- Email: [email protected]
Immunomodulatory drugs in Crohn's disease patients with hepatitis B or C virus infection
February 2002
CORRESPONDENCE 593
prevented by SB203580. Schafer et al. actually stated "SB 203580 also partially i n h i b i t e d . . , basolateral membrane staining observed with CCK alone. The extent of this effect was variable between acini." They even go on to say "Inhibition of p38 MAP kinase/HSP27 phosphorylation by SB 203580, however, did not affect amylase secretion after stimulation with CCK for 5 and 30 minutes." These points largely negate the possibility of SPI-induced HSP27 phosphorylation being a likely mechanism by which they cause basolateral actin redistribution and accompanying secretory effects or saying that it is similar to supramaximal CCK-induced effects, which are dependent on p38 MAP kinase activity. The possibility that "SPIs would up-regulate HSFI, and thereby induce HSP27 expression," seems also highly unlikely, since SPIs show the effects on actin reorganization within 15 minutes. This period is too short for the induction of a transcription factor resulting in synthesis of increased amounts of a fully functional protein. We thank Dr. Blackstone for reinforcing the importance of our findings on cell-permeant serine protease inhibitors, which we have shown causes F-actin reorganization and inhibition of amylase secretion in a manner similar to supramaximal cerulein. However, the molecular mechanisms for these changes remain to be determined. VIJAY P. SINGH ASHOK K. SALUJA MICHAEL L. STEER
Beth Israel-DeaconessMedical Center Department of Surgery Boston, Massachusetts 1. Singh VP, Saluja AK, Bhagat L, Hietaranta AJ, Song A, Mykoniatis A, Van Acker GJ, Steer ML. Serine protease inhibitor causes F-actin redistribution and inhibition of calcium-mediated secretion in pancreatic acini. Gastroenterology 2001;120:1818-1827. 2. Schafer C, Ross SE, Bragado MJ, Groblewski GE, Ernst SA, Williams JA. A role for the p38 mitogen-activated protein kinase/ Hsp 27 pathway in cholecystokinin-induced changes in the actin cytoskeleton in rat pancreatic acini. J Biol Chem 1998;11;273: 24173-24180. 3. O'Konski MS, Pandol SJ. Cholecystokinin JMV-180 and cerulein effects on the pancreatic acinar cell cytoskeleton. Pancreas 1993;8:638-646.
Immunomodulatory Drugs in Crohn's Disease Patients With Hepatitis B or C Virus Infection Dear Sir: Perrillo 1 recently reviewed the main causes of acute flares in chronic hepatitis B, mostly related to a change in the immunologic response to hepatitis B virus (HBV). He reported that reactivation of HBV replication is frequently induced by drug treatments as chemotherapy, immunosuppressives, and corticosteroids. 1 Suppression of the normal immunological response to HBV leads to an enhanced viral replication and widespread infection of hepatocytes. 2 At immunosuppressive drugs discontinuation, the immune competence is restored and infected hepatocytes are rapidly destroyed. 3 Perrillo 1 also reported that the more potent the immunosuppression, the greater the clinical consequences of sudden withdrawal. Corticosteroids and immunomodulatory drugs represent the main treatment strategies in patients with active Crohn's disease (CD), at higher risk of HBV and hepatitis C virus (HCV) infection, due to surgical/endoscopical procedures. 4,5 We therefore assessed the effects of immunomodulatory drugs on the clinical course of liver diseases in CD patients with concomitant HBV or HCV infection. As interferon c~ (IFN-~) treatment for chronic hepatitis has been reported to induce celiac disease, 6,7 showing a T helper cell type 1 (Thl)-mediated immune response as observed in CD, 7,8 possible influence of IFN-e~ for chronic hepatitis on the clinical course of CD was also investigated. HBV markers were tested in 332 CD patients and anti-hepatitis C virus antibodies (anti-HCV) in 325 of 332 CD patients. Positivity for at least 1 HBV or HCV marker was shown by 24.6% of CD, while 1.3% of CD showed concomitant HBsAg and HBcAb positivity. Seropositivity for HBV markers was: HBsAg 2.1%, HBsAb 14.4%, HBcAb 10.9%, HBeAb 7.6%, and HBeAg 0%. Anti-HCV positivity was 7.4% (HCV RNA-positive in 54.2%). Overall, 8 CD patients showing HBV (n = 4) or HCV infection (n = 4) were treated with immunomodulatory drugs for CD and followed-up for at least 1 year. Treatment modalities and effects on the clinical course of hepatic virus infections are reported for each
Table 1. Effects of Immunomodulatory Drugs for CD on the Clinical Course of HBV or HCV Infection Hepatic markers
Treatment
Duration
Effect on CD clinical course
Clinical effect on liver disease
Azathioprine (2 mg/kg)
3 months a
None
None
M-prednisolone (40 mg/day)b
2 months
Remission
None
Deflazacort (30 mg/day)b
40 days
Temporary remission
None
Pt 4. Pt 5. Pt 6.
