- Email: [email protected]
Isotretinoin-associated proctosigmoiditis
GASTROENTEROLOGY 1987;93:606-9
CASE
REPORT
Isotretinoin-Associated
Proctosigmoiditis
P. MARTIN, P. N. MANLEY, W. T. DEPEW, and J. M. BLAKEMAN Gastrointestinal Disease Research Unit, Department of Medicine, and Department of Pathology, Queen’s University Medical School, Kingston, Ontario. Canada
A 17-yr-old boy developed acute proctosigmoiditis after the institution of isotretinoin for the treatment of cystic acne vulgaris. Painless diarrhea, accompanied by mucus and eventually blood, began within days of commencing treatment and persisted while the drug was administered. At sigmoidoscopy patchy mucosal inflammation associated with numerous discrete aphthous ulcers was seen, apparently restricted to the rectosigmoid. Histologic examination of the affected mucosa revealed an acute focal superficial inflammatory infiltrate. Withdrawal of the drug resulted in prompt resolution of symptoms and a reduction in the severity of the inflammation. Fiechallenge with isotretinoin induced a second, almost identical, attack of proctosigmoiditis. Withdrawal was again followed by disappearance of symptoms, and a subsequent sigmoidoscopy and mucosal biopsy were normal. The patient has remained clinically well for 16 mo after his initial presentation. Although the pathogenesis of the colonic mucosal inflammation remains unknown, the relationship of the bouts of proctosigmoiditis to the administration of isotretinoin strongly suggests that the drug was directly responsible.
Isotretinoin (Accutane, Hoffmann-LaRoche, Nutley, N.J.) is a synthetic analogue (1%cis-retinoic acid) of vitamin A that is widely used to treat cystic acne resistant to other forms of therapy. Although it has been suggested that the use of this drug is associated with the onset of inflammatory bowel disease (I), such an association is disputed (2). This report describes a case of proctosigmoiditis that appears to be directly related to the administration of isotretinoin. Received October 30, 1986. Accepted March 16, 1987. Address requests for reprints to: Dr. W. T. Depew, Queen’s University, 78 Barrie Street, Kingston, Ontario 0 1987 by the American Gastroenterological 0016-5085/87/$3.50
K7L 3J7, Canada. Association
Case Report A previously healthy 17-yr-old boy presented with a S-day history of passing blood and mucus per rectum, associated with a modest increase in stool frequency. He had started isotretinoin, 40 mg daily, 4 wk before presentation for the treatment of severe cystic acne unresponsive to other forms of management. The dose of isotretinoin had been increased to 40 mg b.i.d. after 2 wk of treatment. Within a few days of starting the drug an increase in stool frequency from one well-formed stool every second day to l-2 loose stools daily was noted. The patient did not complain of any abdominal pain, tenesmus, urgency, or fever and he had no extraintestinal symptoms. There was no history of antecedent bowel disease. There was no foreign travel, homosexual contact, recent antibiotic usage, or family history of inflammatory bowel disease. Physical examination revealed severe cystic acne vulgaris involving the face and chest. The abdomen was soft and nontender and there were no masses palpable. There were no oral cavity lesions. Digital rectal examination was unremarkable and the perianal tissues were normal. The patient was afebrile. Rigid sigmoidoscopy to 15 cm showed widespread patchy edema and hyperemia of the mucosa with a moderate quantity of mucopus in the lumen. Numerous 2-J-mm aphthous ulcers were seen but the inflamed mucosa was nonfriable (Figure 1). In places, the tiny erosions were covered by small white raised plaques that were easily removed with a swab or water jet to expose the superficial lesions demarcated by a thin halo of hyperemia and submucosal hemorrhage. A rectal biopsy specimen (Figure 2) showed focal nonspecific acute inflammation with a moderate, primarily superficial neutrophilic infiltrate extending into the crypt and surface epithelium. There was no suggestion of chronicity. No granulomata or evidence of pseudomembranous colitis was present. Stool cultures and a careful search for ova and parasites were negative. A rectal swab specifically for Neisseria gonorrhea was negative. Yersinia serology was nonreactive. Additional laboratory tests disclosed the following values: hemoglobin 131 g/L (normochromic, 5% normocytic), WBC 13.8 X lO”/L (80% polymorphs, bands, 0 eosinophils), platelet count 531 x log/L, and erythrocyte sedimentation rate 41 mm/h. Isotretinoin was discontinued. One week later the patient continued to pass S-4 loose stools per day with small amounts of blood and mucus. A flexible sigmoidoscopy to
September 1987
ISOTRETINOIN PROCTOSIGMOIDITIS
607
cm from the anal verge, with scattered
aphthous ulcers again noted. Rectal biopsy specimens once again showed a focal nonspecific acute colitis. Isotretinoin was discontinued and symptoms totally resolved within 5 days. At follow-up 6 mo after stopping the drug the second time, the patient was asymptomatic. A sigmoidoscopy to 20 cm and a rectal biopsy (Figure 3) were normal. He remains clinically well 16 mo after his initial presentation.
