Azathioprine-related pancreatitis in patients with Crohn's disease

GASTROENTEROLOGY

Azathioprine-Related Pancreatitis Patients with Crohn’s Disease RICHARD A. L. STURDEVANT,+ J. DEREN, DAVID H. LAW, and

JOHN JACK

77:883-886,1979

in

W. SINGLETON,

JULIUS

L. McCLEERY

Divisions of Gastroenterology: UCLA School of Medicine, Los Angeles, California; University of Colorado Medical School, Denver, Colorado; University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; University of New Mexico Medical School and the Veterans Administration Hospital, Albuquerque, New Mexico: and Dartmouth Medical School, Hanover, New Hampshire

developed in 6 patients in the National Puncreatitis Cooperative Crohn’s Disease Study. In five of these the diagnosis was confirmed by elevated levels of serum amylase or Jipase. All cases were in the 223 patients who received azathioprine and occurred within the first 21 days of treatment. This incidence of pancreatitis was significantly greater than in the patients treated with sulfasalazine, prednisone, or placebo (P < 0.01).

Pancreatitis occurs in some patients with Crohn’s disease who have no well-established cause of pancreatitis, such as gallstones, or alcoholism.‘-” These cases have been ascribed to azathioprine, corticosteroids, sulfasalazine, or duodenal Crohn’s disease. The National Cooperative Crohn’s Disease Study (NCCDS) provided an opportunity to estimate the frequency of pancreatitis as a complication of azathioprine, prednisone, or sulfasalazine therapy, and to compare the frequency of this complication in patients taking these drugs with that in a placebotreated control group.

Methods The purpose and methods of the NCCDS are described in detail elsewhere.“’ In brief, patients with radiographic or histologic evidence of Crohn’s disease were randomly assigned to treatment with placebo, azathioprine, prednisone, or sulfasalazine. Daily doses were: azathioprine-1 or 2.5 m&kg body weight, maximum 250 mg/day; prednisone-O.25, 0.5, or 0.75 mg/kg body weight, maximum 60 mg/day; sulfasalazine-O.5 or 1 g/15 kg body

Addross rctquests for reprints to: National Cooperative

Crohn’s

Disease Study, Box B-158, 4200 E. 9th Avenue, Denver, Colorado 80262. tDtrc:oasc~d. 0 197~ Ijy thcl American Gastroenterological Association 0016.5085/79/100883-04$02.00

weight, maximum 5 g/day. A composite index of severity of illness, the Crohn’s Disease Activity Index (CDAI),” was calculated at each patient visit. The dose of medication prescribed reflected the CDAI, in accordance with the protocol.‘” The protocol did not include a systematic search for evidence of pancreatitis in all patients. The cases here reported were identified as follows: The investigators caring for study patients detected pancreatitis in 5 patients by observation of an elevated serum amylase or lipase during an episode of abdominal pain. After completion of the patient-study phase of the NCCDS, all case records were reviewed for detection of additional cases of pancreatitis. Each encounter form of each visit of every patient was reviewed without knowledge of drug regimen. A single additional probable case of pancreatitis was identified by the presence in the first 3 wk of therapy of characteristic symptoms (epigastric pain, nausea and vomiting, and fever), signs (epigastric tenderness and abdominal distention), and leukocytosis occurring in a patient who had not previously shown this clinical pattern as a result of Crohn’s disease.

Results Five cases of pancreatitis with elevated serum amylase or lipase concentrations, and one probable case of pancreatitis were identified (Table 1). All were receiving azathioprine (Table 2). The probability that the observed difference in rate of pancreatitis between the azathioprine group and all other treatment groups combined could have occurred by chance alone is less than 0.01 (Fisher’s Exact test). All patients had had barium x-rays within I mo of starting azathioprine; in no case did these show evidence of duodenal Crohn’s disease, The illnesses began 13-21 days after the start of treatment with azathioprine. Pancreatitis was recognized clinically because of the appearance of abdominal pain differing from any pain the patient had

GASTROENTEROLOGY Vol. 77, No. 4, Part 2

STURDEVANT ET AL.

