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Retinal vein thrombosis after infliximab (Remicade) treatment for Crohn’s disease
AJG – April, 2003
Letters to the Editor
939
5. Cherington M. Central nervous system complications of lightning and electrical injuries. Semin Neurol 1995;15:233–40. 6. Ringsberg KC, Lowhagen O, Sivik T. Psychological differences between asthmatics and patients suffering from an asthma-like condition, functional breathing disorder: A comparison between the two groups concerning personality, psychosocial and somatic parameters. Integr Physiol Behav Sci 1993;28: 358 –67. Reprint requests and correspondence: Massimo Montalto, M.D., Istituto di Medicina Interna, Policlinico “A. Gemelli,” Universita` Cattolica del Sacro Cuore, Largo A. Gemelli, 8, Roma 00168, Italy. Received Nov. 7, 2002; accepted Nov. 18, 2002.
Retinal Vein Thrombosis After Infliximab (Remicade) Treatment for Crohn’s Disease TO THE EDITOR: We report an unusual case of a 45-yrold woman who developed branch retinal vein thrombosis after receiving infliximab (Remicade) for Crohn’s disease. This patient had a history of Crohn’s disease for 16 yr, which was complicated by perianal disease and fistula. Also, the patient had a past medical history of right colectomy with partial iliectomy for Crohn’s disease and perianal fistula repair. There was no history of hypertension, hypercholesterolemia, or diabetes. The patient was on prednisone, mesalamine, and azathioprine and had recent symptoms consistent with a flare of her disease, i.e., diarrhea, hematochezia, abdominal pain, and fever. Colonoscopy revealed focal areas of inflammation throughout the colon and rectum in a pattern and distribution consistent with Crohn’s disease. The patient was started on infliximab because of unresponsiveness to medical therapy. She was treated with 340 mg of infliximab at time 0, 2, and 4 wk, and then at 2-month intervals. With three doses of infliximab, her symptoms markedly improved. There was near complete resolution of her disease, but after the third dose of infliximab, the patient experienced visual changes, which she described as “flashing lights,” lasting a few minutes to several hours and occurring in the central visual field. There was no associated pain or headache. The patient was referred to ophthalmology for further evaluation. Direct and indirect ophthalmoscopy revealed a branch retinal vein occlusion in the right eye (Fig. 1). The workup to evaluate the etiology of branch retinal vein thrombosis was negative, including antinuclear antibody titer, anticardiolipin antibodies, protein C and S activity, antithrombin III activity, factor V Leyden mutation, lipid panel, homocystein level, and prothrombin mutation. Retinal vein thrombosis has not been reported as a side effect of infliximab. Vascular complications such as cerebral vein thrombosis and deep venous thrombosis have been associated with Crohn’s disease (1–10), but branch retinal vein thrombosis after 16 yr of disease has not been described. The cause of retinal vein thrombosis in this patient
Figure 1. Retinal hemorrhages along the nerve fiber layer caused by branch retinal vein occlusion.