Discussion This case strongly suggests that isotretinoin can induce an acute proctosigmoiditis that resolves on drug withdrawal and recurs on rechallenge. There is a striking temporal relationship between the
Figure 1. Sigmoidoscopic appearance of acute proctosigmoiditis. a. Three small aphthous ulcers demarcated by a halo of hyperemia at rectosigmoid junction. b. Numerous small, slightly raised focal exudates were seen on the mucosa of the sigmoid colon. When removed, tiny aphthous ulcers could be identified. The intervening mucosa appeared normal.
40 cm showed patchy inflammation to 35 cm from the anal verge with macroscopically normal mucosa proximally. As before, the mucosa was studded with %3-mm lesions consistent with tiny aphthous ulcers. The inflammation was less marked than at the initial sigmoidoscopy. The rectal biopsy specimens were unchanged. Over the ensuing 4 wk the patient’s symptoms resolved completely. Unfortunately, despite numerous other attempts to control his acne he became despondent over his skin condition and a decision was made to reinstitute isotretinoin. Twelve days after reinstitution of the medication at 40 mg daily, the patient redeveloped increased stool frequency without mucus or blood. A flexible sigmoidoscopy to 30 cm showed patchy inflammation to 15
Figure
2. Initial rectal mucosal biopsy specimen showing a moderate neutrophilic and mononuclear infiltrate with superficial accentuation extending into surface and crypt epithelium. There was associated reduction of cytoplasmic mucin in epithelial cells. Hematoxylinphloxine-saffron, x600.
608
MARTIN
Figm ‘e 3. Final
ET AL.
I,ectal biopsy
GASTROENTEROLOGY
specimen
after withdrawal
of isotretinoin
use of the drug and the clinical course. Symptoms in this case first appeared within days of starting isotretinoin and quickly resolved within a month of discontinuing the drug. No other agents, including antibiotics, could be implicated. The sigmoidoscopic and histologic findings were compatible with an acute proctosigmoiditis with features distinct from idiopathic ulcerative colitis and pseudomembranous colitis, and there was no evidence to implicate known intestinal pathogens. Rechallenge with a lower dose of isotretinoin resulted in a recurrence of symptoms within 2 wk. Symptoms disappeared within days of drug withdrawal once again and follow-up sigmoidoscopy and rectal biopsies were normal. The extent of inflammation beyond the rectum and sigmoid colon is unknown. In view of the clinical presentation, sigmoidoscopic findings, and abatement of symptoms and signs after drug withdrawal, a more extensive search for concurrent proximal colonic and small bowel involvement was not believed to be appropriate. Although it is possible that the use of the drug coincided with the onset of an inflammatory bowel disease such as Crohn’s disease, no additional evidence for such a process has appeared in the 16 mo since initial presentation. Together, these observations provide persuasive evidence for an etiologic role of isotretinoin in the
is normal.
Hematoxylin-phloxine-saffron,
Vol. 93, No. 3
x600.
