Rheumatol Int (1992) 12:39-41
RheumahJl_ngy Clinical and Experimental Investigations
9 Springer-Verlag 1992
A prospective analysis of liver biopsies in rheumatoid arthritis patients receiving long term methotrexate therapy M. Tishler 1,, D. Caspi 1, Z. Haiperin z, M. Baratz 3, M. Moshkowitz 4, and M. Yaron 1 Departments of Rheumatology 1, Gastroenterology 2, Pathology a and Medicine 4, Ichilov Hospital, Tel Aviv Medical Center, and the Tel Aviv University Sackler Faculty of Medicine, Tel Aviv, Israel Received April 22, 1991/Accepted October 7, 1991
Summary. Baseline and sequential liver biopsies were perf o r m e d in ten patients with r h e u m a t o i d arthritis ( R A ) treated with methotrexate ( M T X ) for m o r e than 4 years. Liver biopsies were p e r f o r m e d in all patients before the initiation o f M T X therapy and were repeated after reaching a cumulative dose o f 1500 m g or more. In four patients a third biopsy was p e r f o r m e d 3 years after the first one. N o significant worsening o f hepatic architecture was f o u n d in any o f our patients after 4 to 7 89 years o f M T X therapy. N o correlations between histologic findings and various clinical or p h a r m a c o l o g i c a l variables could be found. O u r results suggested that p r o l o n g e d M T X administration in R A patients did n o t cause severe hepatic abnormalities.
Key words: Rheumatoid arthritis - Methotrexate - Hepatotoxicity
Introduction L o n g term low dose methotrexate ( M T X ) therapy has been s h o w n to be effective in the treatment o f r h e u m a t o i d arthritis ( R A ) [1-3]. A l t h o u g h side effects have been c o m m o n l y reported, m o s t o f them are mild and do n o t necessitate withdrawal o f therapy [4]. Earlier studies in patients with psoriasis treated with M T X have shown that 20% o f subjects developed hepatic fibrosis and 10% developed cirrhosis [5]. Liver biopsy studies in R A patient treated with M T X have shown a wide range o f p a t h o l o g y but interpretation o f such d a t a is complicated by the fact that m a n y o f these changes m a y be detected in R A patients w h o never received M T X [6, 7]. There are only a few longitudinal prospective long term studies which have used baseline liver biopsies for c o m p a r i s o n [8-10]. We r e p o r t here on baseline a n d sequential biop* To whom offprint requests should be sent at: Department of Rheumatology, Ichilov Hospital, Tel Aviv 64239, Israel
sies in ten R A patients w h o were treated for m o r e than 4 years with low dose M T X .
Patients and methods Patients. The study group consisted of ten female RA patients treated with MTX for more than 4 years. These patients were among the cohort of patients prospectively followed by us to determine the efficacy and toxicity of MTX in RA patients as described in an earlier study [3]. The clinical characteristics of the patients are summarized in Table 1. Two patients suffered from non-insulin dependent diabetes mellitus and one patient from hypothyroidism treated by eltroxin. All patients received concomitant therapy with various kinds of NSAIDs and two patients (1 and 4) were given low dose prednisone (5 mg/day). Study design. All patients signed an informed consent form prior to study entry, agreeing to the proposed schedule of liver biopsies. Patients were treated with 5-15 mg of MTX given orally or intravenously once a week. Evaluation of efficacy, toxic reactions, adjustment of drug dosage and laboratory assessment was done every 3 weeks. Laboratory tests included a complete blood count, serum aspartate transaminase, alkaline phosphatase, creatinine and erythrocyte sedimentation rate (Westergren). Liver biopsies were performed in all patients before starting MTX treatment and were repeated after reaching a cumulative dose of at least 1500 mg MTX. Four patients had a third biopsy 3 years after the first one. Liver biopsies. Percutaneous liver biopsies were performed by a gastroenterologist under local anaesthesia with 2% lidocaine and involved an overnight stay in hospital. Biopsy specimens were fixed in 10% formalin and stained with hematoxylin-eosin. Pre- and posttreatment biopsies were reviewed blindly at the end of the study by a gastroenterologist (ZH) and a pathologist (MB) without knowledge of the order of histologic specimens. The final histologic classification was agreed upon mutually by the reviewers. Histopathologic findings were classified and graded according to the guidelines established for MTX-treated patients as revised by Roenigk et al. [11]: Grade I - normal mild fatty infiltrate, nuclear variability, portal inflammation, Grade I1 - moderate to severe fatty infiltrate, nuclear variability, portal inflammation, necrosis of hepatocytes, Grade IIIA - mild stellate fibrosis, no septum formation, Grade III B - moderate to severe stellate fibrosis with fibrotic septa, Grade IV - cirrhosis. HLA typing. All patients underwent tissue typing for HLA-A, B, C, and D polymorphism as described by us in an earlier study [3].
