Elsevier

Translational Research

Volume 175, September 2016, Pages 76-91
Translational Research

Review Article
Clinical importance of nonsteroidal anti-inflammatory drug enteropathy: the relevance of tumor necrosis factor as a promising target

https://doi.org/10.1016/j.trsl.2016.03.014Get rights and content

The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID) enteropathy is still unclear, and consequently, there is no approved therapeutic strategy for ameliorating such damage. On the other hand, molecular treatment strategies targeting tumor necrosis factor (TNF) exerts beneficial effects on NSAID-induced intestinal lesions in rodents and rheumatoid arthritis patients. Thus, TNF appears to be a potential therapeutic target for both the prevention and treatment of NSAID enteropathy. However, the causative relationship between TNF and NSAID enteropathy is largely unknown. Currently approved anti-TNF agents are highly expensive and exhibit numerous side effects. Hence, in this review, the pivotal role of TNF in NSAID enteropathy has been summarized and plant-derived polyphenols have been suggested as useful alternative anti-TNF agents because of their ability to suppress TNF activated inflammatory pathways both in vitro and in vivo.

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most commonly used prescription and over-the-counter class of medications globally.1 Although, NSAIDs are extremely efficacious drugs,2 but, their usage is linked with a variety of adverse reactions in the kidney, heart, liver, skin, and gastrointestinal (GI) tract.3 A recent meta-analysis that included 31 trials and 116,429 patients revealed an increase in rates of myocardial infarction, stroke, and cardiovascular death in patients taking either selective or nonselective NSAIDs.4 The GI adverse effects of NSAIDs have also been well documented in several studies,5, 6, 7, 8, 9 meta-analysis10, 11 and Cochrane reviews.12 The ability of NSAIDs to cause ulceration and bleeding in the upper GI tract was first documented by the endoscopic study of Douthwaite and Lintott as early as 1938.13 However, much later, in the year 1993, Bjarnason et al14 reported that NSAIDs have the ability to induce significant small intestinal injury (enteropathy) also. The term NSAID enteropathy has been used to describe the small intestinal toxicity of NSAIDs.15 In context to the severity and importance of NSAID enteropathy, based on their studies, Lanas et al made an important observation that “over the years, NSAID-induced lower GI complications are increasing, whereas upper GI complications are decreasing”.16 Indeed, past decade has seen a decreasing trend in NSAID-induced symptomatic GI events in rheumatoid arthritis (RA) patients17 and, in line with that, in hospitalizations due to upper GI complications, but lower GI complications have shown an apparent increasing trend.18, 19, 20 McCarthy21 expressed similar concern, pointing out that in the Vioxx Gastrointestinal Outcomes Research trial,22 small intestine was the major site of ulceration and bleeding caused by NSAIDs (naproxen and rofecoxib).

The clinical impact and severity of lower GI events has actually been greater than those in the upper GI tract.23 NSAID-induced small intestinal injury includes bleeding (leading to iron deficiency anemia), erosion, and ulceration24, 25; however, serious complications may include massive bleeding, perforation, and strictures, sometimes leading to death.26 These symptoms may persist even after the therapy is discontinued.27 For example, the intestinal lesions reported by Leung et al28 tended to persist for up to 3 months after the discontinuation of aspirin; however, in some cases, they have been reported to persist for up to 16 months after discontinuation.27

Section snippets

Diagnosis of NSAID Enteropathy

Until recently, the clinical relevance or significance of NSAID enteropathy was largely underestimated.29 The main reasons were the difficulty in making a diagnosis, as this damage occurs in regions beyond the reach of typical endoscopic examinations in contrast to the gastroduodenal damage and because of the subclinical nature of NSAID enteropathy (60%–70% cases).29

However, the availability and use of novel diagnostic tools such as capsule endoscopy and double-balloon endoscopy has enabled the

Understanding the Pathogenesis of NSAID Enteropathy

The exact mechanisms underlying NSAID enteropathy are not fully understood35 and consequently, there are no approved therapeutic strategies for ameliorating the intestinal damage caused by NSAIDs.36, 37 Thus, developing effective, preventative or curative therapies for NSAID enteropathy is an unmet challenge and requires proper understanding of the complicated pathogenesis of this disorder.

In recent years, pathogenesis of NSAID enteropathy has been widely investigated.38 Importantly, deficiency

Targeting TNF: What Options We Have?

Anti-TNF agents are available and have already been approved by the United States Food and Drug Administration (FDA) for the treatment of RA,162 inflammatory bowel disease,163 psoriasis,47 and ankylosing spondylitis.164 These drugs include the chimeric TNF antibody (infliximab), humanized TNF antibody (Humira), and soluble TNF receptor-II (Enbrel).47 However, current FDA approved anti-TNF agents, which include high-molecular weight protein–based injectable drugs, are not only expensive but also

Challenges and Future Perspective

As discussed previously, based on literature search, we have developed the probable cascade and interplay between various confounding factors of gastroenteropathy with special and central focus on TNF. However, because there are many feedback loops working for the efficient maintenance of normal body homoeostasis,226 thus, further mechanism-based preclinical and clinical studies are required to establish the causative role of TNF in NSAID enteropathy.

Polyphenols or flavonoids, although seem to

Discussion and Conclusions

Management of NSAID enteropathy has emerged as a clinically relevant issue, mainly because of its potential severity and high frequency of occurrence in humans. A series of therapeutic strategies targeting different mechanisms involved in NSAID enteropathy have been investigated but without any definitive results.38 However, novel NSAIDs developed by Antibe Therapeutics which release NO and hydrogen sulphide (H2S; H2S from ATB-346 and NO from NCX 429; both derivatives of naproxen) encouragingly

Acknowledgments

Conflicts of Interest: All authors have read the journal's policy on disclosure of potential conflicts of interest and have none to declare.

Authorship Agreement: All authors have read the journal's authorship agreement and article has been reviewed and approved by all the named authors.

The authors are thankful to B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre and NIRMA University, Ahmedabad, for providing all the facilities for the successful completion of the work.

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    Institutional Communication Reference Number: PERD430815.

    Devendra Pratap Singh, Swapnil P. Borse, and Manish Nivsarkar have contributed equally.

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