Cyclooxygenase and nonsteroidal anti-inflammatory drugs in gastrointestinal tract:

Is treatment worse than the disease?

Dr. Nina Zidar

Institute of Pathology, Faculty of Medicine

University of Ljubljana

Slovenia

Cyclooxygenase (COX)

• rate limiting enzyme in synthesis of prostanoids

• prostanoids:

- prostaglandins

- prostacyclins

- thromboxane

Functions of COX

• protection of gastric mucosa

• hemostasis

• renal hemodynamics

Physiologic conditions

• inflammation

• cancer

Pathologic conditions

COX isoforms

• constitutive (physiologic) isoform

• expressed in tissues under basal conditions

• responsible for production of prostanoids

• physiological, protective functions

COX-1

• inducible (pathologic) isoform

• undetectable in most normal tissues

• upregulated in pathologic conditions COX-2

Is biology of COX isoforms more complex ?

COX-1 COX-2

COX-1 COX-2

COX-1 COX-2

COX expression in inflammation and cancer

F, 58 years, rheumatoid arthritis

COX-1 COX-2

F, 58 years, rheumatoid arthritis

COX-1 COX-2

Adenocarcinoma of the colon

COX-1 COX-2

Adenocarcinoma of the colon

• Both isoforms, not only COX-1, are important in maintenance of homeostasis.

• Both isoforms, not only COX-2, are involved in various pathologic conditions.

• The concept of constitutive (physiologic) and inducible (pathologic) COX isoforms must be revised.

Zidar N, Odar K, Glavač D, Jerše M, Zupanc T, Štajer D. COX in normal human tissues – is COX-1 really a constitutive isoform and COX-2 an inducible isoform? J Cell Mol Med 2009; 13: 3753-63

Nonsteroidal anti-inflammatory drugs

(COX inhibitors)

Nonsteroidal anti-inflammatory drugs (NSAIDs)

• the most common drugs in human history

• 70 % of people aged >65 years use NSAIDs at least once a week

• anti-inflammatory, analgesic, antipyretic, anticoagulant effects

NSAIDs - side effects

• Cardiovascular: inhibition of platelet COX-1-derived TxA2 - inhibition of platelet aggregation - increasing bleeding time

• Renal: analgesic nephropathy, acute renal failure

• Gastro-intestinal: risk of serious GI complications 5 - 6 times higher than in controls

COX inhibitors (NSAIDs)

Traditional (non-selective)

aspirin

other NSAIDs

Selective COX-2 inhibitors

Coxibs

NSAIDs - clinical indications

• reduction of pain, inflammation and fever

• management of various conditions (osteo-arthritis, rheumatoid arthritis, musculoskeletal pain, headache ….)

• cancer prevention

Umar A, Steele VE, Menter DG, Hawk ET. Mechanisms of nonsteroidal aanti-inflammatory drugs in cancer prevention. Semin Oncol 2016; 43: 65-77

NSAIDs and cancer prevention

• COX-2 overexpression in 40-50 % of colon adenomas and in 80-90 % of colon carcinomas

• NSAIDs use might reduce the risk of colorectal carcinoma

Eberhart CE, Coffey RJ, Radhika A et al. Up-regulation of COX-2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterol 1994; 107: 1183-8 Steinbach G, Lynch PM, Phillips RK et al. The effect of celecoxib, a COX-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342: 1946-52

NSAIDs and cancer prevention

• 1999, Vioxx Gastrointestinal Outcomes Research (VIGOR): 8000 patients with rheumatoid arthritis

• 2003, Vioxx in Colorectal Therapy, Definition of Optimal Regimen (VICTOR): 7000 patients with a history of colon cancer

• 2004, Adenomatous Polyp Prevention on Vioxx (APPROVe): 2600 patients with adenomas

Baron JA, Sandler RS, Bresalier RS, et al. Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet 2008; 372:1756–64

Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343:1520–8

Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib as NSAIDs for osteoarthritis and rheumatoid arthritis in the CLASS study. JAMA 2000; 284:1247–55

Baron JA, Sandler RS, Bresalier RS, et al. Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet 2008; 372:1756–64

NSAIDs and cancer prevention

• 25-65% reduction in adenomas over 3 years

• 40-50% decrease in relative risk for colorectal cancer

• 50% reduction of GI side effects

• Coxibs appeared to be a promising drug for cancer chemoprevention

NSAIDs and cancer prevention

• a double risk for thrombotic cardiovascular events

• trials stopped early

• Rofecoxib was withdrawn from the market

• Beneficial effects in one type of tissue can be accompanied by toxic effects in another.