40 Table 1. Clinical characteristics of ten RA patients undergoing long term treatment with MTX Patient
Age/sex
Disease duration (years)
Duration of therapy (years)
Rheumatoid factor
Sj6gren's syndrome
1 2 3 4 5 6 7 8 9 10
39/F 37/F 67/F 50/F 68/F 69/F 78/F 46/F 55/F 63/F
19 10 16 35 6 12 13 10 8 11
789 4 6 7 4 4 4 6 4 5
Positive Positive Positive Positive Positive Negative Positive Positive Negative Positive
Negative Negative Negative Negative Positive Positive Negative Negative Negative Positive
Table 2. Histologic grading of liver biopsies in RA patients receiving long term MTX therapy Patient
1 2 3 4 5 6 7 8 9 10
First biopsy pretreatment grading I II I I IIIA I II I II I
Second biopsy
Third biopsy
Total cumu- Grade lative MTX dose (mg)/ years
Total cumu- Grade lative MTX dose (mg)/ years
1475/3 2800/4 1680/389 1940/4 2580/4 1920/4 1485/4 1555/389 1870/4 2010/5
7530/789
I
3415/6 6510/7
II I
2900/6
I
I II II I IIIA II II I II I
Statistical analysis. Relationships between variables were investigated using the Pearson and Spearman correlation tests.
Results A total of 24 biopsies were performed in ten patients. There was no evidence of liver cirrhosis in any of the samples. The results of liver histologic grading in these patients is presented in Table 2. Pre-treatment biopsies revealed normal biopsies (grade I) in six out of ten patients, while grade II changes were found in three patients and grade III A in one patient. Repeated biopsies showed a deterioration in two patients who progressed from grade I to grade II. Hepatic steatosis was noted in most of the samples with various degrees of fat accumulation. Portal and lobular inflammation was present in four samples and was confined to portal areas, without affecting bile ducts. Mild portal fibrosis was present only in two samples without a loss of normal architecture or nodular regeneration. Both samples were from the same patient (5) who also suffered from diabetes and hypercholesterolemia. Elevations of transaminase levels were noted in three patients during
Elevation of SGOT during therapy
Other diseases
+ +
Diabetes mellitus Diabetes mellitus
+ Hypothyroidism
the follow-up period. These elevations were usually mild and did not necessitate discontinuation of therapy. N o correlation could be found between the histologic staging and other variables such as total cumulative M T X dose, mean duration of RA, seropositivity, elevations of transaminase levels, the presence o f secondary Sj6gren's syndrome and H L A typing.
