sulphasalazine--induced pseudornernbranous...

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Sulphasalazine--induced pseudornernbranous colitis

H Ut.11 J FREr.MAN, MD, URS P STEINBRECIIFR, MD, WC PETFR KWAN, Ml\ STFl'l lANIE ENSWORTII, MD

HJ FREEMAN, UP STEINBRECHER, WCP KWAN, S ENSWORTH. Sulpha!oalazine-induced pscudomcmbranous colitis. Can J Gastroenterol 1991 ;5 (5): 167- 170. An 18-ycar-oLJ female with ankylosing spon<lylitis developed fever, abJominal pain and diarrhea on two occasions after staning sulphasa lazinc rhempy. Flex ihle sigmoidoscopy revealed pseuJomembranous colitis; fecal cultures were posit ive for Clostridium difficile; and C difficile toxin assay was positive. De5prtc the frequent use of sulphasalazine in the management of inflammarory howcl Jisea~c. this complication has been apparently rare. C linicians should be ~ary of the onset of J iarrhea in pat ients receiving :,ulphasalazine, whether for mflammatory bowel Jisease or other condit ions.

Key Words: 5-aminosalicylicacid , Closcridium , Crohn's disease, Inflammatory bowel disease, Pseudomembranous colitis, Sulf apyridine, Sulphasa/azi11e, U/.cerarive colitis

Colite pseudomembraneuse induite par la sulfasalazine

RESUME: Une patience agee <le 18 ans et atteinte J 'une spondylarthrite ankylosante a souffert de fievre, J e douleurs ab<lomina les ct de <l iarrhee en J eux ucca~ions, aprcs avoir entamc un t ra ite ment pa r la sulfasalazine. Une \1gmoidoscopic a revelc une colite pscudomcmbrancuse. Le diagnostic a etc confi rrne par unc coproculture a la rechcrchc de Clostriclium difficile et la misc en ernlcncc Jc sa toxine. Malgre le recours frequent a la :.ulfasalazine <lans le trn1tcrncnt des mala<lies inflammatoires de l' intest in , cettc complicat ion est arrarcmmcnt rare. Les cl inicicns devraient erre a ttentifs a !'apparition de Jiarrhcc chez lcs patients traites sous sulfasalazine, qu 'ils soient porteurs d 'une maladie inllammaroire de l' intcstin ou d 'une affection autrc.

Departmem of Mcd1r111e (Gm1roe111erology and RheumacolCJg~), UnrwrsiL'I l losp1tal and ,i nn:ernry of Bnrl~h Co/11mh1a, Vancouver, Bn11sh Col11mbia

Correspondence and re/Jrims: /)r Hugh Freeman, AC'U F-137, Gas1roen1crolo1,ry, Univernl'I Hosp11al (UBC' me), 2211 We.1hr()()k Mall, Vancouver, Brmsh Col11mh1a V6T 1W5. Telephone (604) 822-7216

Received fc,r 1,uhl1ca1ion Mcr'I 9, / 99 / Accrpred A11g1111 26, 1991

(,A\ J GASTROINTEROI Vm 5 Nn 5 SH'Tl:Mlll R/0. "Tl )BER 1991

FOLLOWINU Tl IF DISCOVERY Tl IAT

~ulphonami<les pm,scsseJ ant1bac-1erial action, they were commonly uscJ in the treatment of many inflammatory diseases. Svanz (1,2) initial ly used sul fapyridine with salicylic acid for treatment of rheum.itord arth rnrs, which even I ual ly led to the development of sulphasal,mne, a 5-amrnosa licylic acid ,md sul fapymline linked hy an aw honJ (Pharmaci.r Inc, SweJcn), for ulcera1ive colnb. Subsequent invest igations suggesteJ that 5-amin,)sal icy l ic .icid wa~ the therapeut ical ly acuvc moiety (3-5). More recen1 ly, \econJ generation' agents have heen Jcvelopcd to circumvent mle ctlccrs attributec.l to su lphasalazine, particu larly the sulfapyridi ne component. Despite reported adven,e effccLS, su lphasalazine remains useful in the management of patients wnh infl ammatory howcl d isease, anJ recent studies have suggested efficacy of thb agent in some rhcunrntic <li~ordcrs, cg, rheumatoid arth ri tb (6,7).