COX-1 derived TxA2 in platelets promotes platelet aggregation.

ASPIRIN: inhibition of COX-1 derived TxA2 in platelets – inhibition of platelet aggregation

COX-2 derived PGI2 in endothelial cell – inhibition of platelet aggregation

COXIBS: inhibition of COX-2 derived PGI2 in endothelial cells promotes platelet aggregation.

NSAIDs damage in GI tract

De Petris G, Caldero SG, Chen L, et al. Histopathological changes in the gastro-intestinal tract due to drugs: an update for surgical pathologist. Int J Surg Pathol 2014; 22:120–8 Panarelli NC. Drug-induced injury in the gastrointestinal tract. Semin Diagn Pathol 2014; 31:165–75

NSAIDs

Esophagus

Small bowel

Large bowel

Stomach

Pathogenesis of NSAIDs-related injury

• injury to epithelial cells – increased mucosal permeability

• leukocyte-endothelial adhesion in micro-vasculature (ischaemic damage)

• suppression of prostaglandin synthesis (E2, I2) via inhibition of COX

Oesophagus

• pill oesophagitis

• erosions

• ulcers

• strictures

Stomach

• reactive gastropathy (chemical gastritis)

• erosions

• ulcers

• bleeding

• perforation

• collagenous gastritis

• intraepithelial lymphocytosis

Reactive gastropathy Erosions

Peptic ulcer (stomach, duodenum)

Small bowel

• erosions, ulcers

• perforation, bleeding, protein-loss

• mild villous atrophy

• intraepithelial lymphocytosis

• ↑eosinophils

• ↑ apoptosis

Fortun PJ, Wawkey CJ. Nonsteroidal antiinflammatory drugs and the small intestine. Curr Opin Gastroenterol 2005; 21: 169-75

Mild villous atrophy Intraepithelial lymphocytosis

Large bowel

• focal active colitis

• collagenous colitis

• lymphocytic colitis

• eosinophilic colitis

• ischaemic colitis

• pseudomembranous colitis

• ulcers and erosions

Katsinelos P et al. Colopathy associated with the systemic use of nonsteroidal antiinflammatory medications. An underestimated entity. Hepatogastroenterol 2002; 49: 345-8

Collagenous colitis

Lymphocytic colitis

Ischaemic colitis

Eosinophilic colitis

Pseudomembraneous colitis

Ulcer in the terminal ileum and cecum

Diaphragm disease of large and small bowel

• specific for NSAIDs

• obstruction, bleeding, diarrhea, weight loss

• pathogenesis: linear ulcer, followed by repair and fibrosis

• resulting bands of fibrosis constricts the lumen and form diaphragms

Courtney L, Kwok A, Keshava A. Gastrointestinal: diaphragm disease: emerging cause of gastrointestinal obstruction and bleeding. J Gastroenterol Hepatol 2014; 29: 230

Diaphragm disease of large and small bowel

• term. ileum and prox. colon

• usually multiple

• thin, concentric mucosal web of tissue

Munipalle PC, Garud T, Light D. Diaphragmatic disease of the colon: systematic review. Colorectal Dis 2013; 15: 1063-9

Diaphragm disease of large and small bowel

Pernick N. PathologyOutlines.com

NSAIDs damage in GIT – microscopic features

• inflammation (eosinophils!)

• apoptosis

• intraepithelial lymphocytosis

• erosions, ulcers

• collagenous -itides

• ischaemic changes

• diaphragm-like strictures

De Petris G, Caldero SG, Chen L, et al. Histopathological changes in the gastrointestinal tract due to drugs: an update for surgical pathologist. Int J Surg Pathol 2014; 22:120–8

Symptoms

• dyspepsia • abdominal pain • nausea, vomiting • diarrhea • protein loss • bleeding • obstruction

Sostres C, Gargallo CJ, Lanas A. NSAIDs and upper and lower gastrointestinal

mucosal damage. Arthritis Res Ther 2013; 15:S3

Conclusions

• NSAIDs-related GI complications are common and mostly non-specific.

• Life threatening complications are rare.

• Collaboration between clinician and pathologist is essential for correct diagnosis.

• Cessation of NSAIDs - clinical and histological resolution.

• Use the lowest effective dose for the shortest duration possible.

• Generally, GIT lesions tend to reduce or even disappear with chronic use, probably because the mucosa is adapted to aggression.

• Treatment should not be worse than the disease!