Discussion Our prospective study on the hepatotoxic effects of long term M T X therapy in RA patients did not show any clinically significant liver damage after more than 4 years (4-7.5) of therapy. The increasing use of M T X in the treatment of R A has raised several important questions about MTX-induced liver toxicity in these patients. Early reports in 1955 have revealed an increased prevalence of liver fibrosis in leukemic children treated with high dose M T X [12]. Subsequent studies have also documented the development of hepatic fibrosis and cirrhosis in psoriatic patients in whom obesity, diabetes and alcohol consumption were predisposing factors [13]. Assessing the effect of M T X in R A patients has been difficult. Although many studies have revealed different abnormalities in RA patients treated with M T X for long periods, reliable conclusions cannot be drawn. This is due to the fact that most of the studies were not prospective and did not include pretreatment biopsies [7, 14, 15, 18]. Another problem in interpreting previous results is that histologic abnormalities may be related to RA per se or may be secondary to obesity, diabetes or the use of nonsteroidal anti-inflammatory drugs [6,16]. Only a few studies have performed baseline liver biopsies and followed them by sequential samples. Kremer et al. [8] have reported sequential liver biopsies in 29 R A patients for up to 5 years of M T X therapy. They have concluded that although there was a histologic deterioration in hepatic architecture, these changes were not considered clinically significant. However, the total number of biopsied patients treated with M T X for more than 4 years was small (15 patients) and no definite conclusions could be drawn. Another prospective study published recently by Brick et al. [9] has
41 also followed liver biopsies before and after initiation of M T X therapy. In this study 32 patients who had b o t h pre- and post-treatment biopsies did not show any significant changes in liver histology. The follow-up time is not clear since patients were biopsied at cumulative M T X doses which ranged from 237 to 4147 mg. In view of the scarcity of prospective studies and the small n u m b e r of patients involved, the present study adds further to the knowledge of liver histologic changes in long term M T X therapy in R A patients. As reported by others [9, 14], we too could not find any significant deterioration in the hepatic architecture o f our patients. Despite the relatively prolonged therapy (up to 7 89 years), there was no severe fibrosis or cirrhosis in any of our patients. N o association between liver histology and the presence of secondary Sj6gren's syndrome, transaminase level elevations or other accompanying diseases could be found, nor was any correlation observed between H L A type and hepatic histologic grade. Most authors recommend that routine pre-treatment liver biopsies be done only in those patients with a history of liver disease or heavy alcohol intake [8, 9, 17]. Whether R A patients should have serial liver biopsies is still a matter for debate. This issue can be solved only when enough material on biopsies in patients taking M T X for prolonged periods has accumulated.
References 1. Weinblatt ME, Coblyn JS, Fraser PA, Holdsworth DE, Falchuk KR, Trentham DE (1988) Long term prospective study of methotrexate in rheumatoid arthritis. Arthritis Rheum 31:167-t75 2. Kremer JM, Lee JK (1988) A long term prospective study of methotrexate in rheumatoid arthritis: An update after a mean of 53 months. Arthritis Rheum 31:577--584 3. Tishler M, Caspi D, Rosenbach TO, Fishel B, Wigler I, Gazit E, Yaron M (1988) Methotrexate in rheumatoid arthritis: a prospective study in Israeli patients with immunogenetic correlations. Ann Rheum Dis 47:654-659