A number of ga~t rointestinal complicat ions of :.u lphasalazine have heen recognrzeJ. Commonly described siJe effects are nausea, vom iting, anorexia anJ alxlomin,,l p,1111, while others in-

167

FRFEMAN er al

elude pancreatitis, hepatitis, and skin and mucous membrnnc involveme nt (ie, Stevens-Johnson syndrome) (8 ). In recent years, sulphasala: ine-induced exacerhations nf colitis and diarrhe;i have hcen recorded in a number of patients (9- 12). While most antibiotics have heen implicated in the pathogenesis of pseudomembranous colitis, only limited information is avai lable on the potential role of sulphonamides, suc h as sulphasalnzinc. This seem~ surprising given their widespread use, partic ula rly in pat ients with inflammatory bowel disease.

The present report describes a parienr with ankylosing spondylitis who developed ahdom inal pain, fever a nd di a rrhea following su I phasa lazi n c administration. Subsequent investiga tions failed to disclose a cause for her symptoms, but soon after re-introduction of sulphasalazine for a rheumatological disorde r , diarrhea rec urred, sigmoidnscopy showed the presence of pseudnmembranouscoliris, and stools were positive for Clostridi11m difficile cytotoxin.

CASE PRESENTATION An 18-year-nlJ female with a three

year histo ry of ankylosing sponJylitis was referred for e va luation of abdominal pa in and diarrhea for ar least four weeks. Her spondylitis had fai led co respond to standard nonsteroidal amiinflammarory medications, and required treatment with prednistme LO mg daily and phenylbutazonc I 00 mg tid. A trial of thernpy with sulphasalazine rcsulte<l in epigastric pain, fever and watery diarrhea th rec days fol lowing initiation of a 500 mg daily dose. Because abdominal pain a nd diarrhea persisted after discontinuation of the sulphasalazine, the patient was admitted eight days later to her community h ospital for investigation.

Physical exam inarion revealed a temperature of 38°C and a diffusely tender abdomen . Hemoglobin was l 00 g/L with a white blood cell count of 12,800/mm3. Blood rests inc luding serum amylase 11ml liver chemistry tests (serum bilirubin, alkaline phosphatase and aminotransferascs) were nonnal. Abdominal radiographs a nd ultrasound

168

showed no abnormalities except for some free intrapelvic fluid. Gynecologica l exa mination and lapa roscopy revea led a small mnouncoffree fluid but no intra -abdominal or gynecological abnormality; the appendix, small intestine and colon appeared normal. Sigmoidoscopy, fecal cu ltures and an upper gastrointestinal tract barium study with small bowel fo llow-through were norma l. Rectal biopsy and fecal toxin assay forC difficile were not don e. All medications were discontinued except pred nisnne, which was increased to 40 mg daily because of worsening back stiffness and pain. Over the next 20 days, the abdominal pain, fever and diarrhea reso lved , and the prednisone was tapered to LO mg daily with re- institution of phcnylbutazone LOO mg tid. Beca use it was believed that the patient's <1bdominal pain was not explained, she was transferred to University Hospital for further evaluation. She had some mild epigastric discomfort. There was n\l previous personal o r family history of gastrointestinal disease; the patient's brother had ankylosing spondylitis. Except for spondylitis, physical examinati o n at the time of admission to

University Hospital was norma l. Inves tigat ions revealed a hemo

globin of96 g/L with a white blood cell count of 16, 700/mm 3. Blood rests were normal, inc luding liver c hemis try (serum bilirubin, alkaline phosphatase and aminotransfcrases), scrum amylase, electrolytes, carotene, calcium, phosphate , ferrit in, vitamin B12 and red cell fo latc. Urinalysis was normal. Rheumatoid la tex test and antinuclear a ntibodies were negative. Blood, urine and fecal cultures (campylobacter, salmone lla, shige lla, aeromonas, yersinia anJ C difficile) were negative. Fecal parasite studies were negative, as were latex agglutination and tissue cu lture assays for C difficile cytotoxin. Fibreoptic endoscopic examination of the upper and lowe r gastrointestinal tract with biops ies of the stomac h, duodenum and colon were no rmal. Repeat barium radiographs of the esophagus, stomach and small intestine were normal.

