Journal of Internal Medicine 1992 : 231 : 139-141
Short communications Prednimustin treatment in primary biliary cirrhosis : a preliminary study S. LINDGREN,
A. DANIELSSON*, R. OLSSON?,
H. PRYTZS
& S. ERIKSSON From the Department of Medicine, Malmo General Hospital. Malrno. the *Department of Medicine, University Hospital. Urn&. the ?Department of Medicine Sahlgrenska Sjukhriset, Goteborg, and the $Department of Medicine. University Hospital. land, Sweden
Abstract. Lindgren S , Danielsson A, Olsson R, Prytz H. Eriksson S (Department of Medicine, Malmo General Hospital, Malmo, Department of Medicine, University Hospital, Umei, Department of Medicine, Sahlgrenska Sjukhuset, Goteborg, and Department of Medicine, University Hospital, Lund. Sweden). Prednimustin treatment in primary biliary cirrhosis: a preliminary study. Journal of Internal Medicine 1992 : 231 : 139-141. We observed a decrease in serum bilirubin, alkaline phosphatases (ALP) and IgM in five patients with primary biliary cirrhosis (PBC) treated with Prednimustin (Sterecytm) for 6 months. In contrast to pretreatment findings, C3 activation was undetectable during treatment in three patients where normalization of serum IgM was achieved. After discontinuation of Prednimustin. bilirubin and ALP levels rapidly returned to pretreatment values, although IgM remained normal for up to 6 months in some patients. We conclude that Prednimustin might be of value in patients with symptomatic PBC where liver transplantation is not an option, and that it should be evaluated in a controlled study. However, the rapid reactivation of the disease after conclusion of treatment must be considered.
Keywords: chlorambucil, complement, IgM, Prednimustin. primary biliary cirrhosis.
Introduction Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic liver disease thought to be related to abnormalities in immune regulation. Several trials have evaluated immunosuppressive, antifibrotic and cupruretic agents, but their therapeutic effects are uncertain [ 11. Polyconal IgM from PBC patients display complement-activating properties that may be of pathogenetic importance [2, 31. Therefore, a report by Hoofnagle et al. on normalization of serum IgM during treatment with chlorambucil [4] stimulated us to undertake further studies of the effects of
Abbreviations: ALP = alkaline phosphatases, LFT tests. PBC = primary biliary cirrhosis.
=
liver function
chlorambucil in PBC. A significant effect of corticosteroids on liver function tests (LFT) and immunoglobulins has been documented in PBC, although the dose must be kept low in order to prevent hastening of progress of the bone disease [S]. In the present study we used a combination of chlorambucil and low-dose prednisolon (Prednimustin, Sterecyt@; KABI-Pharmacia AB, Helsingborg, Sweden) to evaluate short-term effects on LFT, IgM and complement C3 activation in PBC patients.
Study population Five patients with .symptomatic PBC were treated (one man and four women, of mean age 60 years, range 5 1-68 years). All patients were mitochondria1 antibody positive, had alkaline phosphatase (ALP) levels > 8 pkat I-', bilirubin > 30 pmol I-' and a 139
140
S . L I N D G R E N et al.
liver biopsy compatible with PBC. At the time of inclusion, the platelet count should be > 100 x lo9I-' and white blood count > 3 x lo9I-'. All patients gave their informed consent to participate in the study. The study was approved by the ethical committees at the participating universities, and fulfilled the criteria of the Helsinki convention.
T
-
- 100
1-
E 5
3 50
.-2 -
a 3,
Methods Prednimustin treatment started with 20 mg administered orally (9 mg chlorambucil, 11 mg prednisolon) every 2 d, and was later adjusted so as to maintain the lymphocyte count at 50% of the pretreatment value. The dose of prednimustin was reduced if the white blood count decreased to < 3 x lo91-' or if the platelet count decreased to < 100 x lo9 I-'. The maintenance dose of Prednimustin varied from 10 mg every 2 d to 30 mg daily (4.5-13.5 mg chlorambucil). Blood samples were drawn 2 months before the start of treatment, monthly during the 6-month treatment period, and 2 months after discontinuation of treatment. Liver function tests (bilirubin, aminotransferases, glutamyltranspeptidase, ALP, prothrombin time) and full blood counts were performed according to routine procedures. Immunoglobulins (IgG, IgA, IgM) were quantitated by electroimmunoassay. C 3 activation in serum was estimated by crossed immunoelectrophoresis. [3] Serum levels of procollagen I11 propeptide were analysed by radioimmunoassay (RIAgnosta Procollagen 111, Behringwerke AG, Marburg, Germany).
patients in whom normalization of plasma IgM was achieved.