4. Gispen JG, Alarcon GS, Johnson J J, Acton RT, Barger BO, Koopman WJ (1987) Toxicity to methotrexate in rheumatoid arthritis. J Rheumatol 14:74-79 5. Nyfors A, Poulson H (1976) Liver biopsies from psoriatics related to methotrexate therapy. 2. Findings before and after methotrexate therapy in 88 patients: a blind study. Aeta Pathol Microbiol Scand 84:262-270 6. Lefkowitz AM, Farrow IJ (1955) The liver in rheumatoid arthritis. Ann Rheum Dis 14:162-168 7. Hoffmeister RT (1983) Methotrexate therapy in rheumatoid arthritis. 15 years experience. Am J Med 75:69-73 8. Kremer JM, Lee RG, Tolman KG (1989) Liver histology in rheumatoid arthritis patients receiving long term methotrexate therapy. Arthritis Rheum 32:121-127 9. Brick JE, Moreland LW, A1-Kawas F, Chang W, Layne RD, DiBartolomeo AG (1989) Prospective analysis of liver biopsies before and after methotrexate therapy in rheumatoid arthritis. Semin Arthritis Rheum 19:31-44 10. Loo AP, MacKenzie AH, Tutrill RJ, Leatherman JR (1985) Liver histology in rheumatoid arthritis before and after prolonged methotrexate therapy. Arthritis Rheum 28:$14 II. Roenigh HH, Auerbach R, Marbach AI, Weinstein GD (1982) Methotrexate guidelines: revised. J Am Acad Dermatol 6:145155 12. Colsky J, Greenspan EM, Warren TN (1955) Hepatic fibrosis in children with acute leukemia after therapy with folic acid antagonists. Arch Pathol Lab Med 59:198-206 13. Roenigk HH, Bergfeld WF, St Jaques R, Owens FJ, Hawk WA (1971) Hepatotoxicity of methotrexate in the treatment of psoriasis. Arch Dermatol 103:250-261 14. Aponte J, Petrelli M (1988) Histopathologic findings in the liver of rheumatoid arthritis patients treated with long term bolus methotrexate. Arthritis Rheum 31:1457-1464 15. Mackenzie AH (1985) Hepatotoxicity of prolonged methotrexate therapy for rheumatoid arthritis. Clev Clin Q 52:129-135 16. Hoyumpa AM, Greene HL, Dunn GD, Schenker S (1975) Fatty liver: biochemical and clinical characteristics. Am J Dig Dis 20:1142-1170 17. Bridges SL, Alarcon GS, Koopman WJ (1989) Editorial: Methotrexate induced liver abnormalities in rheumatoid arthritis. J Rheumataol 16:1180-1182 18. Willkens RF, Leonard PA, Clegg DO, Tolman KG, Ward JR, Marks CR, Greene ML, Roth GH, Jackson CG, Cannon GW, Lee RG (1990) Liver histology in patients receiving low dose pulse methotrexate for the treatment of arthritis. Ann Rheum Dis 49:591-593
Announcement 1st International Workshop on Hypertrophic Osteoarthropathy. Florence, Italy, June 21-24, 1992 Information: Fiorino Viaggi- Congress Department, Via Antonio Gramsci, 333-335, 50019 Sesto Fiorentino, I-Florence, Italy, Tel. 39 55 4493431; Fax 3955 442907
RheumahJl_ngy Clinical and Experimental Investigations
9 Springer-Verlag 1992
A prospective analysis of liver biopsies in rheumatoid arthritis patients receiving long term methotrexate therapy M. Tishler 1,, D. Caspi 1, Z. Haiperin z, M. Baratz 3, M. Moshkowitz 4, and M. Yaron 1 Departments of Rheumatology 1, Gastroenterology 2, Pathology a and Medicine 4, Ichilov Hospital, Tel Aviv Medical Center, and the Tel Aviv University Sackler Faculty of Medicine, Tel Aviv, Israel Received April 22, 1991/Accepted October 7, 1991
Summary. Baseline and sequential liver biopsies were perf o r m e d in ten patients with r h e u m a t o i d arthritis ( R A ) treated with methotrexate ( M T X ) for m o r e than 4 years. Liver biopsies were p e r f o r m e d in all patients before the initiation o f M T X therapy and were repeated after reaching a cumulative dose o f 1500 m g or more. In four patients a third biopsy was p e r f o r m e d 3 years after the first one. N o significant worsening o f hepatic architecture was f o u n d in any o f our patients after 4 to 7 89 years o f M T X therapy. N o correlations between histologic findings and various clinical or p h a r m a c o l o g i c a l variables could be found. O u r results suggested that p r o l o n g e d M T X administration in R A patients did n o t cause severe hepatic abnormalities.
