placebo regarding to ACR20 response (p < 0.05) while celecoxib 200 mg bid leads to higher ACR20 response rates in weeks 2 and 6 compared to naproxen (p < 0.05) [12]. Also published in 1999, Emery et al. compared celecoxib with diclofenac over 24 weeks to evaluate the long-
term efficacy and safety of celecoxib in RA (n = 655) [33]. The efficacy for both drugs was found to be comparable with a similar reduction of common arthritis assessments such as physicians and patients’ assessment, VAS, modified HAQ, swollen and tender joints. The ACR20 response rate was measured to be 25% in the celecoxib arm and 22% in the diclofenac arm. At week 16 only, the investigators detected a significantly lower number of tender joints in the celecoxib group; this difference diminished in week 20 [33]. Also in 1999, Bensen and Thao investigated the efficacy of celecoxib in 1004 patients with active OA [34,35]. Celecoxib was compared with naproxen and placebo and was associated with a significant improvement of the signs and

symptoms of OA as well as sustained pain relieve throughout the 12-week study duration [34]. Furthermore, the functional status as measured using the WOMAC score was significantly better in all active treatment groups at the end of treatment (p < 0.001) while celecoxib 100 mg bid was significantly superior to naproxen and placebo in terms of pain reduction (p < 0.001) [35].
Shortly after, Thao et al. published their analysis on the impact of celecoxib on health-related quality of life (HRQOL) and functional status in RA patients [36]. In this prospective, randomized parallel-group trial (n = 1149), naproxen and pla- cebo served as the comparators. After 12 weeks, all treatment arms demonstrated significant improvements in both func- tional status and quality of life compared to placebo. Celecoxib (200 mg bid) was superior to naproxen in HAQ disability improvements at weeks 2 and 12 (p < 0.001) [36]. Celecoxib was shown to be comparably effective than naproxen in improvement of Medical Outcome Study Short Form 36 (SF-36). There was no difference between celecoxib 200 bid and 400 bid with regard to HRQOL as determined using the SF-36 [36].
One smaller trial published in 2014 by Choi et al. compared celecoxib with pelubiprofen and reported equipotency for pain reduction as measured with VAS in patients with RA [37].
Regarding exclusively knee OA, Gordo et al. recently com- pared celecoxib with ibuprofen. The results showed equal- effectiveness in terms of pain reduction as measured using VAS and superiority of celecoxib as well as ibuprofen over placebo for the WOMAC scores (p ≤ 0.03) [38]. When only looking at morning stiffness, results in the celecoxib group were better compared to both, ibuprofen (p = 0.022) and placebo (p = 0.0006) [38]. Tindal et al. studied the impact of a long-term celecoxib use on radio- graphic progression in OA of the knee (n = 160) and hip (n = 184) [39]. Analysis of the taken radiographs found no evidence for disease progression with the exception of significant hip joint- space narrowing (p = 0.029). The observed hip-joint narrowing was small and also seen prior to the celecoxib use; no dose- dependence was revealed [39]. In 2012, Essex et al. compared celecoxib with naproxen in the treatment of knee OA. The pri- mary endpoint, a 20% improvement in the WOMAC OA score from baseline to 6 months study duration, was achieved in 52.7 vs. 49.7% of patients in the celecoxib and naproxen group, respectively (p ≥ 0.05) [40]. Among the celecoxib users, signifi- cantly fewer discontinuations related to adverse events of the GI tract occurred (4.1 vs. 15.1%, p < 0.0001) [40]. Similar results demonstrating equipotency of celecoxib compared to naproxen were seen in Asian and Hispanic patients with OA [41,42].
A meta-analysis published in 2017 found celecoxib to be a rather weak NSAID in the treatment of OA with diclofenac being much more potent in terms of pain reduction and improvement of function [43]. Frequent, non-serious side effects are summarized in Table 3.

7.2.Cardiovascular safety
Cardiovascular (CV) safety of coxibs has been a matter of concern, in particular since both rofecoxib and valdecoxib have been with- drawn from the market in 2004/2005 due to increased cardiovas- cular risk [27,44–47]. An older investigation on the CV safety of

Table 3. Most frequent non-serious side effects. Side effect Frequency
Headache 9–19%
Dyspepsia 4–15.3%

Reference [12,32,33,35]

nonfatal stroke. Celecoxib was demonstrated to be not inferior compared to both naproxen and ibuprofen with regard to car- diovascular safety. The intention-to-treat analysis showed com- parable numbers of CV events in the celecoxib arm with 2.3% vs.

