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`1.5
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`Ex. 1067 - Page 2
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`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Nonsteroidal Anti-Inflammatory Drugs Activate Quiescent Inflammatory
`
`Bowel Disease
`
`HERBERT J. KAUFMANN, M.D.; and HOWARD L. TAUBIN, M.D.; Katona h, New York; and Bridgeport,
`Connecticut
`
`Four patients with quiescent inflammatory bowel disease
`had prompt, exacerbations when given nonsteroidal anti-
`inflammatory drugs. Nonsteroidal anti-inflammatory drugs
`can have noxious effects on the distal intestine as well as
`on the proximal gut Eight previous cases of exacerbation
`w ulcerative colitis have been reported, as have instances
`of de-novo colitis and ileitis in persons treated with
`nonsteroidal anti-inflammatory drugs who did not have
`preexisting inflammatory bowel disease. Nonsteroidal
`aAti-inflammatory drug ingestion should be considered in
`the differential diagnosis of inflammatory bowel disease.
`These drugs should be administered to patients with
`inflammatory bowel disease only after consideration of
`their possible harmful effects.
`
`NONSTEROIDAL anti-inflammatory drugs can be harmful
`to the stomach and duodenum and are a common cause
`of peptic ulcer and upper gastrointestinal bleeding (1).
`llowever, the same drugs can cause problems in the more
`, distal gut. We have seen four patients with quiescent
`, inflammatory bowel disease whose colitis became active
`shortly after they were given nonsteroidal anti-inflamma-
`tory drugs. A causal connection seems likely. European
`, observers (Table 1) have reported such cases (7, 10,
`17), as well, as instances of de-novo colitis (2-4, 6, 9, 11-
`16, 18) related to nonsteroidal anti-inflammatory drugs,
`but no cases in this hemisphere have been reported.
`
`1t
`
`Case Reports
`PATIENT 1
`A white man born in 1919 became ill with inflammatory
`bowel disease in 1963. He was treated with sulfasalazine and
`improved. In 1965 he was hospitalized for a severe exacerbation
`and treated with intravenous corticosteroids. Rectal sparing
`was present. He had been well except for mild symptoms sec-
`ondary to variations in his diet.
`In 1975 routine sigmoidoscopy showed polyps, and colonos-
`copy showed extensive pseudopolyposis with two areas of active
`inflammation in the left colon. In 1977 he was treated for bursi-
`tis with phenylbutazone and indomethacin and shortly devel-
`oped bloody diarrhea. Sigmoidoscopy showed a normal rectum
`with a discreet ulcer surrounded by pseudopolyps at about 20
`cm. He was given prednisone and later sulfasalazine, and in 2
`months the ulcer healed. In 1979 while asymptomatic colonos-
`copy showed an inflamed stricture at 30 cm.
`Comment: This patient probably had Crohn disease in view
`of the rectal sparing and segmental nature of the disease. For 14
`years he was virtually asymptomatic and became sick only
`when given nonsteroidal anti-inflammatory drugs.
`PATIENT 2
`A Norwegian man born in 1930 was treated for bursitis with
`phenylbutazone uneventfully in 1976. In 1983 rectal bleeding
`
`/*From Northern Westchester Hospital Center, Mount Kisco, and the New York
`Medical College, Valhalla, New York; and Bridgeport Hospital, Bridgeport, and
`Yale University School of Medicine, New Haven, Connecticut.
`
`Annals of Internal Medicine. 1987;107:513-516.
`
`was noted. Sigmoidoscopy to 25 cm was normal. One year later
`he had painful, bloody diarrhea, and colonoscopy showed an
`inflamed stricture in the sigmoid and an area of inflammation in
`the splenic flexure region. Biopsy samples showed chronic in-
`flammation. He was diagnosed as having Crohn disease and was
`treated with prednisone and sulfasalazine with a good response.
`Flexible sigmoidoscopy was normal after 2 months of treat-
`ment. He stopped all medications and remained well until. 1986
`when he was given indomethacin for sciatica. Twenty-four
`hours later he developed bloody diarrhea. Flexible sigmoidosco-
`py to 60 cm showed uniformly inflamed mucosa. Stool exami-
`nation showed no evidence of infectious microorganisms. He
`was treated with prednisone and was asymptomatic in 3 weeks.
`Comment: This patient had Crohn disease in remission.
`When he was given indomethacin he developed a diffuse colitis
`within 24 hours, quite different from his original segmental dis
`ease. Whether this represented an exacerbation of his underly
`ing inflammatory bowel disease or was an idiosyncratic reaction
`to indomethacin as can happen in patients who have not had
`inflammatory bowel disease is moot.