Results
Discussion
The results are summarized in Fig. 1. For each individual patient bilirubin and ALP values decreased during treatment, but rapidly increased again after conclusion of treatment. In contrast, IgM values remained at a lower level for up to 6 months in three patients. The treatment had to be temporarily withdrawn in two patients due to platelet counts < 70 x 10' I-'. No other serious side-effects were noted. Procollagen 111 propeptide levels, aminotransferases, IgG and IgA were not affected by the treatment. All patients showed evidence of C3 activation in serum prior to treatment. C3 activation could not be detected during treatment in the three
In agreement with Hoofnagle et al. [4] we observed a decrease in serum bilirubin and alkaline phosphatases during treatment with Prednimustin. The most significant finding in our small group of patients was the rebound effect with regard to bilirubin and ALP after discontinuation of treatment. Although the treatment period was too short to allow evaluation of the effect on the disease process, this suggested that there was rapid reactivation of some disease-mediating factor(s), after partial suppression during treatment. The bone-marrow-suppressive effects of chlorambucil necessitate a careful follow-up of blood counts during treatment. Apart
0
N
A
Fig. 1 . Mean values+SEM for bilirubin. alkaline phosphatases (ALP) and IgM from five patients before (B) and after (A) treatment. The values during treatment represent the lowest (nadir. N) value observed.
PREDNIMUSTIN IN PBC
from rapidly reversible thrombocytopenia in two patients, resulting in temporary withdrawal of the drug, no serious side-effects were observed. Two possible mediators of tissue damage in PBC are IgM and complement [ 2 , 3, 61. At low doses, alkylating agents appear to inhibit predominantly Blymphocyte function. Our own and previous results 141 suggest that IgM levels can be titrated by chlorambucil. thereby reducing the reactivity of the complement system and possibly other mediators [3, 61. Interestingly, in three patients IgM levels remained low up to 6 months after discontinuation of treatment. However, the rapid return of bilirubin and ALP to pretreatment values despite continuous suppression of IgM in some patients suggests additional immuno-suppressive effects of Prednimustin. The long-term toxicity of chlorambucil, particularly with regard to an increased risk of nonlymphocytic leukaemia. prevents its use in early PBC where the prognosis is favourable [ 7 ] . In patients with more advanced disease, liver transplantation must be considered. However, in patients of this category where liver transplantation is, for various reasons, not an option, Prednimustin might be of value and should be evaluated in a controlled, longterm trial. The apparent rapid reactivation of the disease after conclusion of treatment must then be considered.
141
Acknowledgements SterecytB was kindly supplied by KABI-Pharmacia.
References 1 Wiesner RH. Grambsch PM. Lindor I>L. Ludwig J , Dickson ER.
2
3
4
5
6
7
Clinical and statistical analyses of new and evolving therapies for primary biliary cirrhosis. Hepatology 1988 : 8 : 668-76. Lindgren S. Eriksson S. IgM in primary biliary cirrhosis. Physicochemical and complement activating properties. 1I d CIin Med 1 9 8 2 ; 99: 6 3 6 4 5 . Lindgren S. Johnson U. Complement activation in primary biliary cirrhosis: an in vitro model. 1 lab CIin Med 1985: 105: 432-5. Hoofnagle JH. Davis GL, Schafer DF et al. Randomixed trial of chlorambucil for primary biliary cirrhosis. Gastroenterology 1 9 8 6 ; 91: 1327-34. Mitchison HC. Bassendine MF. Mfllcolm AJ et al. A pilot, double-blind, controlled 1 -year trial of prednisolon treatment in primary biliary cirrhosis: hepatic improvement but greater bone loss. Hepatology 1989 : 10: 420-29. Lindgren S. Accelerated non-protcolytic cleavage of C3 in plasma from patients with primary biliary cirrhosis. 1 IAb Clin Med 1 9 8 9 : 114: 655-61. Roll J. Boyer JL, Barry D.Klatskin G. The prognostic importance of clinical and histologic features in asymptomatic and symptomatic primary biliary cirrhosis. N Engl 1 Med 1 9 8 3 : 308: 1-7.
Received 2 7 June 1991. accepted 16 September 1991. Correspondence: Stefan Lindgren. MD, Department of Medicine, University of Lund. Malmo General Hospital. S-27 401 Malmo. Sweden.