remains uncertain. However, the temporal relation of this occurrence to infliximab treatment raises concern for this as a possible medication-related complication. The purpose of this case report is to raise awareness about this as a potential side effect of infliximab in patients being treated for Crohn’s disease. Srinivas R. Puli, M.D. David D. Benage, M.D. Department of Internal Medicine St. John’s Mercy Medical Center St. Louis, Missouri
REFERENCES 1. Akobeng AK, Miller V, Thomas AG. Epilepsy and Crohn’s disease in children. J Pediatr Gastroenterol Nutr 1988;26:458 – 60. 2. Lam A, Borda IT, Inwood MJ, et al. Coagulation studies in ulcerative colitis and Crohn’s disease. Gastroenterology 1975; 68:245–51. 3. Weber P, Husemann S, Vielhaber H, et al. Coagulation and fibrinolysis in children, adolescent and young adults with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1999;28:418 –29. 4. Johns DR. Cerebrovascular complications of inflammatory bowel disease. Am J Gastroenterol 1991;86:367–70. 5. Levine A, Lahav J, Zahavi I, et al. Activated protein C resistance in paediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1998;26:172–4. 6. Paradis K, Bernstein ML, Adelson JW. Thrombosis as a complication of inflammatory bowel disease in children: A report of four cases. J Pediatr Gastroenterol Nutr 1985;4:659 –62. 7. Erte D, Ozguven E, Acar Y, et al. Thrombembolic complications in children with Crohn’s disease. J Pediatr Gastroenterol Nutr 1999;28:540 –1. 8. Bridger S, Evans N, Parker A, et al. Multiple cerebral venous
940
Letters to the Editor
thromboses in a child with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1997;25:533–6. 9. Hassan KO, Jenkins HR. Multiple venous thrombosis in inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1998; 27:616 –7 (letter). 10. Al-Malik H. Cerebral venous thrombosis as a complication of Crohn disease: A case report. J Pediatr Gastroenterol Nutr 2001;32:209 –11. Reprint requests and correspondence: Srinivas R. Puli, M.D., St. John’s Mercy Medical Center, Housestaff Mailbox, 615 South New Ballas Road, St. Louis, MO 63141. Received Nov. 7, 2002; accepted Nov. 18, 2002.
Acute Reversible Rhabdomyolysis During Interferon ␣2b Therapy for Hepatitis C TO THE EDITOR: A 70-yr-old man treated with interferon ␣2b (INF ␣2b) for chronic hepatitis C presented with acute rhabdomyolysis. Hepatitis C was diagnosed 6 months previously (confirmed by results of polymerase chain reaction), and liver biopsy showed moderate chronic hepatitis (histological activity index (HAI) 15, fibrosis 2) (1). Treatment with INF ␣2b (3 MIU three times wk) was started. Two weeks later, he was referred to our unit of Internal Medicine for sudden appearance of fever (38°C), weakness, and acute generalized myalgia. On admission, he denied any antecedent signs of infection, any trauma, and assumption of any other drugs except for INF. General physical examination resulted normal. Laboratory findings showed a marked increase in the concentrations of creatine kinase at 3.641 U/L (normal range 5–70 U/L) with normal concentrations of the isoform creatine kinase-MB (CK-MB), lactate dehydrogenase at 717 U/L (normal range 80 –240 U/L). Myoglobinuria was present (88 mg/L). There were no pathological alterations in concentrations of creatinine, urea nitrogen, C-reactive protein, blood cell counts, or glucose. No electrolyte abnormalities were detectable. With the diagnosis of rhabdomyolysis, INF ␣2b treatment was discontinued. The patient was treated with i.v. fluids and bicarbonate to maintain an alkaline urine output. Within 4 days, fever and myalgia disappeared, and weakness significantly improved; the creatine kinase declined to normal values (101 U/L). At the follow-up visit at 2 and 4 months, the patient was in good condition, and creatine kinase was within the normal range. Rhabdomyolysis has been reported as an unusual adverse reaction to several drugs, in particular in patients treated with statin (2). A few cases of acute rhabdomyolysis associated with INF ␣2b have been reported. Greenfield et al. described a patient 10 wk after initiation of INF ␣2b treatment starting with 5 MU three times/wk for chronic active hepatitis C (3). Reinhold et al. recently described a fatal outcome of fulminant rhabdomyolysis with multiple organ failure in a 56-yr-old man receiving adjuvant high-dose INF
AJG – Vol. 98, No. 4, 2003