`PATIENT 3
`A white man born in 1928 had elevated serum alkaline phos-
`phatase and transaminase levels starting in 1971, In 1980 liver
`biopsy results showed nonspecific changes, and an endoscopic
`retrograde cholangiopancreatogram was reported as normal but
`those films were not available for review. The alkaline phospha-
`tase level continued to rise to as much as six times normal. He
`had no itching. In 1985 he was started on piroxicam for os-
`teoarthritis. He immediately developed loose stools, which be-
`come bloody in 3 days. Two weeks later flexible sigmoidoscopy
`showed uniform inflammation to 55 cm, and colonoscopy
`showed mild to moderate pancolitis. Stool studies did not show
`infectious microorganisms. He had a good response to sulfasala-
`zine and was asymptomatic in 2 months. In 1986 endoscopic
`retrograde cholangiopancreatogram showed marked narrowing
`of the intrahepatic ducts consistent with sclerosing cholangitis.
`He remains asymptomatic on sulfasalazine.
`Comment: In retrospect,: this man had laboratory evidence
`suggesting sclerosing cholangitis 14 years before he developed
`colitis. Although he may have sclerosing cholangitis and an
`acute unrelated colitis secondary to piroxicam, it seems likely
`that he had subclinical ulcerative colitis made overt by the
`nonsteroidal anti-inflammatory drug, because in many people
`with sclerosing cholangitis the inflammatory bowel disease may
`be relatively minor.
`PATIENT 4
`A white man born in 1942 had rectal bleeding beginning in
`1977 and was found to have ulcerative proctitis limited to the
`distal 10 cm of colon. His subsequent treatment included sulfa-
`salazine and occasional hydrocortisone enemas. In 1984 fiber-
`optic sigmoidoscopy showed normal mucosa, but a biopsy sam-
`ple taken at that time showed severe chronic inflammation. He
`continued receiving sulfasalazine and in February 1986, sigmoi-
`doscopic appearance and biopsy samples taken at that time
`were normal. Sulfasalazine therapy was stopped. In July 1986
`while free of gastrointestinal symptoms he developed low back
`strain and was treated with naproxen. Approximately 7 days
`later he noted bright red blood in his bowel movements. He was
`treated with rectal hydrocortisone but did not respond. A limit-
`
`01987 American College of Physicians (cid:9)
`
`513
`
`Ex. 1067 - Page 3
`
`

`

`Table 1. Distal Intestinal Inflammation in Patients Receiving Nonsteroidal Anti-Inflammatory Drugs
`
`Reference Patients
`or
`Subjects
`
`Previous
`Inflammatory
`Bowel
`Disease
`
`Indication
`
`Drug
`
`Duration
`of
`Administration
`
`Not stated but < 3
`weeks
`6 months
`
`2 days; 3 days
`(rechallenge)
`
`No
`
`No
`
`No
`
`Arthritis
`
`Arthritis
`
`Arthritis
`
`Indomethacin
`suppositories
`Indomethacin
`suppositories
`Naproxen
`
`Indomethacin
`
`No
`
`Arthritis
`
`Indomethacin
`
`4 days
`
`Yes
`
`Experimental trial
`
`Inclomethacin
`enemas
`Indomethacin
`
`Not stated
`
`No
`
`Arthritis
`
`Ibuprofen, naproxen
`
`10 days and 1 month
`(same patient); 4
`months, 2 months
`
`Organ
`
`Lesion
`
`Rectum
`
`Rectum
`
`Rectum
`
`Small intestine
`
`Colon
`
`Colon
`
`Small intestine,
`colon
`Colon
`
`Ulcer and
`hemorrhage
`Proctitis
`
`Proctitis
`
`Inflammation and
`ulcers
`Inflammation and
`perforated
`diverticula
`Colitis
`
`Ulcers
`
`Colitis, bleeding
`diverticula,
`perforated
`diverticula
`Colitis
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`12
`
`13
`14
`15
`16
`
`17
`18
`19$
`201
`
`1
`
`1
`
`I
`
`Rats*
`
`2
`
`3
`
`Dogs•
`
`3
`
`4
`
`2
`4
`
`1
`I
`1
`2
`
`1
`I
`6
`16
`
`Yes
`
`No
`No
`
`No
`No
`No
`No
`
`Yes
`No
`Not stated
`Not stated
`
`Pain
`Pain
`Not stated
`Arthritis
`
`Arthritis
`Back pain
`Not stated
`Not stated
`
`Ankylosing
`spondylitis,
`osteoarthritis,
`carpal tunnel
`syndrome, joint
`pains
`Arthritis, pain
`Arthritis, pain
`
`Indomethacin,
`benorylate,
`ibuprofen,
`flurbiprofen
`
`Mefenamic acid
`Mefenamic acid
`
`1 week, 4 weeks, 1
`week, 8 weeks
`
`Colon
`
`3 years, 8 months
`1 month, 3 months,
`6 weeks, 3 months
`and "some weeks"
`(same patient)
`6 months
`6 weeks
`3 months
`2 weeks j'
`
`1 day
`4 weeks
`Not stated
`Not stated
`
`"shortly," 1 clay, 1
`day, 1 week
`
`Colon
`Ileum, colon
`
`Colitis
`Ileocolitis
`
`Colon
`Colon
`Colon
`Colon, ileum
`
`Colon
`Colon
`Ileum
`Ileum
`
`Colon
`
`Colitis
`Colitis
`Colitis
`Beal and colonic
`perforation
`Colitis
`Ulcers
`Ulcers and strictures
`Blood and protein
`loss
`Colitis
`
`Mefenamic acid
`Mefenamic acid
`Mefenamic acid
`Indomethacin slow
`release
`Ibuprofen
`Naproxen, aspirin
`Not specified
`Not specified
`
`Indomethacin,
`phenylbutazone,
`piroxicam,
`naproxen
`
`Current series (cid:9)
`
`4
`
`Yes
`
`Sciatica, bursitis,
`back pain
`
`• Rats and dogs killed at 24 hours had lesions; those killed later had more intense lesions. Rats killed at less than 24 hours had no lesions. No dogs were killed earlier
`than 24 hours.