664

previously had with Crohn’s disease. Usually this pain was associated with nausea and vomiting and was suggestive, by character and location, of pancreatitis. Three patients who had stopped azathioprine because of the pain stated that restarting azathioprine produced worsening or recurrence of the pain within a few hours, and in one patient within a few minutes. No patient had a formal physician-controlled “challenge” with azathioprine. Serum amylase or lipase determinations were carried out at the time indicated in Table 1. In each of five cases the value was substantially above the upper limit of normal for the hospital laboratory. In the sixth case the value was at the upper limit of normal. No patient had a previous history of pancreatitis, cholelithiasis, hyperparathyroidism, excessive alcohol ingestion, or abdominal trauma. None of the patients was taking any other drug, and none had elevation of serum calcium at the time of upper abdominal symptoms of pancreatitis. In five patients, azathioprine was discontinued, and all clinical evidence of pancreatitis disappeared within 10 days. One patient, treated early in the study, had become asymptomatic by the time his elevated serum amylase value was recognized, and he continued to be asymptomatic with normal amylase values while taking azathioprine throughout the 22 mo of his subsequent participation in the study. No patient died, required surgery, or had a complication of pancreatitis.

Discussion Azathioprine was associated with pancreatitis in at least 4.4% of patients receiving it in the National Cooperative Crohn’s Disease Study. Ninety-five percent confidence limits on this figure

Table

1.

Patients

with Pancreotitis

in the National

suggest that pancreatitis might occur in between 0.2 and 6.7% of all patients with Crohn’s disease given azathioprine (Table 2). This is a minimum estimate, since routine serum amylase screening was not employed in detection of these cases. Three cases of azathioprine-related pancreatitis in Crohn’s disease have been previously reported in detail,“,4.7 and 5 others noted in abstract.“,’ Before this report, a total of 214 patients treated with azathioprine for Crohn’s disease in controlled or uncontrolled trials have been reported.“.A,“~‘” Of these patients, 3 have developed pancreatitis; these cases were among 7 patients given azathioprine in a single trial.’ Thus there is a 1.4% overall incidence of pancreatitis in the reported experience with azathioprine in Crohn’s disease. This incidence is within the 95% confidence limits calculated from the incidence in the NCCDS. Azathioprine was found to be significantly more likely to cause pancreatitis than sulfasalazine, prednisone, or placebo. These latter three treatments were not associated with development of pancreatitis in any NCCDS patient, and calculated 95% confidence limits indicate that the true incidence is less than 2.8% with each treatment. Our results do not shed light on the suggestion, made by Huizenga administration of predniet al.,” that concomitant sane may protect against development of pancreatitis, since none of the 6 patients here reported was taking steroids at the time they developed pancreatitis. In this regard, however, 2 cases reported in the literature were taking prednisone at the time of onset of pancreatitis.“,7 The mechanism by which azathioprine causes pancreatitis is not known. Preexisting involvement of the duodenum by Crohn’s disease does not appear to be the mechanism, since none of our patients had radiologic evidence of duodenal Crohn’s disease either at the time of their on-study barium x-rays

Cooperative

Crohn’s Disease Study Maximum

Patient No. 1 2 3 4 5 6

Age

Sex

CDAI at entry0

30 29 24 23 37 32

M F M M M F

69 345 261 266 106 94

Crohn’s disease in bowelb

Duodenal ulcer”

1, C I, C C I I I, C

No No No Yes No No

Azathioprine daily dose (msl 70 125 125 150 70 70

Time from 1st dose to pain of pancreatitis (doysl 15 13 16 16 21 17

serum

Time from

amylase

1st dose to

or lipase (75 upper limit norm01 for Job)

amylase or lipase determination

520 140 660 175 157 100

(days1 24 17 21 21 35 23

ulcer by upper GI barium x-ray, endoscopy, or a CDAI = Crohn’s Disease Activity Index. b I = Ileum; C = Colon. c No = no duodenal ulcer identified on barium x-ray 3 mo after episode of pancreatitis, but not found on barium x-ray done 2 wk both. Yes = duodenal after onset of pancreatitis.