development of mucosal inflammation in this patient. The literature concerning the association of bowel disease and isotretinoin therapy is sparse and inconclusive. Korelitz (2) has stated, based on his own experiences and those of others (3), that there is no apparent association with either the onset of inflammatory bowel disease or exacerbations of preexisting disease. Hoffmann-LaRoche, makers of Accutane, had identified, as of November 1986, a total of 18 cases of inflammatory bowel disease possibly associated with the use of isotretinoin (Dean DM, personal communication). However, none of these cases have such a clearly defined association of symptoms and signs with drug usage and their subsequent disappearance after drug withdrawal. In each case, there appears to have been either preexisting inflammatory bowel disease or other complicating factors such as the use of antibiotics at the onset of the symptoms of inflammation. In the present case, only isotretinoin could be implicated in relation to the onset of symptoms and the developmeht of acute mucosal inflammation. The mechanisms by which isotretinoin might induce colonic inflammatory disease remain completely conjectural. Synthetic retinoids have significant inhibitory effects on the differentiation and
September
1987
growth of a variety of cells including epithelial cells, and it is possible that some primary disturbance of epithelial cell maturation results in initial microscopic ulceration which then progresses to macroscopic inflammation (4). It has been proposed that retinoids influence glycoprotein synthesis (5). Isotretinoin-induced alterations in glycoprotein metabolism, perhaps involving mucous glycoproteins, may compromise colonic mucosal integrity and permit violation of mucosal defense by luminal factors that stimulate inflammation. Retinoids are also known to influence gene expression (6). Alterations in phenotypic expression by colonic epithelial cells might similarly serve as a stimulus for the production of an inflammatory response. Finally, it has been shown in animal models that the synthetic retinoids induce killer T-cell activity (7). It is possible that a similar induction at the level of the gut mucosa results in epithelial cell injury and subsequent mucosal inflammation in individuals who are otherwise immunologically predisposed. Based on our experience with this patient, we conclude that there is an association between isotretinoin and the development of acute colorectal mucosal inflammatory disease. The colorectal in-
ISOTRETINOIN
PROCTOSIGMOIDITIS
609
flammation can resolve promptly after withdrawal of isotretinoin and recurs upon reintroduction. As this particular reaction has been described rarely, despite the increasing use of isotretinoin, this adverse effect is likely idiosyncratic and thus requires the participation of other, as yet unknown, processes for its complete clinical expression. References 1. Compendium of pharmaceutical and specialities. 21st ed. Schnell BR, Clarke WTW, Gray J, et al., eds. Toronto: Southam Murray, 1986:34. 2. Korelitz BI. Systemic 13-cis-retinoic acid therapy and exacerbation of colitis. JAMA 1984;252:2463. 3. Bruno DP, Beacham BE, Burnett JW. Adverse effects of isotretinoin therapy. Cutis 1984;33:484-6. 4. Goodman DS. Vitamin A and retinoids in health and disease. N Engl J Med 1984;310:1023-31. 5. Sbidoji Y, Sasak W, Silverman-Jones CS, et al. Recent studies on the involvement of retinyl phosphate as a carrier of mannose in biological membranes. Ann NY Acad Sci 1981; 359:345-57. 6. Sporn MB, Robert AB. The role of retinoids in differentiation and carcinogenesis. Cancer Res 1983:43:3034-40. 7. Dennert G, Crowley C, Kouba J, et al. Retinoic acid stimulation of the induction of mouse killer T-cells in allogeneic and syngeneic systems. J Nat Cancer Inst 1979;62:89-94.
CASE
REPORT
Isotretinoin-Associated
Proctosigmoiditis
P. MARTIN, P. N. MANLEY, W. T. DEPEW, and J. M. BLAKEMAN Gastrointestinal Disease Research Unit, Department of Medicine, and Department of Pathology, Queen’s University Medical School, Kingston, Ontario. Canada
A 17-yr-old boy developed acute proctosigmoiditis after the institution of isotretinoin for the treatment of cystic acne vulgaris. Painless diarrhea, accompanied by mucus and eventually blood, began within days of commencing treatment and persisted while the drug was administered. At sigmoidoscopy patchy mucosal inflammation associated with numerous discrete aphthous ulcers was seen, apparently restricted to the rectosigmoid. Histologic examination of the affected mucosa revealed an acute focal superficial inflammatory infiltrate. Withdrawal of the drug resulted in prompt resolution of symptoms and a reduction in the severity of the inflammation. Fiechallenge with isotretinoin induced a second, almost identical, attack of proctosigmoiditis. Withdrawal was again followed by disappearance of symptoms, and a subsequent sigmoidoscopy and mucosal biopsy were normal. The patient has remained clinically well for 16 mo after his initial presentation. Although the pathogenesis of the colonic mucosal inflammation remains unknown, the relationship of the bouts of proctosigmoiditis to the administration of isotretinoin strongly suggests that the drug was directly responsible.