`t One patient received ordinary indomethacin tablets for 10 years, then slow-release indomethacin for 2 weeks.
`For a more detailed report, now see Gastroenterology. 1987;93:480-9.
`
`ed colonoscopic examination showed diffuse inflammatory
`changes extending to above 50 cm from the anus. He was hospi-
`talized and treated with intravenous corticosteroids. He re-
`sponded slowly but ultimately the corticosteroids were discon-
`tinued and he was maintained in remission on sulfasalazine.
`Comment: This man had well-documented limited inflamma-
`tory bowel disease, which had become completely asymptomat-
`ic. The exacerbation that followed treatment with naproxen was
`more extensive and more severe than his original illness.
`
`Discussion
`The complex relationships between prostaglandins and
`other eicosanoids to the gut in general (21) and to ulcer-
`ative colitis in particular (22) have been reviewed recent-
`ly. Rampton and Hawkey (22) stated that it is unclear
`whether eicosanoid excess or deficiency is important
`pathogenetically, or whether the experimental findings
`relating to prostaglandins in ulcerative colitis are impor-
`tant or simply epiphenomena. Nonsteroidal anti-inflam-
`
`matory drugs block cycloxygenase and hence the forma-
`tion of prostaglandins and thromboxanes. Further,
`sulfasalazine and its active breakdown product, 5-amino-
`salicylic acid, block the formation of prostaglandins (23,
`24). In addition, patients with active ulcerative colitis
`make excess rectal prostaglandin E2 whether or not they
`are receiving treatment for their disease (25).
`It would therefore seem reasonable, in view of the fore-
`going, that the administration of nonsteroidal anti-in-
`flammatory drugs would benefit ulcerative colitis (26)
`However, neither orally administered (23) nor rectally
`administered (27) indomethacin nor orally administered
`benoxyprofen (28) had any effect. Reports of rectally
`administered nonsteroidal anti-inflammatory drugs have
`been confusing. One study (29) showed sigmoidoscopic
`abnormalities in seven of eight patients treated with in-
`domethacin suppositories and in another (30), 9% had
`rectal irritation. A third study (31) of various nonsteroi-
`
`514
`
`October 1987 • Annals of Internal Medicine • Volume 107 • Number 4
`
`Ex. 1067 - Page 4
`
`

`

`dal anti-inflammatory drugs given to arthritic patients in
`suppository form failed to show injury to their recta. A
`colonoscopic study did not show abnormalities of the co-
`lon or ileum in patients. given oral nonsteroidal anti-in-
`flammatory drugs (32).
`Sulfasalazine inhibits inactivation of prostaglandins
`(33). Because sulfasalazine maintains remission in ulcer-
`ative colitis, it was thought that cytoprotection of the
`colon might result from the use of orally administered
`prostaglandins. In hamsters, clindamycin-induced colitis
`can be prevented by such maneuvers (34). This, howev-
`er, was not the case in humans: 5 of 12 patients with
`ulcerative colitis in remission had flares within 1 month.
`and 3 more had diarrhea when given 15 (R) 15-methyl
`prostaglandin E2 (35 ) .
`There is laboratory and clinical evidence that nonster-
`oidal anti-inflammatory drugs are harmful to the lower
`gut (Table 1). Enterocolitis in dogs (8) and ulcerative
`small intestinal lesions in rats (5) can be produced by
`orally administered indornethacin. Diarrhea and net se-
`cretion can be shown in hamsters treated with nonsteroi-
`dal anti-inflammatory. drugs (36) .