AZATHIOPRINE-RELATED

Table

,?.

Frequency

of Pancreatitis

in the National

Patients developing pancreatitis Azathioprine

5 (amylase-confirmed) 6 (amylase-confirmed probable) 0 0 0

Sulfasalazinc Prednisonc Placebo

limits are estimates from these treated with the drug indicated.‘”

(taken

1 mo

of

development

Cooperative

of

data

of intervals

pancreatitis)

in subsequent x-rays carried out in 3 of the 6 patients. Other than allergy, the possible pathogenctic mechanisms suggested for the pancreatitis associated with diuretic drug ingestion (cellular derangeimpaired pancreatic blood ment by hypokalemia, flow, and inspissated secretions in ducts)“’ seem unlikely to explain azathioprine-associated pancreatitis. However, the temporal relationships of azathioprine-associated pancreatitis in Crohn’s discase are at least suggestive of an allergic mechanism. Onset of the reaction in the 3rd wk of exposure is compatible with the time frame of development of antibodies or cellular immune response. So also is the recurrence of symptoms within a few hours of reintroduction of azathioprine, noted in 3 of our patients, in 3 previously reported cases with Crohn’s disease,“4i and 1 with ulcerative colitis.” It is unclear why patients with Crohn’s disease should be peculiarly susceptible to such an allergic reaction. Whether the drug causes pancreatitis in patients who do not have Crohn’s disease is uncertain. Renal transplant patients who have been reported to develop pancreatitis have all been receiving other drugs, including steroids.” The striking timing of the onset of pancreatitis in Crohn’s disease patients in the 3rd wk of therapy has not been a regular feature in renal transplant patients, but was noted in the rccently reported case of azathioprine-induced pancreatitis in ulcerative colitis.” A single case of possible azathioprine-related pancreatitis after I yr of treatment for systemic lupus erythematosis has recently been reported.” We are not aware of other reports of pancrcatitis in patients being treated solely with azathioprine for other illnesses, but it may have occurred at a low frequency and not been detc?cted. [Jnlike the pancreatitis reported with Rifampitin,” the development of pancreatitis in NCCDS patients did not appear to be dose-related. Three of the six patients were taking 2.5 mg per kilogram body weight per day, and three only 1 mg per kilogram or

IN PATIENTS

Crohn’s Disease

Patients receiving drug

plus

“95% confidence Crohn’s disease

within

PANCREATITIS

Developing

% pancreatitis 4.4 5.3

132 146 178

0 0 0 contain

the true

CROHN’S

DISEASE

885

Study

113 113

which

WITH

frequency

Confidence

95% limits (%)‘I

0.2, 8.7 0.7, 9.9 0, 2.8 0, 2.5 0.2.1 of pancreatitis

in patients

with

per day. Also in contrast to pancreatitis associated with other drugs, patients with Crohn’s disease were unlikely to develop this reaction if they safely took the medication through the 3rd wk. The NCCDS found no statistically significant benefit of azathioprine over placebo in control of active symptomatic Crohn’s disease, nor in reduction of frequency of relapses or recurrence of Crohn’s disease. These findings, together with the observed 4.4% incidence of pancreatitis, suggest that azathioprim may have no place in the routine treatment of Crohn’s disease. However, uncontrolled observations’” and a recent long-term controlled trial” raise the possibility that azathioprine may be useful prophylactically in a selected subgroup of patients. The related drug, 6_mercaptopurine, has been reported to bc of benefit in a long-term trial, but is also associated with pancreatitis.”