HBsAg+, HBcAb+, HBeAb + HBsAg+, HBcAb+, HBeAb+ HBsAg+, HBcAb+, HBeAb + HBsAg+ Anti-HCV+, HCV-RNA+ Anti-HCV+, HCV-RNA-
Azathioprine (2 mg/kg) M-prednisolone (40 mg/day)b Prednisone (from 25 rag/day to 10 mg/day)b
3 years 2 months 1 year
Remission Remission Chronically active course, steroid-dependence
Pt 7. Pt 8.
Anti-HCV+, HCV-RNAAnti-HCV+, HCV-RNA-
Azathioprine (2 mg/kg) Anti-TNF-e(Infliximab) (5 mg/kg/ev)
16 months O, 2, 6 weeks
Remission Perianal fistula closure
None None Acute flare up (ALE x 10, AST x 6, HCV-RNA+) at steroid discontinuation None None
CD Pt 1. Pt 2. Pt 3.
Pt, patient; M-prednisolone, methylprednisolone. aDiscontinued due to hyperamilasemia. bCorticosteroids were slowly tapered (5 mg/week) in all patients.
594
CORRESPONDENCE
patient in Table 1. Among the 24 anti-HCV positive CD, 4 were treated with immunomodulatory drugs: 2 corticosteroids, 1 azathioprine, and 1 anti-TNF-~x monoclonal antibody (Infliximab). Among patients with concomitant HBV infection, 4 CD showing HBsAg positivity were treated with immunomodulatory drugs: 2 with corticosteroids and 2 with azathioprine (Table 1). In any of these 8 patients, immunomodulatory drugs appeared to influence the clinical course of asymptomatic HBV or HCV infection. However, one patient with ileo-colonic CD and asymptomatic HCV infection since 1989 showed an acute flare up of HCV infection at steroid discontinuation. In 1997, a total proctocolectomy was performed due to a chronically active and steroid-dependent CD. After surgery, steroids were slowly tapered (5 mg/week) and discontinued, followed by low-grade fever and weakness. Abnormal ALT (× 10) and AST (×6) values with HCV-RNA positivity occurred, and a liver biopsy detected a chronic active hepatitis. IFN-c~ treatment (Intron, 5 MU × 3/week for 6 months) induced clinical remission and ALT values normalization. In our series, chronic hepatitis C was diagnosed by ultrasoundassisted liver biopsy in 6 of 325 CD: 5 of 6 CD were treated with IFN-~x (Intron), showing no influence on the clinical course of CD in at least 1 year follow-up. Immunomodulatory drugs may increase hepatitis B and C viremia and reduce ALT levels, related to an increased intracellular viral replication, while steroid discontinuation may be followed by rebound in ALT levels and reduction of viremia) 3,9,1o Corticosteroids and immunosuppressive drugs are also reviewed by Perrillo 1 as frequent causes of HBV reactivation in transplanted or neoplastic patients, requiring higher doses of immunomodulatory drugs than CD patients. It is not surprising that in our limited experience, immunomodulatory drugs for CD appeared not to influence the clinical course of concomitant HBV or HCV infection in patients with CD. Our observations suggest that although a high proportion of CD patients show asymptomatic HBV and/or HCV infection and immunosuppressive drugs may affect the clinical course of HBV and HCV infection,1-3,9a° this should not influence treatment strategies for CD, including IFN-o~ therapy for concomitant chronic hepatitis C. However, according to Perrillo, 1 our data also support that acute flares in chronic HCV or HBV infection may be observed at corticosteroid discontinuation in patients with steroid-dependent CD. LIVIA BIANCONE GIOVANNA DEL VECCHIO BLANCO FRANCESCO PALLONE on behalf of The Italian Group for The Study of The Colon and Rectum
Cattedra di Gastroenterologia Dipartimento di Medicina Interna Universit2~ di Roma "Tor Vergata" Rome, Italy
GASTROENTEROLOGY Vol. 122, No. 2