Isotretinoin (Accutane, Hoffmann-LaRoche, Nutley, N.J.) is a synthetic analogue (1%cis-retinoic acid) of vitamin A that is widely used to treat cystic acne resistant to other forms of therapy. Although it has been suggested that the use of this drug is associated with the onset of inflammatory bowel disease (I), such an association is disputed (2). This report describes a case of proctosigmoiditis that appears to be directly related to the administration of isotretinoin. Received October 30, 1986. Accepted March 16, 1987. Address requests for reprints to: Dr. W. T. Depew, Queen’s University, 78 Barrie Street, Kingston, Ontario 0 1987 by the American Gastroenterological 0016-5085/87/$3.50
K7L 3J7, Canada. Association
Case Report A previously healthy 17-yr-old boy presented with a S-day history of passing blood and mucus per rectum, associated with a modest increase in stool frequency. He had started isotretinoin, 40 mg daily, 4 wk before presentation for the treatment of severe cystic acne unresponsive to other forms of management. The dose of isotretinoin had been increased to 40 mg b.i.d. after 2 wk of treatment. Within a few days of starting the drug an increase in stool frequency from one well-formed stool every second day to l-2 loose stools daily was noted. The patient did not complain of any abdominal pain, tenesmus, urgency, or fever and he had no extraintestinal symptoms. There was no history of antecedent bowel disease. There was no foreign travel, homosexual contact, recent antibiotic usage, or family history of inflammatory bowel disease. Physical examination revealed severe cystic acne vulgaris involving the face and chest. The abdomen was soft and nontender and there were no masses palpable. There were no oral cavity lesions. Digital rectal examination was unremarkable and the perianal tissues were normal. The patient was afebrile. Rigid sigmoidoscopy to 15 cm showed widespread patchy edema and hyperemia of the mucosa with a moderate quantity of mucopus in the lumen. Numerous 2-J-mm aphthous ulcers were seen but the inflamed mucosa was nonfriable (Figure 1). In places, the tiny erosions were covered by small white raised plaques that were easily removed with a swab or water jet to expose the superficial lesions demarcated by a thin halo of hyperemia and submucosal hemorrhage. A rectal biopsy specimen (Figure 2) showed focal nonspecific acute inflammation with a moderate, primarily superficial neutrophilic infiltrate extending into the crypt and surface epithelium. There was no suggestion of chronicity. No granulomata or evidence of pseudomembranous colitis was present. Stool cultures and a careful search for ova and parasites were negative. A rectal swab specifically for Neisseria gonorrhea was negative. Yersinia serology was nonreactive. Additional laboratory tests disclosed the following values: hemoglobin 131 g/L (normochromic, 5% normocytic), WBC 13.8 X lO”/L (80% polymorphs, bands, 0 eosinophils), platelet count 531 x log/L, and erythrocyte sedimentation rate 41 mm/h. Isotretinoin was discontinued. One week later the patient continued to pass S-4 loose stools per day with small amounts of blood and mucus. A flexible sigmoidoscopy to
September 1987
ISOTRETINOIN PROCTOSIGMOIDITIS
607
cm from the anal verge, with scattered
aphthous ulcers again noted. Rectal biopsy specimens once again showed a focal nonspecific acute colitis. Isotretinoin was discontinued and symptoms totally resolved within 5 days. At follow-up 6 mo after stopping the drug the second time, the patient was asymptomatic. A sigmoidoscopy to 20 cm and a rectal biopsy (Figure 3) were normal. He remains clinically well 16 mo after his initial presentation.
Discussion This case strongly suggests that isotretinoin can induce an acute proctosigmoiditis that resolves on drug withdrawal and recurs on rechallenge. There is a striking temporal relationship between the
Figure 1. Sigmoidoscopic appearance of acute proctosigmoiditis. a. Three small aphthous ulcers demarcated by a halo of hyperemia at rectosigmoid junction. b. Numerous small, slightly raised focal exudates were seen on the mucosa of the sigmoid colon. When removed, tiny aphthous ulcers could be identified. The intervening mucosa appeared normal.
40 cm showed patchy inflammation to 35 cm from the anal verge with macroscopically normal mucosa proximally. As before, the mucosa was studded with %3-mm lesions consistent with tiny aphthous ulcers. The inflammation was less marked than at the initial sigmoidoscopy. The rectal biopsy specimens were unchanged. Over the ensuing 4 wk the patient’s symptoms resolved completely. Unfortunately, despite numerous other attempts to control his acne he became despondent over his skin condition and a decision was made to reinstitute isotretinoin. Twelve days after reinstitution of the medication at 40 mg daily, the patient redeveloped increased stool frequency without mucus or blood. A flexible sigmoidoscopy to 30 cm showed patchy inflammation to 15
Figure
2. Initial rectal mucosal biopsy specimen showing a moderate neutrophilic and mononuclear infiltrate with superficial accentuation extending into surface and crypt epithelium. There was associated reduction of cytoplasmic mucin in epithelial cells. Hematoxylinphloxine-saffron, x600.
608
MARTIN
Figm ‘e 3. Final
ET AL.