Key words: Rheumatoid arthritis - Methotrexate - Hepatotoxicity
Introduction L o n g term low dose methotrexate ( M T X ) therapy has been s h o w n to be effective in the treatment o f r h e u m a t o i d arthritis ( R A ) [1-3]. A l t h o u g h side effects have been c o m m o n l y reported, m o s t o f them are mild and do n o t necessitate withdrawal o f therapy [4]. Earlier studies in patients with psoriasis treated with M T X have shown that 20% o f subjects developed hepatic fibrosis and 10% developed cirrhosis [5]. Liver biopsy studies in R A patient treated with M T X have shown a wide range o f p a t h o l o g y but interpretation o f such d a t a is complicated by the fact that m a n y o f these changes m a y be detected in R A patients w h o never received M T X [6, 7]. There are only a few longitudinal prospective long term studies which have used baseline liver biopsies for c o m p a r i s o n [8-10]. We r e p o r t here on baseline a n d sequential biop* To whom offprint requests should be sent at: Department of Rheumatology, Ichilov Hospital, Tel Aviv 64239, Israel
sies in ten R A patients w h o were treated for m o r e than 4 years with low dose M T X .
Patients and methods Patients. The study group consisted of ten female RA patients treated with MTX for more than 4 years. These patients were among the cohort of patients prospectively followed by us to determine the efficacy and toxicity of MTX in RA patients as described in an earlier study [3]. The clinical characteristics of the patients are summarized in Table 1. Two patients suffered from non-insulin dependent diabetes mellitus and one patient from hypothyroidism treated by eltroxin. All patients received concomitant therapy with various kinds of NSAIDs and two patients (1 and 4) were given low dose prednisone (5 mg/day). Study design. All patients signed an informed consent form prior to study entry, agreeing to the proposed schedule of liver biopsies. Patients were treated with 5-15 mg of MTX given orally or intravenously once a week. Evaluation of efficacy, toxic reactions, adjustment of drug dosage and laboratory assessment was done every 3 weeks. Laboratory tests included a complete blood count, serum aspartate transaminase, alkaline phosphatase, creatinine and erythrocyte sedimentation rate (Westergren). Liver biopsies were performed in all patients before starting MTX treatment and were repeated after reaching a cumulative dose of at least 1500 mg MTX. Four patients had a third biopsy 3 years after the first one. Liver biopsies. Percutaneous liver biopsies were performed by a gastroenterologist under local anaesthesia with 2% lidocaine and involved an overnight stay in hospital. Biopsy specimens were fixed in 10% formalin and stained with hematoxylin-eosin. Pre- and posttreatment biopsies were reviewed blindly at the end of the study by a gastroenterologist (ZH) and a pathologist (MB) without knowledge of the order of histologic specimens. The final histologic classification was agreed upon mutually by the reviewers. Histopathologic findings were classified and graded according to the guidelines established for MTX-treated patients as revised by Roenigk et al. [11]: Grade I - normal mild fatty infiltrate, nuclear variability, portal inflammation, Grade I1 - moderate to severe fatty infiltrate, nuclear variability, portal inflammation, necrosis of hepatocytes, Grade IIIA - mild stellate fibrosis, no septum formation, Grade III B - moderate to severe stellate fibrosis with fibrotic septa, Grade IV - cirrhosis. HLA typing. All patients underwent tissue typing for HLA-A, B, C, and D polymorphism as described by us in an earlier study [3].