Diarrhea Abdominal pain
Infection (upper respiratory tract) Nausea
Skin rash Fatigue
Elevated liver enzymes
0–12% 1–11% 0.9–13% 0.7–6.9% 3–5.7%
2.5% in the naproxen arm and 2.7% in the ibuprofen arm (p < 0.001 for both comparisons) [57]. The on-treatment analysis rendered similar results. Off note, the risk for GI events was significantly lower with celecoxib compared to both, naproxen (p = 0.01) and ibuprofen (p = 0.002). A secondary analysis of the PRECISION trial even showed a favorable outcome for celecoxib: the primary endpoint was defined as NSAID toxicity including

celecoxib inpatients witha historyofcolorectalneoplasia found an increased, dose-dependent CV risk (composite endpoint of death from CV causes, myocardial infarction, stroke, and heart failure) when comparing celecoxib with placebo [48]. Metanalyses though were able to show that also tNSAIDs exhibit an increased CV risk [49,50]. Further metanalyses on celecoxib did not find an increased CV risk when comparing celecoxib to tNSAIDs, only naproxen might bear a slightly lower CV risk [51–55]. Trelle et al. included 31 trials (n= 116.429 patients) and showed that celecoxib was safer when being compared to ibuprofen, diclofenac and other selective COX-2 inhibitors regarding the risk of myocardial infarction, CV death and even death from any cause; only naproxen was superior to celecoxib [52]. In the study of White et al., 39 trials on different indications (including RA, OA, ankylosing spondylitis but also low back pain and Alzheimer’s) comparing celecoxib (n = 7.462 and 19.773, respectively) with placebo (n = 4.057) and tNSAIDs (n = 13.990) have been included and analyzed [53]. No difference in the incidence of combined CV events (definition of CV events based on the Antiplatelet Trialists’ Collaboration [APTC] [56],) was found for neither comparison with placebo, nor tNSAIDs [53]. Hernández- Díaz studied 16 trials and calculated the pooled relative risk (RR) for myocardial infarction for celecoxib and other (t)NSAIDs compared to no NSAID use [54]. The RR for celecoxib was lower than for naproxen, ibuprofen, diclofenac, and rofecoxib. In non- users of low-dose aspirin only, naproxen seemed superior to celecoxib, though [54]. Last but not least, Hippisley-Cox and col- leagues conducted a population-based, nested case–control ana- lyses of 9218 cases with a first ever event of myocardial infarction. While the use of rofecoxib, diclofenac, and ibuprofen was asso- ciated with a significantly increased risk for myocardial infarction, this was not the case for celecoxib [55].
Contrary to etoricoxib (HR 1.35, 95% CI 1.19–1.54), cele- coxib was not associated with an increased risk for a first episode of atrial fibrillation (HR 0.94, 95% CI 0.79–1.11) in an analysis of a Swedish population-based cohort of 7 million subjects [51].
More recent clinical phase 4 trials with the focus on CV safety though rather emphasize the findings of the cited metanalyses. Nissen et al. investigated the CV safety of celecoxib, naproxen and ibuprofen in patients with any arthritis, established CV disease or an increased risk for developing a CV disease and the requirement of daily NSAIDs in a head-
to-head trial called PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen) [57]. A total of 24.081 patients have been included and were randomly assigned to either receive celecoxib, naproxen or ibuprofen. The primary endpoint was designed as a composite of CV death, nonfatal myocardial infarction or
major CV events, but also clinically important GI, renal and all- cause mortality events. The risk for such a major toxicity was higher in both, the naproxen (HR 1.20, 95% CI 1.04–1.39, p = 0.02) and the ibuprofen arm (HR 1.38, 95% CI 1.19–1.59, p < 0.001) [58]. The results of the PRECISION trial have not been without controversy though and were criticized for several rea- sons. Amongst other things, most of the participants were at a low cardiovascular risk of approx. 1% (90% patients with osteoarthritis). The relative risk of celecoxib for severe CV events is known to be 1.36 [59] which makes it difficult to determine any difference amid the given statistical upper bound of 1.4 (power: 80%) [57,60]. Furthermore, more than half of the patients in each group stopped taking the drug by the end of the study and another 30% have been lost to follow-up [57,60]. Besides this problem, the dose of celecoxib within the trial was limited to approx. 200 mg daily due to regulatory restrictions while physi- cians were allowed to adjust naproxen and ibuprofen doses, reaching near-maximal mean doses of 852 and 2045 mg, respec- tively [57,61]. In contrast to these numbers and the rather low analgesic effect of celecoxib in OA [43], it is very unlikely that equipotent doses have been compared [61]. Interestingly, within PRECISION, the dropout rate for insufficient clinical response was significantly higher among celecoxib users, compared to ibupro- fen (p < 0.001) as well as naproxen (p = 0.004), which supports the hypothesis of non-equipotent dosing [15,57]. Since the nega- tive effects of any NSAID are closely dose-dependent, the low celecoxib dose might have granted a potential safety advantage (see the used doses in [48]), which is already annotated by the authors of PRECISION [57].
An interesting European trial investigated recently whether switching to celecoxib from a continuous tNSAID medication in RA and OA patients ≥60 years (free from known CV dis- eases) would have an impact of individual CV safety (SCOT trial, Standard Care vs. Celecoxib Outcome Trial) [16]. The primary endpoint was hospitalization for nonfatal myocardial infarction, biomarker-positive acute coronary syndrome, non- fatal stroke, and CV death. Over 7200 patients were rando- mized and n = 3647 switched to celecoxib. In the remaining patients, standard care (mostly ibuprofen or naproxen) was continued. Through a median follow-up time of 3 years, the non-inferiority of celecoxib compared to tNSAIDs regarding CV safety was proven in the intention-to-treat analysis with an HR for primary CV events of 1.04 (95%-CI 0.81–1.33, p = 0.75), but not in the on-treatment analysis [16]. Unfortunately, the inter- pretation of the SCOT trial is considerably complicated by a disproportional withdrawal from celecoxib (48.2% in the celecoxib arm with 23.3% of them due to lack of efficacy vs. 31.5% in the tNSAID arm with 9.7% for lack of efficacy) [16].