FABIANA CASTIGLIONE
Cattedra di Gastroenterologia Universit2* di Napoli "Federico H " Naples, Italy GIAMPAOLO BRESCI
Azienda Ospedaliera Pisana Pisana, Italy GIANCARLO STURNIOLO
Universit21 di Padova Padova, Italy 1. Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 2 0 0 1 ; 1 2 0 : 1 0 0 9 - 1 0 2 2 . 2. Liaw YF. Hepatitis viruses under immunosuppressive agents. J Gastroenterol Hepatol 1 9 9 8 ; 1 3 : 1 4 - 2 0 . 3. Markovic S, Drozina G, Vovk M, Fidler-Jenko M. Reactivation of hepatitis B but not hepatitis C in patients with malignant lymphoma and immunosuppressive therapy. A prospective study in 305 patients. Hepatogastroenterology 1999;46:2925-2930. 4. Longo F, Hebuterne X, Tran A, Staccini P, Hastier P, Schneider S, Benzaken S, Tirtaine C, Rampal P. Prevalence of hepatitis C in patients with chronic inflammatory bowel disease in the region of Nice and evaluation of risk factors. Gastroenterol Clin Biol 2000; 24:77-81. 5. Biancone L, Pavia M, Del Vecchio Blanco G, D'lncb R, Castiglione F, De Nigris F, Doldo P, Cosco C, Vavassori P, Bresci GP, Arrigoni A, Cadau G, Rispo A, Fries W, Mallardi B, Sturniolo GC, Pallone F, and the GISC. Hepatitis B and C virus infection in Crohn's disease. Inflamm Bowel Dis 2001;7:287-294. 6. Cammarota G, Cuoco L, Cianci R, Pandolfi F, Gasbarrini G. Onset of coeliac disease during treatment with interferon for chronic hepatitis C. Lancet 2 0 0 0 ; 3 5 6 : 1 4 9 4 - 1 4 9 5 . 7. Monteleone G, Pender SL, Alstead E, Hauer AC, Lionetti P, MacDonald i3. Role of interferon-alpha in promoting T helper cell type 1 responses in the small intestine in coeliac disease. Gut 2001; 48:425-429. 8. Monteleone G, Biancone L, Marasco R, Morrone G, Marasco O, Luzza F, Pallone F. Interleukin-12 (11.-12) is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology 1 9 9 7 ; 1 1 2 : 1 1 6 9 - 1 1 7 8 . 9. Rakela J, Redeker AG, Weliky B. Effect of short-term prednisone therapy on aminotransferase levels and hepatitis B virus markers in chronic type B hepatitis. Gastroenterology 1 9 8 3 ; 8 4 : 9 5 6 - 9 6 0 . 10. Fong TL, Valinluck B, Govindarajan S, Charboneau F, Adkins RH, Redeker AG. Short-term prednisone therapy affects aminotransferase activity and hepatitis C virus RNA levels in chronic hepatitis C. Gastroenterology 1 9 9 4 ; 1 0 7 : 1 9 6 - 1 9 9 . doi:10.1053/gast.2002.31602
CORRESPONDENCE 593
prevented by SB203580. Schafer et al. actually stated "SB 203580 also partially i n h i b i t e d . . , basolateral membrane staining observed with CCK alone. The extent of this effect was variable between acini." They even go on to say "Inhibition of p38 MAP kinase/HSP27 phosphorylation by SB 203580, however, did not affect amylase secretion after stimulation with CCK for 5 and 30 minutes." These points largely negate the possibility of SPI-induced HSP27 phosphorylation being a likely mechanism by which they cause basolateral actin redistribution and accompanying secretory effects or saying that it is similar to supramaximal CCK-induced effects, which are dependent on p38 MAP kinase activity. The possibility that "SPIs would up-regulate HSFI, and thereby induce HSP27 expression," seems also highly unlikely, since SPIs show the effects on actin reorganization within 15 minutes. This period is too short for the induction of a transcription factor resulting in synthesis of increased amounts of a fully functional protein. We thank Dr. Blackstone for reinforcing the importance of our findings on cell-permeant serine protease inhibitors, which we have shown causes F-actin reorganization and inhibition of amylase secretion in a manner similar to supramaximal cerulein. However, the molecular mechanisms for these changes remain to be determined. VIJAY P. SINGH ASHOK K. SALUJA MICHAEL L. STEER