␣2b (20 Mio. 1E m⫺2 daily) (4). The authors revealed that the manufacturers of INF ␣2b have received only 11 reports worldwide. Remarkably, the manifestation of muscle injury occurred when the dose of INF ␣2b was being increased in both patients described, suggesting that rhabdomyolysis represents at least a dose-dependent side effect of this drug. With respect to the previous reports, in our patient, the dosage of INF ␣2b was unaltered and significantly lower; moreover, the clinical and laboratory alterations were milder, and the recovery of the patient was quite quicker. These findings seem to confirm that muscle injury could be (if rare) a side effect of INF ␣2b, and to suggest that it may occur also at low doses. INF ␣2b discontinuation leads to a complete recovery of the disease. Measurement of creatine kinase activity could be recommended after initiation of INF ␣2b treatment and after every increasing of its dosage to precociously individualize and prevent irreversible rhabdomyolysis. Maurizio Gabrielli, M.D. Luca Santarelli, M.D. Michele Serricchio, M.D. Diego Leo, M.D. Paolo Pola, M.D. Antonio Gasbarrini, M.D. Internal Medicine and Angiology Department Catholic University of the Sacred Heart Rome, Italy
REFERENCES 1. Desmet VJ, Gerber M, Hoofnangle JH, et al. Classification of chronic hepatitis: Diagnosis, grading and staging. Hepatology 1994;19:1513–20. 2. Omar MA, Wilson JP. FDA adverse event reports on statinassociated rhabdomyolysis. Ann Pharmacother 2002;36:288 – 95. 3. Greenfield SM, Harvey RS, Thompson RP. Rhabdomyolysis after treatment with interferon alfa. BMJ 1994;309:512. 4. Reinhold U, Hartl C, Hering R, et al. Fatal rhabdomyolysis and multiple organ failure associated with adjuvant high-dose interferon alfa in malignant melanoma. Lancet 1997;349:540 –1. Reprints requests and correspondence: Antonio Gasbarrini, M.D., Internal Medicine and Angiology Department, Catholic University of the Sacred Heart, Gemelli Hospital, Largo Gemelli 8, Rome 00168, Italy. Received Nov. 8, 2002; accepted Nov. 18, 2002.
Celiac Disease in Patients With HCV Genotype 1A TO THE EDITOR: Recently, we have diagnosed celiac disease in two patients infected with hepatitis C virus (HCV) genotype 1a, and we found the paper on celiac disease authored by Volta et al. (1) interesting and relevant.
Letters to the Editor
939
5. Cherington M. Central nervous system complications of lightning and electrical injuries. Semin Neurol 1995;15:233–40. 6. Ringsberg KC, Lowhagen O, Sivik T. Psychological differences between asthmatics and patients suffering from an asthma-like condition, functional breathing disorder: A comparison between the two groups concerning personality, psychosocial and somatic parameters. Integr Physiol Behav Sci 1993;28: 358 –67. Reprint requests and correspondence: Massimo Montalto, M.D., Istituto di Medicina Interna, Policlinico “A. Gemelli,” Universita` Cattolica del Sacro Cuore, Largo A. Gemelli, 8, Roma 00168, Italy. Received Nov. 7, 2002; accepted Nov. 18, 2002.
Retinal Vein Thrombosis After Infliximab (Remicade) Treatment for Crohn’s Disease TO THE EDITOR: We report an unusual case of a 45-yrold woman who developed branch retinal vein thrombosis after receiving infliximab (Remicade) for Crohn’s disease. This patient had a history of Crohn’s disease for 16 yr, which was complicated by perianal disease and fistula. Also, the patient had a past medical history of right colectomy with partial iliectomy for Crohn’s disease and perianal fistula repair. There was no history of hypertension, hypercholesterolemia, or diabetes. The patient was on prednisone, mesalamine, and azathioprine and had recent symptoms consistent with a flare of her disease, i.e., diarrhea, hematochezia, abdominal pain, and fever. Colonoscopy revealed focal areas of inflammation throughout the colon and rectum in a pattern and distribution consistent with Crohn’s disease. The patient was started on infliximab because of unresponsiveness to medical therapy. She was treated with 340 mg of infliximab at time 0, 2, and 4 wk, and then at 2-month intervals. With three doses of infliximab, her symptoms markedly improved. There was near complete resolution of her disease, but after the third dose of infliximab, the patient experienced visual changes, which she described as “flashing lights,” lasting a few minutes to several hours and occurring in the central visual field. There was no associated pain or headache. The patient was referred to ophthalmology for further evaluation. Direct and indirect ophthalmoscopy revealed a branch retinal vein occlusion in the right eye (Fig. 1). The workup to evaluate the etiology of branch retinal vein thrombosis was negative, including antinuclear antibody titer, anticardiolipin antibodies, protein C and S activity, antithrombin III activity, factor V Leyden mutation, lipid panel, homocystein level, and prothrombin mutation. Retinal vein thrombosis has not been reported as a side effect of infliximab. Vascular complications such as cerebral vein thrombosis and deep venous thrombosis have been associated with Crohn’s disease (1–10), but branch retinal vein thrombosis after 16 yr of disease has not been described. The cause of retinal vein thrombosis in this patient
Figure 1. Retinal hemorrhages along the nerve fiber layer caused by branch retinal vein occlusion.