A systematic meta-analysis of the available trials on tNSAIDs and coxibs regarding myocardial infarction was pub- lished in 2017, not yet including the data from the SCOT trial though [16,62]. Analyzing big data (n = 446.763), the use of any (t)NSAID was associated with an increased risk of myocar- dial infarction. Odds ratios (95% CI) were calculated as follows: celecoxib 1.24 (0.91–1.82), ibuprofen 1.48 (1.00–2.26), diclofe- nac 1.50 (1.06–2.04), naproxen 1.53 (1.07–2.33) and rofecoxib 1.58 (1.07–2.17) [62]. The increased risk was seen to be dose- dependent and highest during the first month of NSAID use [62]. Comparing these findings with the recent clinical trials, celecoxib again seems to be at least comparable to common tNSAIDs in terms of CV risk.

7.3.Gastrointestinal safety
Since the reduction of gastrointestinal (GI) ulcers and further complications such as intestinal bleeding was the main pur- pose for the development of the coxibs, most of the con- ducted clinical trials also investigated gastrointestinal safety in detail. Consequently, GI safety is well examined and the available data is solid.
Already the phase 2 trials of Simon et al. included a GI safety trial on healthy persons. The GI effects of either cele- coxib, naproxen or placebo after application for 1 week were investigated endoscopically in healthy volunteers in a double- blind design. While none of the celecoxib (n = 64) or placebo (n = 32) users developed gastric ulcers, the incidence in the naproxen arm (n = 32) was 19% (p = 0.011) [32]. In 1999, the group around Simon investigated efficacy and GI safety of celecoxib (three doses, total n = 693) compared to naproxen (n = 225) and placebo (n = 231) in RA patients. To assess GI safety, an upper GI-tract endoscopy was performed within 7 days prior to the first dose of the study medication and again at the end of study visit. The endoscopic results after 12 weeks of therapy showed significantly more gastroduodenal ulcers under naproxen than celecoxib in any dose or placebo (p < 0.001); ulcer incidence was comparable between celecoxib and placebo (p > 0.4) [12]. Additionally, concomitant corticos- teroid use was not associated with an effect on ulceration [12].
In the trial of Emery et al., almost two-thirds of the included patients (n = 326 celecoxib vs. 329 diclofenac) underwent endo- scopy at week 24, revealing gastroduodenal ulcers in 4% of the celecoxib arm and 15% of the diclofenac arm (p < 0.001) [33]. Moreover, withdrawal for any gastrointestinal-related events (e.g. abdominal pain, dyspepsia) was reported to be almost three times higher among the diclofenac-prescribed patients than the celecoxib users (p < 0.001) [33]. Corticosteroid use had no impact on ulcer frequency [33].
In 2000, the results of the large-scaled CLASS trial (Celecoxib Long-term Arthritis Safety Study, n = 8059 patients with either RA or OA) have been published [63]. Celecoxib was compared with ibuprofen and diclofenac. Notably, high-dose regimens have been chosen (celecoxib 400 mg bid, ibuprofen 800 mg tid, diclofenac 75 mg bid). The incidence for upper GI ulcer complications was not different between celecoxib and both tNSAIDs (0.76 vs. 1.45%, p = 0.09). The composite mea- sure of GI ulcer complications and symptomatic ulcers though was reported to be lower in the celecoxib arm compared to