`In addition to the four patients we have described,
`eight others have had exacerbations of inflammatory
`bowel disease while on nonsteroidal anti-inflammatory
`drugs (7, 10, 17). Twenty patients without previous low-
`er intestinal inflammatory disease have developed colitis
`or ileocolitis (2-4, 6, 9, 11-16, 18). Some Of these patidnts
`have had perforations. In two cases the slow release cap-
`sule was found in or:adjacent to the perforation (16).
`There are two epiderniologic reports, one linking the
`use of analgesics to ulcerative colitis (37) and the other
`the use of nonsteroidal anti-inflammatory drugs to intes-
`tinal hemorrhage and perforation ( 3 8). Additionally, by
`using indium-1 1 1, nonsteroidal anti-inflammatory drugs
`can be shown to cause ileal inflammation related to ileo-
`cecal blood loss and protein loss that can be reversed by
`sulfasalazine (19, 20, 39). Patients with rheumatoid ar-
`thritis have been shown to have histologic inflammatory
`lesions of the intestine, but these patients were on treat-
`ment, many with nonsteroidal anti-inflammatory drugs
`(40). Finally, a recent report details a sprue-like small
`intestinal lesion caused by sulindac (41).
`There are few reports that nonsteroidal anti-inflamma-
`tory drugs are beneficial to the bowel. One report sug-
`gests that intrarectal indomethacin can reverse acetic
`acid-induced colitis in rats (42), and one patient with
`microscopic colitis improved when given indomethacin
`(43).
`Our patients all had inactive or minimally active in-
`flammatory bowel disease when given nonsteroidal
`inflammatory drugs. Because the pathogenesis of inflam-
`matory bowel disease is unknown, it is impossible to say
`whether their episodes of colitis were exacerbations of
`their underlying diseases or unrelated events caused by
`nonsteroidal anti-inflammatory drugs in patients with
`predisposed colonic mucosae. The symptoms occurred
`soon after starting nonsteroidal anti-inflammatory drug
`therapy, in Patient 2 within 24 hours and in Patient 3 in
`less than 3 days. Most patients without previous evidence
`
`of inflammatory bowel disease who have developed colitis
`while receiving nonsteroidal anti-inflammatory drugs
`have been receiving the drugs for substantially longer pe-
`riods of time. Different pathogenic mechanisms may ex-
`plain the existence of these two patterns (17).
`Nonsteroidal anti-inflammatory drugs can be harmful
`to the distal intestine. Exposure to such drugs should be
`considered in the differential diagnosis of inflammatory
`bowel disease, and they should be given with caution, if
`at all, to patients with known ulcerative colitis or Crohn
`disease.
`
`ACKNOWLEDGMENTS: The authors thank Nona Willoughby for help in
`the literature search, and Melanie Dunkelberger for manuscript preparation.
`
`Requests for reprints should be addressed to Herbert J. ICaufmann, M.D.;
`111 Bedford Road; Katonah, NY 10536.
`
`References
`1. BARTLE WR, GUPTA AK, LAZOR 1. Nonsteroidal anti-inflammatory
`drugs and gastrointestinal bleeding: a case-control study. Arch Intern
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`2. WALLS 3, BELL D, SCHORR W. Rectal bleeding`and indomethacin [Let-
`ter]. Br Med J. 1968;2:52.
`3. LEVY N, GASPAR E. Rectal bleeding and indomethacin suppositories
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`4. BAAS EU, EWE K, HOHN P. Granulomatose Kolitis nach Naproxen
`[Letter]. Dtsch Med Wochenschr. 1976;101:1434,
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`tinal inflammation. Dig Dis Sci, 1977;22:749-60,
`6. COUTROT S, ROLAND D, BARBIER J, VAN DER MARCQ P, ALCALAY
`M, MATUCHANSKY C. Acute perforation of colonic diverticula associat-
`ed with short-term indomethacin [Letter]. Lancet. 1978;2:1055-6.
`7. CAMPIERI M, LANFRANCHI GA, BAZZOCCHI G, et al. Prostaglandins,
`indomethacin, and ulcerative colitis [Letter]. Gastroenterology.
`1980;78:193.
`8. STEWART TH, HETENYI C, ROWSELL H, ORIZOGA M. Ulcerative en-
`terocolitis in dogs induced by drugs. _I Pathol 1980; 131:363-78.
`9. ScHwARTz HA. Lower gastrointestinal side effects of nonsteroidal, anti-
`inflammatory drugs. J Rheumatol 1981,8:952-4.
`10. RAMPTON DS, SLADEN GE. Relapse of ulcerative proctocolitis during
`treatment with nonsteroidal anti-inflammatory drugs. Postgrad Med J.
`1981;57:297-9.
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