Short communications Prednimustin treatment in primary biliary cirrhosis : a preliminary study S. LINDGREN,
A. DANIELSSON*, R. OLSSON?,
H. PRYTZS
& S. ERIKSSON From the Department of Medicine, Malmo General Hospital. Malrno. the *Department of Medicine, University Hospital. Urn&. the ?Department of Medicine Sahlgrenska Sjukhriset, Goteborg, and the $Department of Medicine. University Hospital. land, Sweden
Abstract. Lindgren S , Danielsson A, Olsson R, Prytz H. Eriksson S (Department of Medicine, Malmo General Hospital, Malmo, Department of Medicine, University Hospital, Umei, Department of Medicine, Sahlgrenska Sjukhuset, Goteborg, and Department of Medicine, University Hospital, Lund. Sweden). Prednimustin treatment in primary biliary cirrhosis: a preliminary study. Journal of Internal Medicine 1992 : 231 : 139-141. We observed a decrease in serum bilirubin, alkaline phosphatases (ALP) and IgM in five patients with primary biliary cirrhosis (PBC) treated with Prednimustin (Sterecytm) for 6 months. In contrast to pretreatment findings, C3 activation was undetectable during treatment in three patients where normalization of serum IgM was achieved. After discontinuation of Prednimustin. bilirubin and ALP levels rapidly returned to pretreatment values, although IgM remained normal for up to 6 months in some patients. We conclude that Prednimustin might be of value in patients with symptomatic PBC where liver transplantation is not an option, and that it should be evaluated in a controlled study. However, the rapid reactivation of the disease after conclusion of treatment must be considered.
Keywords: chlorambucil, complement, IgM, Prednimustin. primary biliary cirrhosis.
Introduction Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic liver disease thought to be related to abnormalities in immune regulation. Several trials have evaluated immunosuppressive, antifibrotic and cupruretic agents, but their therapeutic effects are uncertain [ 11. Polyconal IgM from PBC patients display complement-activating properties that may be of pathogenetic importance [2, 31. Therefore, a report by Hoofnagle et al. on normalization of serum IgM during treatment with chlorambucil [4] stimulated us to undertake further studies of the effects of
Abbreviations: ALP = alkaline phosphatases, LFT tests. PBC = primary biliary cirrhosis.
=
liver function
chlorambucil in PBC. A significant effect of corticosteroids on liver function tests (LFT) and immunoglobulins has been documented in PBC, although the dose must be kept low in order to prevent hastening of progress of the bone disease [S]. In the present study we used a combination of chlorambucil and low-dose prednisolon (Prednimustin, Sterecyt@; KABI-Pharmacia AB, Helsingborg, Sweden) to evaluate short-term effects on LFT, IgM and complement C3 activation in PBC patients.
Study population Five patients with .symptomatic PBC were treated (one man and four women, of mean age 60 years, range 5 1-68 years). All patients were mitochondria1 antibody positive, had alkaline phosphatase (ALP) levels > 8 pkat I-', bilirubin > 30 pmol I-' and a 139
140
S . L I N D G R E N et al.
liver biopsy compatible with PBC. At the time of inclusion, the platelet count should be > 100 x lo9I-' and white blood count > 3 x lo9I-'. All patients gave their informed consent to participate in the study. The study was approved by the ethical committees at the participating universities, and fulfilled the criteria of the Helsinki convention.
T
-
- 100
1-
E 5
3 50
.-2 -
a 3,
Methods Prednimustin treatment started with 20 mg administered orally (9 mg chlorambucil, 11 mg prednisolon) every 2 d, and was later adjusted so as to maintain the lymphocyte count at 50% of the pretreatment value. The dose of prednimustin was reduced if the white blood count decreased to < 3 x lo91-' or if the platelet count decreased to < 100 x lo9 I-'. The maintenance dose of Prednimustin varied from 10 mg every 2 d to 30 mg daily (4.5-13.5 mg chlorambucil). Blood samples were drawn 2 months before the start of treatment, monthly during the 6-month treatment period, and 2 months after discontinuation of treatment. Liver function tests (bilirubin, aminotransferases, glutamyltranspeptidase, ALP, prothrombin time) and full blood counts were performed according to routine procedures. Immunoglobulins (IgG, IgA, IgM) were quantitated by electroimmunoassay. C 3 activation in serum was estimated by crossed immunoelectrophoresis. [3] Serum levels of procollagen I11 propeptide were analysed by radioimmunoassay (RIAgnosta Procollagen 111, Behringwerke AG, Marburg, Germany).
patients in whom normalization of plasma IgM was achieved.