both tNSAIDs (0.44 vs. 1.27%, p = 0.04) [63]. No difference for the incidence of upper GI ulcer complications have been seen for corticosteroid users. Furthermore, incidence of upper GI ulcer complications and the composite endpoint were not different in patients with a co-medication of aspirin. These results of this publication have been controversial. The study sums up two separate trials which were not indicated in the published article [63]: one comparing celecoxib with diclofe- nac over 12 months and another comparing celecoxib with ibuprofen for 15 months [27,64,65]. The primary outcome in these trials was originally defined as GI ulcer complications such as ulcer bleeding and not as symptomatic ulcers [65]. Furthermore, Silverstein et al. only reported the outcomes of the first 6 months of the trials; between months 6 and 16, the reported differences favoring celecoxib became insignificant [27,64,65]. The findings of the CLASS trial are therefore difficult to interpret.
A later investigation by Chan et al. showed a similar risk for recurrent ulcer bleeding in high-risk patients (defined as history of ulcer bleeding) when comparing celecoxib plus placebo with diclofenac plus omeprazole over 6 months (4.9 vs. 6.4%, p = 0.60) [66]. The randomized trial only included patients under current therapy with tNSAIDs and presenting themselves with ulcer bleed- ing (helicobacter pylorus [H.p.] negative). This finding was sup- ported in 2005 by Lai et al. who were able to show that there was no difference for the risk of a recurrent ulcer bleeding when comparing celecoxib alone with naproxen plus lansoprazole (3.7 vs. 6.3%, p = 0.37) [67]. In the same study, age above 65 years was identified as an independent risk factor for ulcer recurrences (HR 18.52, 95% CI 2.26–142.86) [67]. Two years later, the same team around Chan demonstrated in a double-blind and placebo-controlled trial that a combination of celecoxib with esomeprazole was superior to celecoxib alone in preventing recurrent ulcer bleeding in arthritis patients at high risk (0 vs. 8.9%, p = 0.0004) [68]. High risk was defined as a history of ulcer bleeding plus additional risk factors such as old age and/or comorbid illnesses [68]. In 2010, the results of the large- scaled CONDOR study (Celecoxib vs. Omeprazole and Diclofenac for At-risk Osteoarthritis and Rheumatoid arthritis patients, n = 4484) have been published by Chan and impressively showed the superiority of celecoxib over diclofenac plus omeprazole in redu- cing upper and lower GI events (gastroduodenal/small bowel/
large bowel bleeding, gastric-outlet obstruction, intestinal perfora- tion, anemia of defined GI or presumed GI occult origin; composite endpoint) in patients ≥60 years [9]. Diclofenac plus omeprazole was associated with a more than four times increased risk of a GI event (HR 4.3, 95% CI 2.6–7.0, p < 0.0001) [9]. Just recently, Chan et al. were able to show that celecoxib was even superior over naproxen in terms of rebleeding rates in patients with a history of ulcer bleeding and permanent medication with aspirin, when both NSAIDs were combined with esomeprazole (5.6 vs 12.3%, HR 0.44, 95% CI 0.23–0.82) [69].
The findings of Chan and Lai, respectively, are in line with the results of a large retrospective cohort study, which found the use of celecoxib in combination with a proton-pump inhibitor beneficial regarding the prevention of GI hospitaliza- tion, in particular on patients ≥75 years [70].
Other investigators also studied the GI tolerability of celecoxib. Goldstein et al. reported a lower cumulative incidence of