Beth Israel-DeaconessMedical Center Department of Surgery Boston, Massachusetts 1. Singh VP, Saluja AK, Bhagat L, Hietaranta AJ, Song A, Mykoniatis A, Van Acker GJ, Steer ML. Serine protease inhibitor causes F-actin redistribution and inhibition of calcium-mediated secretion in pancreatic acini. Gastroenterology 2001;120:1818-1827. 2. Schafer C, Ross SE, Bragado MJ, Groblewski GE, Ernst SA, Williams JA. A role for the p38 mitogen-activated protein kinase/ Hsp 27 pathway in cholecystokinin-induced changes in the actin cytoskeleton in rat pancreatic acini. J Biol Chem 1998;11;273: 24173-24180. 3. O'Konski MS, Pandol SJ. Cholecystokinin JMV-180 and cerulein effects on the pancreatic acinar cell cytoskeleton. Pancreas 1993;8:638-646.
Immunomodulatory Drugs in Crohn's Disease Patients With Hepatitis B or C Virus Infection Dear Sir: Perrillo 1 recently reviewed the main causes of acute flares in chronic hepatitis B, mostly related to a change in the immunologic response to hepatitis B virus (HBV). He reported that reactivation of HBV replication is frequently induced by drug treatments as chemotherapy, immunosuppressives, and corticosteroids. 1 Suppression of the normal immunological response to HBV leads to an enhanced viral replication and widespread infection of hepatocytes. 2 At immunosuppressive drugs discontinuation, the immune competence is restored and infected hepatocytes are rapidly destroyed. 3 Perrillo 1 also reported that the more potent the immunosuppression, the greater the clinical consequences of sudden withdrawal. Corticosteroids and immunomodulatory drugs represent the main treatment strategies in patients with active Crohn's disease (CD), at higher risk of HBV and hepatitis C virus (HCV) infection, due to surgical/endoscopical procedures. 4,5 We therefore assessed the effects of immunomodulatory drugs on the clinical course of liver diseases in CD patients with concomitant HBV or HCV infection. As interferon c~ (IFN-~) treatment for chronic hepatitis has been reported to induce celiac disease, 6,7 showing a T helper cell type 1 (Thl)-mediated immune response as observed in CD, 7,8 possible influence of IFN-e~ for chronic hepatitis on the clinical course of CD was also investigated. HBV markers were tested in 332 CD patients and anti-hepatitis C virus antibodies (anti-HCV) in 325 of 332 CD patients. Positivity for at least 1 HBV or HCV marker was shown by 24.6% of CD, while 1.3% of CD showed concomitant HBsAg and HBcAb positivity. Seropositivity for HBV markers was: HBsAg 2.1%, HBsAb 14.4%, HBcAb 10.9%, HBeAb 7.6%, and HBeAg 0%. Anti-HCV positivity was 7.4% (HCV RNA-positive in 54.2%). Overall, 8 CD patients showing HBV (n = 4) or HCV infection (n = 4) were treated with immunomodulatory drugs for CD and followed-up for at least 1 year. Treatment modalities and effects on the clinical course of hepatic virus infections are reported for each
Table 1. Effects of Immunomodulatory Drugs for CD on the Clinical Course of HBV or HCV Infection Hepatic markers
Treatment
Duration
Effect on CD clinical course
Clinical effect on liver disease
Azathioprine (2 mg/kg)
3 months a
None
None
M-prednisolone (40 mg/day)b
2 months
Remission
None
Deflazacort (30 mg/day)b
40 days
Temporary remission
None
Pt 4. Pt 5. Pt 6.