During the next week in hospital, the symptoms of the patient's spondylitis remained unchanged despite dis-

continuatitm of prednistme. ln an cffmt to reduce reliance on phenylhutazonc, sulphasa lazine 500 mg daily was re-in· stituted; rec urrent abdominal parn and dia rrhea developed approx imately 2 h after ingestion of the fourth 500 mg tablet. Flex ible sigmo idoscopy was repeated the fo llowing Jay and rcvealt'J multiple pseudomembrnnes fmm 5 tll 2 5 c m; biopsies confirmed pscudomembranous colitis. Repeat feca l cultures were negative except for detection o(C difficile; fecal C difficile cytmnxin 1 issue culture assay was now positive at a titre of greater than I : 1000. An indiumlabe lled white blood cell scan revealed increased diffuse activity wrthm the large bowel. Oral vancomycin 500 mg qid was instituted , but abdnminal pam and diarrhea pers isted, nnd fever over 39t1C developed. Abdomin,11 film~ revealed dilated small and large bowel hut no free ai r in the pcrilt)neal cavity. Intravenous metronidazolc 500 mg every l 2 h was added afte r two days, along with central venous total parenteral nutrition . Over the next two weeks, the patient's symptoms gradually resolved, permitting re-institution of ora l imakc and discontinuation of medicat ion,. Repea t flexible sigmoidoscopy with hiopsy was normal, and fecal C difficile cytotox in assays were negative.

DISCUSSION The present patient was referred he

cause of fever, abdominal pain and watery diarrhea following ,1Jministration of cnceric-coated sulphasalazine (Salazopyrin; Pharmacia Inc, Sweden). Initial investi.gations prior to re-introduct ion of sulphasa lazine , including fecal cultures, tox in assays, endoscopy and contrast radiographs of the gastrointestinal trac t, were norma l. The pa tient'~ symptoms reso lved sptintaneously, but recurred promptly after c hallenge with sulphasalazine. Suhsequent studies revealed histologically confirmed pseudomembranous colitis associated with C difficile cycotoxin. While this agent has been widely used in the past for the treatment of inflammatory bowel disease, the patient descrihed in the c urrent report wai treated with sulphasalazinc in an effort

CAN J GASTROENTEROL VOL 5 NO 5 SEl'TEMBE:R/0<.'TOBER 1991

10 control sympwms associated with ankylosing spon<lyl itis. Although there is one prior rcpon of pseudomemhranous colitis attributed directly to sulphasalazine treatment, this occurred in a patil'nt with pre -ex ist ing Crohn's disease (13). The present patient had no history suggesting a preexisting primary gastrointestinal disorder, and investigations of the gastrointestinal tracr perfnrmeJ only a short time prior t11 rl.'-introduction of sulphasalazinc for spondyli tis were normal. The observations in the prcsen1 ratienr provide strong evidence char C difficile-associated diarrhea and pseudomembranous co litis may develop in patients treated with sulphasalazine. To Jatc, this complicat ion has not been reported with other 5-aminosalicylic acid-containing products.

Prior reports have documcnteJ a

number of adverse gas1rnintcs1inal -specifica ll y colonic - effects after sulphasalazine administration. Werlin .md Grand (9) dcscribcJ two children with ulcerative colitis and bloody diarrhea fo llowing sulphasalazine administration; sympr,ims abo recurred with

REFERENCES I. Svartz N. Salawpyrin, a new

,ulfonilamiJe prepar.ition. Act.I Med Scand 1942;1 10:557-98.