remains uncertain. However, the temporal relation of this occurrence to infliximab treatment raises concern for this as a possible medication-related complication. The purpose of this case report is to raise awareness about this as a potential side effect of infliximab in patients being treated for Crohn’s disease. Srinivas R. Puli, M.D. David D. Benage, M.D. Department of Internal Medicine St. John’s Mercy Medical Center St. Louis, Missouri
REFERENCES 1. Akobeng AK, Miller V, Thomas AG. Epilepsy and Crohn’s disease in children. J Pediatr Gastroenterol Nutr 1988;26:458 – 60. 2. Lam A, Borda IT, Inwood MJ, et al. Coagulation studies in ulcerative colitis and Crohn’s disease. Gastroenterology 1975; 68:245–51. 3. Weber P, Husemann S, Vielhaber H, et al. Coagulation and fibrinolysis in children, adolescent and young adults with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1999;28:418 –29. 4. Johns DR. Cerebrovascular complications of inflammatory bowel disease. Am J Gastroenterol 1991;86:367–70. 5. Levine A, Lahav J, Zahavi I, et al. Activated protein C resistance in paediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1998;26:172–4. 6. Paradis K, Bernstein ML, Adelson JW. Thrombosis as a complication of inflammatory bowel disease in children: A report of four cases. J Pediatr Gastroenterol Nutr 1985;4:659 –62. 7. Erte D, Ozguven E, Acar Y, et al. Thrombembolic complications in children with Crohn’s disease. J Pediatr Gastroenterol Nutr 1999;28:540 –1. 8. Bridger S, Evans N, Parker A, et al. Multiple cerebral venous
940
Letters to the Editor
thromboses in a child with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1997;25:533–6. 9. Hassan KO, Jenkins HR. Multiple venous thrombosis in inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1998; 27:616 –7 (letter). 10. Al-Malik H. Cerebral venous thrombosis as a complication of Crohn disease: A case report. J Pediatr Gastroenterol Nutr 2001;32:209 –11. Reprint requests and correspondence: Srinivas R. Puli, M.D., St. John’s Mercy Medical Center, Housestaff Mailbox, 615 South New Ballas Road, St. Louis, MO 63141. Received Nov. 7, 2002; accepted Nov. 18, 2002.