References 1. Block

MB, (;cnant HK, Kirsner JB: Pancreatitis as an adverse reaction to salicylazosulfapyridint:. N Engl 1 Med 282:380-382, 1970 2. Leggo DA, Hoffman HN, Carlson HC: Pancreatitis as a complication of regional enteritis of the duodenum. Gastroentcrrology 61:834-837, 1971 MA: Acute pancroatitis as a complic;a3. Nogueria JR, Freedman tion of Imuran therapy in regional onteritir;. Gastrocnterology 62:1040-1041. 1972 H, Rudolph E, Bull FE: Azathioprinc-induced pan4. Kawanishi creatitis. N Engl J Mcd 2H9:357, 1973 5. Huizenga KA, Shorter RG, Phillips SF: Pancrcatitis: a specific complication of azathioprinc therapy in Crohn’s disease (ahstr). Gastroenterology 70:895, 1976 6. Nakashima Y. Howard JM: Drug-induced acute pancreatitis. Surg Gyn Obstet 145:105-109, 1977 7. Paloyan D, Lcvin B, Simonowitz D: Azathioprinc-associated acute pancreatitis. Am J Dig Dis 22:8X-840, 1977 8. O’Donoghuc DP, Dawson AM, Powell-Tuc.k 1. et al: Doubhblind withdrawal trial of azathioprine as maintenance trcatment for Crohn’s disease. Lancct 2:955-957. 1978 9. Present DH, Wisch N, Glass JL: Thr: efficacy of immunosuppressive therapy in Crohn’s disease. A randomized longterm douhlc-blind study (ahstr). (:astroc:ntc:rology 72:1114, 1977 10. Winship DH, Summers RW, Best WR. ctt al: National Cooper-

886

11.

12. 13. 14. 15.

16.

17.

STURDEVANT

ET AL.

ative Crohn’s Disease Study: Study Design and Conduct of the Study. Gastroenterology 829~842,1979 Best WR, Becktel JM, Singleton JW, et al: Development of a Crohn’s Disease Activity Index. Gastroenterology 70:439-444, 1976 Brooke BN, Cave DR. King DW: The place of azathioprine for Crohn’s disease. Lancet 1:1041-1042,1976 Rhodes J, Bainton D, Beck P, et al: Controlled trial of azathioprine in Crohn’s disease. Lancet 2:1273-1276,197l Willoughby HMT, Kumar PJ, Beckett J, et al: Controlled trial of azathioprine in Crohn’s disease. Lancet 2:944-947,1971 Klein M, Binder HJ, Mitchell M, et al: Treatment of Crohn’s disease with azathioprine: a controlled evaluation. Gastroenterology 66:916-922,1974 Rosenberg JL, Levin B, Wall AJ, et al: A controlled trial of azathioprine in Crohn’s disease. Am J Dig Dis 20:721-726, 1975 Allan R, Steinberg DM, Williams JA, et al: Crohn’s disease in-

GASTROENTEROLOGY,

18. 19. 20. 21. 22. 23.

24.

Vol. 77, No. 4, Part 2

volving the colon: an audit of clinical management. Gastroenterology 73:723-732,1977 Wallenstein S, Persson S: Azathioprine therapy for Crohn’s disease. Acta Chir Stand 138:521-526,1972 Avery-Jones F, Brown P, Lennard-Jones JE, et al: Azathioprim for Crohn’s disease (letter). Lancet 2:795,1969 Snedecor GW. Cochran WG: Statistical Methods. Sixth edition. Ames, Iowa, Iowa State University Press, 1967, p 21Off lsenberg JN: Pancreatitis, amylase clearance, and azathioprine. J Pediatr 93:1043-1044,1978 Corrodi P, Knoblauch M, Binswanger U, et al: Pancreatitis after renal transplantation. Gut 16:285-289,1975 Herskowitz LJ, Olansky S, Lang PG: Acute pancreatitis associated with long-term azathioprine therapy. Arch Dermatol 115:179, 1979 Poole G, Stradling P, Worlledge S: Potentially serious effects of high-dose twice weekly Rifampicin. Br Med J 3:343-347, 1971