I,ectal biopsy
GASTROENTEROLOGY
specimen
after withdrawal
of isotretinoin
use of the drug and the clinical course. Symptoms in this case first appeared within days of starting isotretinoin and quickly resolved within a month of discontinuing the drug. No other agents, including antibiotics, could be implicated. The sigmoidoscopic and histologic findings were compatible with an acute proctosigmoiditis with features distinct from idiopathic ulcerative colitis and pseudomembranous colitis, and there was no evidence to implicate known intestinal pathogens. Rechallenge with a lower dose of isotretinoin resulted in a recurrence of symptoms within 2 wk. Symptoms disappeared within days of drug withdrawal once again and follow-up sigmoidoscopy and rectal biopsies were normal. The extent of inflammation beyond the rectum and sigmoid colon is unknown. In view of the clinical presentation, sigmoidoscopic findings, and abatement of symptoms and signs after drug withdrawal, a more extensive search for concurrent proximal colonic and small bowel involvement was not believed to be appropriate. Although it is possible that the use of the drug coincided with the onset of an inflammatory bowel disease such as Crohn’s disease, no additional evidence for such a process has appeared in the 16 mo since initial presentation. Together, these observations provide persuasive evidence for an etiologic role of isotretinoin in the
is normal.
Hematoxylin-phloxine-saffron,
Vol. 93, No. 3
x600.
development of mucosal inflammation in this patient. The literature concerning the association of bowel disease and isotretinoin therapy is sparse and inconclusive. Korelitz (2) has stated, based on his own experiences and those of others (3), that there is no apparent association with either the onset of inflammatory bowel disease or exacerbations of preexisting disease. Hoffmann-LaRoche, makers of Accutane, had identified, as of November 1986, a total of 18 cases of inflammatory bowel disease possibly associated with the use of isotretinoin (Dean DM, personal communication). However, none of these cases have such a clearly defined association of symptoms and signs with drug usage and their subsequent disappearance after drug withdrawal. In each case, there appears to have been either preexisting inflammatory bowel disease or other complicating factors such as the use of antibiotics at the onset of the symptoms of inflammation. In the present case, only isotretinoin could be implicated in relation to the onset of symptoms and the developmeht of acute mucosal inflammation. The mechanisms by which isotretinoin might induce colonic inflammatory disease remain completely conjectural. Synthetic retinoids have significant inhibitory effects on the differentiation and
September
1987
growth of a variety of cells including epithelial cells, and it is possible that some primary disturbance of epithelial cell maturation results in initial microscopic ulceration which then progresses to macroscopic inflammation (4). It has been proposed that retinoids influence glycoprotein synthesis (5). Isotretinoin-induced alterations in glycoprotein metabolism, perhaps involving mucous glycoproteins, may compromise colonic mucosal integrity and permit violation of mucosal defense by luminal factors that stimulate inflammation. Retinoids are also known to influence gene expression (6). Alterations in phenotypic expression by colonic epithelial cells might similarly serve as a stimulus for the production of an inflammatory response. Finally, it has been shown in animal models that the synthetic retinoids induce killer T-cell activity (7). It is possible that a similar induction at the level of the gut mucosa results in epithelial cell injury and subsequent mucosal inflammation in individuals who are otherwise immunologically predisposed. Based on our experience with this patient, we conclude that there is an association between isotretinoin and the development of acute colorectal mucosal inflammatory disease. The colorectal in-
ISOTRETINOIN
PROCTOSIGMOIDITIS
609
flammation can resolve promptly after withdrawal of isotretinoin and recurs upon reintroduction. As this particular reaction has been described rarely, despite the increasing use of isotretinoin, this adverse effect is likely idiosyncratic and thus requires the participation of other, as yet unknown, processes for its complete clinical expression. References 1. Compendium of pharmaceutical and specialities. 21st ed. Schnell BR, Clarke WTW, Gray J, et al., eds. Toronto: Southam Murray, 1986:34. 2. Korelitz BI. Systemic 13-cis-retinoic acid therapy and exacerbation of colitis. JAMA 1984;252:2463. 3. Bruno DP, Beacham BE, Burnett JW. Adverse effects of isotretinoin therapy. Cutis 1984;33:484-6. 4. Goodman DS. Vitamin A and retinoids in health and disease. N Engl J Med 1984;310:1023-31. 5. Sbidoji Y, Sasak W, Silverman-Jones CS, et al. Recent studies on the involvement of retinyl phosphate as a carrier of mannose in biological membranes. Ann NY Acad Sci 1981; 359:345-57. 6. Sporn MB, Robert AB. The role of retinoids in differentiation and carcinogenesis. Cancer Res 1983:43:3034-40. 7. Dennert G, Crowley C, Kouba J, et al. Retinoic acid stimulation of the induction of mouse killer T-cells in allogeneic and syngeneic systems. J Nat Cancer Inst 1979;62:89-94.