2. Svartz N. The treatment of I 24 ca,es of ulcerative coli us with Sah1zopyrin and attempt~ at Jc:-emit izarion in cases ofhyper~cn,itivenl',, to , ul fo. Acta Med Scrmd I 948;206:465-72. Azad Khan AK, Pirb J, T ruclove SC. An experiment w determine• 1 hl· .ict 1ve thernpcu1 ic moiety of sulph,1salazme. Lmcct I 977;ii:892-5.

4. van Hee:, PAM, Bakker JI l. van TongercnJ l lM . Effect of :,ulphapyridinc, 5-amino,alicylic acid, and placeho in pmient, wirh idinparhic proctit is: A study ro determinc the acrive therapeutic mnicty nf sulphasalazme. Gut 1980;2 I :6 32-5.

5. Campieri M, L:mfranchi G, Bazzocchi G, ct al. T remmcnt of ulcernt ivc c11lit i, with high Josage 5-aminosalicylic acid enemas. L111ce1 1981 ;ii:270- l.

6. Dixon JS. Bit>chem,cal and clinical change, in rheum:1111id anhrn '" Thl'1r relation ro rhe act 1011 nf .int irheumatoid drug,. St·m in A rthrit i:, Rheum 1982; l 2: 191 -207.

drug challenge and rapidly resolved with ccs,a ti nn of sulphasalazine. Schwanz ct al ( I 0) described challenge studies in a 35-ycar-old physician fol lowing oral and rectal sulphasalazinc administrntion. Endoscopic and histological relarse of ulcerative coli ris, as well as iridocyclitis, fo llowed both routes of drug ddivery. Similarobscrvat ions were made in a nine-year-olJ male with pre-existing ulcerative col itis; in this patient, however, an assay for C difficile cytotoxin was negative (lZ). Pseudomembranous colitis anJ 11 positive assay for C difficile cytotoxin were described in a patient with known Crohn's disease ( l 3); sigmoidoscopic examination three months ea rli e r showeJ on ly "diffuse mucosa! edema anJ multip le ulceration:," without pseudomemhrnnes. Fecal studies were not reported prior w su lphasalazine administration. Subse4ucnt sulphasalazine therapy, hnwevcr, resulted in symptomatic relapse; repeat cnd\)Scopic evaluation sht)wed pseudomemhranou, colitis and concomitant detection ofC difficile cywrox in. Although C difficile cywrnxin ha, heen frequently is,,lnted

7. Bml I lA, l)1xon JS, Pickup ME, ct al. A hiochcm1cal assc,sment nf sulphasala:ine in rheumal<lid art hri11s. J Rheumatol 1982;9: 36-45.

8. Taff et SL, Das KM. Sulfasala:ine. Adver,e effects ,mJ desens1tizati,m. D,g Di, Sci l 981;28:!ff3-4 I.

9. Wedin SL, Grand RJ. 111oody diarrhea A new complication pf sulfasalazine.

J rcdiarr I 978;92:450-1. I 0. Schwartz AG, Targan SR. Saxnn A,

Weinstein WM. Sulfasalazinc- induced cxaccrhation of ulcerative col11 is. N Engl J Med 1982; 106:409-1 2.

11. Adler RD. Sulfasalazinc-induccd exaccrhat inn nf ulcerntive coli11s. N EnglJ Med 1982;307:315. (Lett)

12. R111g FA. Hmhficld NB, Machin G/\, Scntt RB. Sulfasalazine-induced C1llitis cmnplicating idiopathic ulcerative colnis. Can Med As,ocJ 1984;131:41-5.

l 1. Pokorney Bl l, Nichols TW. Psi.:udnmemhranou:, c,llitis. A comp I icnrion of sulfas,1 lazinc I hcrnpy 111 ,1 pm1cnt with Cmhn':, eolitb. Am J GaMroenreml 1981; 76: 374-6.