endoscopically proven upper GI ulcers in celecoxib users when being compared with naproxen users (nine vs. 41%, p < 0.001 for gastric and p < 0.03 for duodenal ulcers) [71]. Of note, the ulcers in the celecoxib arm were not significantly associated with a concurrent corticosteroid use [71]. The same team also investi- gated the effects of tNSAIDs and celecoxib on the small bowels [10]. In a double-blind, placebo-controlled trial, video capsule endoscopy was used at baseline and end of study to detect small- bowel injuries in patients using either celecoxib, naproxen plus omeprazole or placebo. The incidence for mucosal breaks in the small bowels was highest in the naproxen plus omeprazole group (55%), followed by celecoxib (16%) and placebo (7%), p < 0.001 for both comparisons with the naproxen arm. Placebo was superior to celecoxib (p = 0.04) [10]. This finding emphasizes the fact that PPIs only protect the mucosa of the upper GI tract. Indeed, also the CONDOR study reports increased numbers of clinically significant anemia of presumed occult origin (including possible small-bowel blood loss) in patients using diclofenac plus omeprazole com- pared to celecoxib users [9].
When Choi et al. compared celecoxib with pelubiprofen and reported equipotency for pain reduction, they also found a significantly reduced frequency of gastrointestinal adverse reaction in the celecoxib arm (20.8 vs. 8.8%, p = 0.045); 61.8% of celecoxib users had prednisolone as a concomitant medica- tion [37].
Since a large-scaled trial on etoricoxib vs. diclofenac (n > 34.000) failed to prove a superiority of etoricoxib over diclo- fenac in reducing lower GI clinical events [72], the reduced incidence of lower GI events under celecoxib reported in the CONDOR [9] trial and from Goldstein et al. [10] is presumably substance-specific for celecoxib rather than a class-specific effect of the coxibs.
A prespecified, secondary analysis of the PRECISION trial [57] revealed less clinical significant GI events such as bleed- ing, obstruction, perforation or symptomatic ulcers in the celecoxib arm when being compared with ibuprofen (HR 0.43, 95% CI 0.27–0.68, p = 0.0003) as well as naproxen (HR 0.51, 95% CI 0.32–0.81, p = 0.004) [73]. These results were independent of the individual H. p. status. Besides, the risk for development of an iron deficiency anemia was lower under celecoxib (HR 0.43, 95% CI 0.27–0.68, p = 0.0003 for compar- ison with ibuprofen and HR 0.40, 95% CI 0.25–0.62, p < 0.0001 for comparison with naproxen) [73]. In patients with an aspirin co-medication, celecoxib was still superior to ibuprofen in terms of GI events (HR 0.52, 95% CI 0.29–0.94, p = 0.03) and to naproxen when regarding iron deficiency anemia (HR 0.42, 95% CI 0.23–0.77, p = 0.005) [73].
Data regarding the concomitant therapy with corticosteroids such as prednisolone is limited. In some of the celecoxib trials, concomitant corticosteroid use was an exclusion criteria ([32,66,68]) or its use/non-use or impact on the GI tract was not discussed at all [9,10,67,69]. In other trials though, at least low doses of corticosteroids of usually up to 10 mg prednisone equivalent were allowed ([12,33,63,71]). Interestingly, none of these studies found a difference of ulcer incidence between corticosteroid users and non-users in either of the NSAID groups (including tNSAIDs as well as celecoxib). When investigating the prevalence of endoscopic gastric damage in RA patients depend- ing on their medication, Tsujimoto et al. recently found

a prevalence of 16.7% (285 out of 1700 patients) and identified prednisolone dose and usage of NSAIDs as independent risk factors (p < 0.001 for both). Of interest, endoscopic damage (LANZA score for gastric lesions) was significantly lower under selective COX-2 inhibition (p = 0.01) despite corticosteroid use [74]. The significance of this finding for celecoxib is limited by the use of either celecoxib, etodolac or meloxicam in the arm defined as being COX-2 selective [74].
Interpreting these trials, it is therefore difficult to conclude whether or not celecoxib should be preferably used in the frequent setting of a concomitant corticosteroid medication, which is common in RA patients. Since celecoxib though is associated with less unwanted gastrointestinal adverse effects and reduced upper GI (re-)bleeding rates in patients with an increased risk, its use in concomitant corticosteroid therapy might be favorable if the individual patient does not have CV comorbidities. Nevertheless, a combination with PPIs should be ensured, in particular when using high corticosteroid doses and/or anticoagulant drugs.

7.4.Safety in pregnancy and lactation
Since pain as a symptom of different rheumatic diseases, including RA, also affects young people, the safety of cele- coxib in pregnant and breast-feeding women is of concern. Contrary to other COX-2 inhibitors, celecoxib is studied at least in breastfeeding women [75]. The European League against Rheumatism (EULAR) published recommendations drawn from the current data on that topic [75]. While all COX-2 inhibitors should be avoided in pregnancy (hints for slightly increased rate of miscarriages and congenital malformations, generally lack of sufficient data though, grade of recommendation B-D), the use of celecoxib can be considered during lactation (grade of recommendation D) [75–78].