Acute Reversible Rhabdomyolysis During Interferon ␣2b Therapy for Hepatitis C TO THE EDITOR: A 70-yr-old man treated with interferon ␣2b (INF ␣2b) for chronic hepatitis C presented with acute rhabdomyolysis. Hepatitis C was diagnosed 6 months previously (confirmed by results of polymerase chain reaction), and liver biopsy showed moderate chronic hepatitis (histological activity index (HAI) 15, fibrosis 2) (1). Treatment with INF ␣2b (3 MIU three times wk) was started. Two weeks later, he was referred to our unit of Internal Medicine for sudden appearance of fever (38°C), weakness, and acute generalized myalgia. On admission, he denied any antecedent signs of infection, any trauma, and assumption of any other drugs except for INF. General physical examination resulted normal. Laboratory findings showed a marked increase in the concentrations of creatine kinase at 3.641 U/L (normal range 5–70 U/L) with normal concentrations of the isoform creatine kinase-MB (CK-MB), lactate dehydrogenase at 717 U/L (normal range 80 –240 U/L). Myoglobinuria was present (88 mg/L). There were no pathological alterations in concentrations of creatinine, urea nitrogen, C-reactive protein, blood cell counts, or glucose. No electrolyte abnormalities were detectable. With the diagnosis of rhabdomyolysis, INF ␣2b treatment was discontinued. The patient was treated with i.v. fluids and bicarbonate to maintain an alkaline urine output. Within 4 days, fever and myalgia disappeared, and weakness significantly improved; the creatine kinase declined to normal values (101 U/L). At the follow-up visit at 2 and 4 months, the patient was in good condition, and creatine kinase was within the normal range. Rhabdomyolysis has been reported as an unusual adverse reaction to several drugs, in particular in patients treated with statin (2). A few cases of acute rhabdomyolysis associated with INF ␣2b have been reported. Greenfield et al. described a patient 10 wk after initiation of INF ␣2b treatment starting with 5 MU three times/wk for chronic active hepatitis C (3). Reinhold et al. recently described a fatal outcome of fulminant rhabdomyolysis with multiple organ failure in a 56-yr-old man receiving adjuvant high-dose INF
AJG – Vol. 98, No. 4, 2003
␣2b (20 Mio. 1E m⫺2 daily) (4). The authors revealed that the manufacturers of INF ␣2b have received only 11 reports worldwide. Remarkably, the manifestation of muscle injury occurred when the dose of INF ␣2b was being increased in both patients described, suggesting that rhabdomyolysis represents at least a dose-dependent side effect of this drug. With respect to the previous reports, in our patient, the dosage of INF ␣2b was unaltered and significantly lower; moreover, the clinical and laboratory alterations were milder, and the recovery of the patient was quite quicker. These findings seem to confirm that muscle injury could be (if rare) a side effect of INF ␣2b, and to suggest that it may occur also at low doses. INF ␣2b discontinuation leads to a complete recovery of the disease. Measurement of creatine kinase activity could be recommended after initiation of INF ␣2b treatment and after every increasing of its dosage to precociously individualize and prevent irreversible rhabdomyolysis. Maurizio Gabrielli, M.D. Luca Santarelli, M.D. Michele Serricchio, M.D. Diego Leo, M.D. Paolo Pola, M.D. Antonio Gasbarrini, M.D. Internal Medicine and Angiology Department Catholic University of the Sacred Heart Rome, Italy
REFERENCES 1. Desmet VJ, Gerber M, Hoofnangle JH, et al. Classification of chronic hepatitis: Diagnosis, grading and staging. Hepatology 1994;19:1513–20. 2. Omar MA, Wilson JP. FDA adverse event reports on statinassociated rhabdomyolysis. Ann Pharmacother 2002;36:288 – 95. 3. Greenfield SM, Harvey RS, Thompson RP. Rhabdomyolysis after treatment with interferon alfa. BMJ 1994;309:512. 4. Reinhold U, Hartl C, Hering R, et al. Fatal rhabdomyolysis and multiple organ failure associated with adjuvant high-dose interferon alfa in malignant melanoma. Lancet 1997;349:540 –1. Reprints requests and correspondence: Antonio Gasbarrini, M.D., Internal Medicine and Angiology Department, Catholic University of the Sacred Heart, Gemelli Hospital, Largo Gemelli 8, Rome 00168, Italy. Received Nov. 8, 2002; accepted Nov. 18, 2002.
Celiac Disease in Patients With HCV Genotype 1A TO THE EDITOR: Recently, we have diagnosed celiac disease in two patients infected with hepatitis C virus (HCV) genotype 1a, and we found the paper on celiac disease authored by Volta et al. (1) interesting and relevant.