HBsAg+, HBcAb+, HBeAb + HBsAg+, HBcAb+, HBeAb+ HBsAg+, HBcAb+, HBeAb + HBsAg+ Anti-HCV+, HCV-RNA+ Anti-HCV+, HCV-RNA-
Azathioprine (2 mg/kg) M-prednisolone (40 mg/day)b Prednisone (from 25 rag/day to 10 mg/day)b
3 years 2 months 1 year
Remission Remission Chronically active course, steroid-dependence
Pt 7. Pt 8.
Anti-HCV+, HCV-RNAAnti-HCV+, HCV-RNA-
Azathioprine (2 mg/kg) Anti-TNF-e(Infliximab) (5 mg/kg/ev)
16 months O, 2, 6 weeks
Remission Perianal fistula closure
None None Acute flare up (ALE x 10, AST x 6, HCV-RNA+) at steroid discontinuation None None
CD Pt 1. Pt 2. Pt 3.
Pt, patient; M-prednisolone, methylprednisolone. aDiscontinued due to hyperamilasemia. bCorticosteroids were slowly tapered (5 mg/week) in all patients.
594
CORRESPONDENCE
patient in Table 1. Among the 24 anti-HCV positive CD, 4 were treated with immunomodulatory drugs: 2 corticosteroids, 1 azathioprine, and 1 anti-TNF-~x monoclonal antibody (Infliximab). Among patients with concomitant HBV infection, 4 CD showing HBsAg positivity were treated with immunomodulatory drugs: 2 with corticosteroids and 2 with azathioprine (Table 1). In any of these 8 patients, immunomodulatory drugs appeared to influence the clinical course of asymptomatic HBV or HCV infection. However, one patient with ileo-colonic CD and asymptomatic HCV infection since 1989 showed an acute flare up of HCV infection at steroid discontinuation. In 1997, a total proctocolectomy was performed due to a chronically active and steroid-dependent CD. After surgery, steroids were slowly tapered (5 mg/week) and discontinued, followed by low-grade fever and weakness. Abnormal ALT (× 10) and AST (×6) values with HCV-RNA positivity occurred, and a liver biopsy detected a chronic active hepatitis. IFN-c~ treatment (Intron, 5 MU × 3/week for 6 months) induced clinical remission and ALT values normalization. In our series, chronic hepatitis C was diagnosed by ultrasoundassisted liver biopsy in 6 of 325 CD: 5 of 6 CD were treated with IFN-~x (Intron), showing no influence on the clinical course of CD in at least 1 year follow-up. Immunomodulatory drugs may increase hepatitis B and C viremia and reduce ALT levels, related to an increased intracellular viral replication, while steroid discontinuation may be followed by rebound in ALT levels and reduction of viremia) 3,9,1o Corticosteroids and immunosuppressive drugs are also reviewed by Perrillo 1 as frequent causes of HBV reactivation in transplanted or neoplastic patients, requiring higher doses of immunomodulatory drugs than CD patients. It is not surprising that in our limited experience, immunomodulatory drugs for CD appeared not to influence the clinical course of concomitant HBV or HCV infection in patients with CD. Our observations suggest that although a high proportion of CD patients show asymptomatic HBV and/or HCV infection and immunosuppressive drugs may affect the clinical course of HBV and HCV