When used within the approval status, celecoxib is a safe and extraordinarily well-examined drug. It showed equipotency to traditional NSAIDs in the treatment of RA and OA while har- boring less unwanted gastrointestinal adverse effects. Additionally, use of a PPI is able to further reduce upper GI (re-)bleeding in patients with an increased risk, even under concomitant aspirin. For patients with RA, a positive impact on quality of life as well as the functional status has been shown. Moreover, the long half-life renders celecoxib particularly use- ful for chronic pain conditions, which are often associated with RA and OA. The reduced rate of GI adverse effects is not limited to the upper GI tract but also includes the lower GI tract: celecoxib leads to less bleedings within in the small bowels, when being compared to tNSAIDs plus PPI. Since a large clinical trial was not able to show a similar effect for etoricoxib, this somewhat protective effect on the lower GI tract might be celecoxib-specific. Therefore, it might be a good choice in particular for older patients with an increased risk for GI bleeding. The role of celecoxib in the setting of a concomitant medication with corticosteroids (particularly in RA) remains unclear to some degree. It might be of use in patients with a high risk for an upper GI bleeding and without

known CV diseases. Depending on the corticosteroid dose, PPI prescription should be ensured though.
The withdrawal of rofecoxib in 2004 raised serious concerns about cardiovascular safety of coxibs in general and lead to regulatory restrictions in particular in Europe: celecoxib became contraindicated in patients with established CV dis- eases. Recent phase 4 trials though were conducted to prove non-inferiority regarding CV safety of celecoxib compared with tNSAIDs in both, patients with established CV disease as well as patients free of CV diseases. Even though those trials exhibit methodological deficits and conclusions especially in patients with an established CV disease are difficult to draw, the short-term and low-dose use of celecoxib seems to be safe. Nonetheless, application of any NSAID (tNSAIDs as well as coxibs) is associated with an increased CV risk and should be avoided in patients with known CV diseases whenever possible.

9.Expert opinion
Among NSAIDs, celecoxib in doses ≤400 mg daily is a proper option for patients with moderate arthritis pain and without an established cardiovascular disease. Celecoxib is also useful in older patients with a high risk for gastrointestinal bleeding on any level. The results of the large phase 4 cardiovascular safety trials (PRECISION, SCOT [16,57]) are promising, but sub- stantial flaws in study design as well as conduction impair their validity and the clinical conclusions based on those results. In particular, further investigation of the safety of higher celecoxib doses is of outstanding clinical interest. In Europe, where celecoxib is contraindicated in established car- diovascular disease, the approval status has not changed since the publication of PRECISION and SCOT. With a constantly aging society in industrialized nations and a projected propor- tion of almost 26% adults having arthritis among the popula- tion in the US by 2040 (2012: 22.7%) [79], there is without doubt a need for potent but safe analgesics.
In 5 years’ time, celecoxib most likely will assert its position in the anti-inflammatory armamentarium of attending physi- cians worldwide and might be used in particular in patients with moderate arthritis pain and an individually high risk for gastrointestinal bleeding. The prescription of celecoxib in patients with an increased cardiovascular risk or even an established cardiovascular disease remains somewhat difficult and should be avoided or restricted to low doses in regions where it is approved amidst these comorbidities. The authors are not sure whether more long-lasting post-marketing trials will help to increase the knowledge of cardiovascular safety of celecoxib. As we have seen in the prominent samples above, they are difficult to design and conduct due to regulatory dose restrictions. Maybe real-world evidence [80] can help us to gain more data on the safety in everyday clinical practice that in turn could support the conduction of more sufficient clinical trials. Nevertheless, from our experience, celecoxib is an effective and well-tolerated drug particularly in inflamma- tory arthritis when used in suitable patients.


This manuscript was not funded.

Authors’ contributions
MK reviewed the literature and drafted the manuscript. CB contributed important intellectual content to the manuscript and was involved in reviewing the literature. Both authors read and approved the final manuscript.


Marvin was used for drawing, displaying and characterizing chemical structures, substructures, and reactions, Marvin Version 19.2.0, 2019 ChemAxon (http://www.chemaxon.com).

Ethical approval
All procedures performed in this survey were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Data obtained in this study did not interfere with the course of treatment for patients included.

Declaration of interest
C Baerwald has received lecture fees from Merck & Co, Merck Sharp &
Dohme, Mundipharma and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Marco Krasselt http://orcid.org/0000-0002-1842-0754


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