14. LaMont JT, Trnka YM. Therapeutic 11npl ic,11 ions ,if ClostT1dium difficile

CAN J GASTRl)ENTEROL VOL 5 Nl) 5 SEl'TEMIIEl{/<..x. TLlllt'R 1991

Sulphasalazine-induced colitis

from patients with well established 111-

CTammatory bowel disease by different investigators ( 14-24), its role in diseast· pathogenesis remains unclear. lt is, however, intriguing char pscudomembranes have rarely heen recorded in thb sett111g (14,15), perhaps reCTecting limited pathologica l reactivity of dw coltmic mucosa in patient, with e11her ulcerative colitis or Crohn's disease in response to toxin(s) from this organ ism.

The present report describes endoscopic, histologic.11 and micmhiolngical studies showing C difficile-related pseudomcmbrnnous colitis in a patient admin istercd su lph;1sal.1zine for ankylosing sponJylitis; unequivtx:ally normal stud ies were documented im mediately prior LO drug ,1dminis1ratinn. A lthough surprisingly rare in view nf its cnmmtm use, sulphasah1zine evidently ha~ rhe pntential to c,1use a li fethreatening disorder, pse udomcmhranous colitis. As such, c linicia ns should be very wary of the onset of diarrhe,1 in p.nicnts administered stdphasalazine, including pat ienrs t reared for di,order~ other than inflammatory hnwcl dbcasL·.

r,,xm during rel:1p,e of chn,n1c 111flammatmy howcl d1,e,ist·. L111n·t 1980;1: 381-4.

15. Tmka YM, L:1Mont JT. Associmion of Clo.1rridi11111 d1ffic1le tox111 with sympto111.1t1c reh1p,e nf chronil inflammatory h11wel J1,e;1,e. Ga,rmentl•rology 1981;80:693-6.

16. Meyer, S, Mayer L, Bui tone I::, l'k,1111>1111 E. Jan,1w1tz 11[). Occurrence nf Clo,tridium difficile toxin during the course of infla111111atory hmvd d1sea,e . l3a,troenterology 1981 ;80:697 • 700.

17. Dorman SA, L1ggorrn E, Winn WC. Bee ken WL. bolation of Clo.1tridiwn difficile from parienr, with inac1 ive Crohn\ dise.1sc. (,;i:,t mentemlngy 1982;82: 1148-5 1.

18. f\,lton RP. RcaJ AE. Clo,md1um difficile 111 toxic megncolon complicating acute intla111mah1ry howel d1sca,c. Br Med J 1982;285:4 75-6.

19. Keighley MRI\ Youngs l), Juhn,..,n M, Allan RN, Burdon [)W. Closcrid11m1 difficile wxin in acute d1.1rrhe<> <.:omplicaung mflammmory bowel disease. Gui 1982;2 3:410-4 .

20. l~rCl'nfield C, Aguilar Ramirez JR,

169

FREFMAN et al

PounJcr RE, ct ,ii. Closmdium difficile anJ inOammatory bnwcl Ji,ea,e. Cur 1983;24:713-7.

2 I. Rolny P, Jarncroc G, Mollby R.

170

Occurrence ofClostridi11m difficile cox in in inOamm;Hory hliwel dbca,c. Scam! J Gastroentcrol 198 3; 18:6 1-4.

22. Wright JM, AJams SP, G ribble MJ, Bowie WR. Closrridium difficile in Crohn's disease. Can J Surg 1984;27:4 35-7 .

23. 1-lyam, JS, McLaughlin JC. Lack of relatio nshi p between Clostridium difficile tox in nnd inflammatory bowel

d isease 111 children. J C lin G,1,troenrero l L985;7:387-90.

24. DcRiJder Pl I, Kadw 0. Crohn', disease with pcn,btcncc of Clostridium difficile, surgica l elimination. J C lin Gm,trocnterol 1985;7:269-72.

CAN J GASTROFNTEROL Vo1 5 No 5 S!: l'TEMBl·R/(X.TOHER 1991

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