infection,1-3,9a° this should not influence treatment strategies for CD, including IFN-o~ therapy for concomitant chronic hepatitis C. However, according to Perrillo, 1 our data also support that acute flares in chronic HCV or HBV infection may be observed at corticosteroid discontinuation in patients with steroid-dependent CD. LIVIA BIANCONE GIOVANNA DEL VECCHIO BLANCO FRANCESCO PALLONE on behalf of The Italian Group for The Study of The Colon and Rectum
Cattedra di Gastroenterologia Dipartimento di Medicina Interna Universit2~ di Roma "Tor Vergata" Rome, Italy
GASTROENTEROLOGY Vol. 122, No. 2
FABIANA CASTIGLIONE
Cattedra di Gastroenterologia Universit2* di Napoli "Federico H " Naples, Italy GIAMPAOLO BRESCI
Azienda Ospedaliera Pisana Pisana, Italy GIANCARLO STURNIOLO
Universit21 di Padova Padova, Italy 1. Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 2 0 0 1 ; 1 2 0 : 1 0 0 9 - 1 0 2 2 . 2. Liaw YF. Hepatitis viruses under immunosuppressive agents. J Gastroenterol Hepatol 1 9 9 8 ; 1 3 : 1 4 - 2 0 . 3. Markovic S, Drozina G, Vovk M, Fidler-Jenko M. Reactivation of hepatitis B but not hepatitis C in patients with malignant lymphoma and immunosuppressive therapy. A prospective study in 305 patients. Hepatogastroenterology 1999;46:2925-2930. 4. Longo F, Hebuterne X, Tran A, Staccini P, Hastier P, Schneider S, Benzaken S, Tirtaine C, Rampal P. Prevalence of hepatitis C in patients with chronic inflammatory bowel disease in the region of Nice and evaluation of risk factors. Gastroenterol Clin Biol 2000; 24:77-81. 5. Biancone L, Pavia M, Del Vecchio Blanco G, D'lncb R, Castiglione F, De Nigris F, Doldo P, Cosco C, Vavassori P, Bresci GP, Arrigoni A, Cadau G, Rispo A, Fries W, Mallardi B, Sturniolo GC, Pallone F, and the GISC. Hepatitis B and C virus infection in Crohn's disease. Inflamm Bowel Dis 2001;7:287-294. 6. Cammarota G, Cuoco L, Cianci R, Pandolfi F, Gasbarrini G. Onset of coeliac disease during treatment with interferon for chronic hepatitis C. Lancet 2 0 0 0 ; 3 5 6 : 1 4 9 4 - 1 4 9 5 . 7. Monteleone G, Pender SL, Alstead E, Hauer AC, Lionetti P, MacDonald i3. Role of interferon-alpha in promoting T helper cell type 1 responses in the small intestine in coeliac disease. Gut 2001; 48:425-429. 8. Monteleone G, Biancone L, Marasco R, Morrone G, Marasco O, Luzza F, Pallone F. Interleukin-12 (11.-12) is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology 1 9 9 7 ; 1 1 2 : 1 1 6 9 - 1 1 7 8 . 9. Rakela J, Redeker AG, Weliky B. Effect of short-term prednisone therapy on aminotransferase levels and hepatitis B virus markers in chronic type B hepatitis. Gastroenterology 1 9 8 3 ; 8 4 : 9 5 6 - 9 6 0 . 10. Fong TL, Valinluck B, Govindarajan S, Charboneau F, Adkins RH, Redeker AG. Short-term prednisone therapy affects aminotransferase activity and hepatitis C virus RNA levels in chronic hepatitis C. Gastroenterology 1 9 9 4 ; 1 0 7 : 1 9 6 - 1 9 9 . doi:10.1053/gast.2002.31602