Results
Discussion
The results are summarized in Fig. 1. For each individual patient bilirubin and ALP values decreased during treatment, but rapidly increased again after conclusion of treatment. In contrast, IgM values remained at a lower level for up to 6 months in three patients. The treatment had to be temporarily withdrawn in two patients due to platelet counts < 70 x 10' I-'. No other serious side-effects were noted. Procollagen 111 propeptide levels, aminotransferases, IgG and IgA were not affected by the treatment. All patients showed evidence of C3 activation in serum prior to treatment. C3 activation could not be detected during treatment in the three
In agreement with Hoofnagle et al. [4] we observed a decrease in serum bilirubin and alkaline phosphatases during treatment with Prednimustin. The most significant finding in our small group of patients was the rebound effect with regard to bilirubin and ALP after discontinuation of treatment. Although the treatment period was too short to allow evaluation of the effect on the disease process, this suggested that there was rapid reactivation of some disease-mediating factor(s), after partial suppression during treatment. The bone-marrow-suppressive effects of chlorambucil necessitate a careful follow-up of blood counts during treatment. Apart
0
N
A
Fig. 1 . Mean values+SEM for bilirubin. alkaline phosphatases (ALP) and IgM from five patients before (B) and after (A) treatment. The values during treatment represent the lowest (nadir. N) value observed.
PREDNIMUSTIN IN PBC
from rapidly reversible thrombocytopenia in two patients, resulting in temporary withdrawal of the drug, no serious side-effects were observed. Two possible mediators of tissue damage in PBC are IgM and complement [ 2 , 3, 61. At low doses, alkylating agents appear to inhibit predominantly Blymphocyte function. Our own and previous results 141 suggest that IgM levels can be titrated by chlorambucil. thereby reducing the reactivity of the complement system and possibly other mediators [3, 61. Interestingly, in three patients IgM levels remained low up to 6 months after discontinuation of treatment. However, the rapid return of bilirubin and ALP to pretreatment values despite continuous suppression of IgM in some patients suggests additional immuno-suppressive effects of Prednimustin. The long-term toxicity of chlorambucil, particularly with regard to an increased risk of nonlymphocytic leukaemia. prevents its use in early PBC where the prognosis is favourable [ 7 ] . In patients with more advanced disease, liver transplantation must be considered. However, in patients of this category where liver transplantation is, for various reasons, not an option, Prednimustin might be of value and should be evaluated in a controlled, longterm trial. The apparent rapid reactivation of the disease after conclusion of treatment must then be considered.
141
Acknowledgements SterecytB was kindly supplied by KABI-Pharmacia.
References 1 Wiesner RH. Grambsch PM. Lindor I>L. Ludwig J , Dickson ER.
2
3
4
5
6
7
Clinical and statistical analyses of new and evolving therapies for primary biliary cirrhosis. Hepatology 1988 : 8 : 668-76. Lindgren S. Eriksson S. IgM in primary biliary cirrhosis. Physicochemical and complement activating properties. 1I d CIin Med 1 9 8 2 ; 99: 6 3 6 4 5 . Lindgren S. Johnson U. Complement activation in primary biliary cirrhosis: an in vitro model. 1 lab CIin Med 1985: 105: 432-5. Hoofnagle JH. Davis GL, Schafer DF et al. Randomixed trial of chlorambucil for primary biliary cirrhosis. Gastroenterology 1 9 8 6 ; 91: 1327-34. Mitchison HC. Bassendine MF. Mfllcolm AJ et al. A pilot, double-blind, controlled 1 -year trial of prednisolon treatment in primary biliary cirrhosis: hepatic improvement but greater bone loss. Hepatology 1989 : 10: 420-29. Lindgren S. Accelerated non-protcolytic cleavage of C3 in plasma from patients with primary biliary cirrhosis. 1 IAb Clin Med 1 9 8 9 : 114: 655-61. Roll J. Boyer JL, Barry D.Klatskin G. The prognostic importance of clinical and histologic features in asymptomatic and symptomatic primary biliary cirrhosis. N Engl 1 Med 1 9 8 3 : 308: 1-7.
Received 2 7 June 1991. accepted 16 September 1991. Correspondence: Stefan Lindgren. MD, Department of Medicine, University of Lund. Malmo General Hospital. S-27 401 Malmo. Sweden.