40 Table 1. Clinical characteristics of ten RA patients undergoing long term treatment with MTX Patient
Age/sex
Disease duration (years)
Duration of therapy (years)
Rheumatoid factor
Sj6gren's syndrome
1 2 3 4 5 6 7 8 9 10
39/F 37/F 67/F 50/F 68/F 69/F 78/F 46/F 55/F 63/F
19 10 16 35 6 12 13 10 8 11
789 4 6 7 4 4 4 6 4 5
Positive Positive Positive Positive Positive Negative Positive Positive Negative Positive
Negative Negative Negative Negative Positive Positive Negative Negative Negative Positive
Table 2. Histologic grading of liver biopsies in RA patients receiving long term MTX therapy Patient
1 2 3 4 5 6 7 8 9 10
First biopsy pretreatment grading I II I I IIIA I II I II I
Second biopsy
Third biopsy
Total cumu- Grade lative MTX dose (mg)/ years
Total cumu- Grade lative MTX dose (mg)/ years
1475/3 2800/4 1680/389 1940/4 2580/4 1920/4 1485/4 1555/389 1870/4 2010/5
7530/789
I
3415/6 6510/7
II I
2900/6
I
I II II I IIIA II II I II I
Statistical analysis. Relationships between variables were investigated using the Pearson and Spearman correlation tests.
Results A total of 24 biopsies were performed in ten patients. There was no evidence of liver cirrhosis in any of the samples. The results of liver histologic grading in these patients is presented in Table 2. Pre-treatment biopsies revealed normal biopsies (grade I) in six out of ten patients, while grade II changes were found in three patients and grade III A in one patient. Repeated biopsies showed a deterioration in two patients who progressed from grade I to grade II. Hepatic steatosis was noted in most of the samples with various degrees of fat accumulation. Portal and lobular inflammation was present in four samples and was confined to portal areas, without affecting bile ducts. Mild portal fibrosis was present only in two samples without a loss of normal architecture or nodular regeneration. Both samples were from the same patient (5) who also suffered from diabetes and hypercholesterolemia. Elevations of transaminase levels were noted in three patients during
Elevation of SGOT during therapy
Other diseases
+ +
Diabetes mellitus Diabetes mellitus
+ Hypothyroidism
the follow-up period. These elevations were usually mild and did not necessitate discontinuation of therapy. N o correlation could be found between the histologic staging and other variables such as total cumulative M T X dose, mean duration of RA, seropositivity, elevations of transaminase levels, the presence o f secondary Sj6gren's syndrome and H L A typing.
Discussion Our prospective study on the hepatotoxic effects of long term M T X therapy in RA patients did not show any clinically significant liver damage after more than 4 years (4-7.5) of therapy. The increasing use of M T X in the treatment of R A has raised several important questions about MTX-induced liver toxicity in these patients. Early reports in 1955 have revealed an increased prevalence of liver fibrosis in leukemic children treated with high dose M T X [12]. Subsequent studies have also documented the development of hepatic fibrosis and cirrhosis in psoriatic patients in whom obesity, diabetes and alcohol consumption were predisposing factors [13]. Assessing the effect of M T X in R A patients has been difficult. Although many studies have revealed different abnormalities in RA patients treated with M T X for long periods, reliable conclusions cannot be drawn. This is due to the fact that most of the studies were not prospective and did not include pretreatment biopsies [7, 14, 15, 18]. Another problem in interpreting previous results is that histologic abnormalities may be related to RA per se or may be secondary to obesity, diabetes or the use of nonsteroidal anti-inflammatory drugs [6,16]. Only a few studies have performed baseline liver biopsies and followed them by sequential samples. Kremer et al. [8] have reported sequential liver biopsies in 29 R A patients for up to 5 years of M T X therapy. They have concluded that although there was a histologic deterioration in hepatic architecture, these changes were not considered clinically significant. However, the total number of biopsied patients treated with M T X for more than 4 years was small (15 patients) and no definite conclusions could be drawn. Another prospective study published recently by Brick et al. [9] has
41 also followed liver biopsies before and after initiation of M T X therapy. In this study 32 patients who had b o t h pre- and post-treatment biopsies did not show any significant changes in liver histology. The follow-up time is not clear since patients were biopsied at cumulative M T X doses which ranged from 237 to 4147 mg. In view of the scarcity of prospective studies and the small n u m b e r of patients involved, the present study adds further to the knowledge of liver histologic changes in long term M T X therapy in R A patients. As reported by others [9, 14], we too could not find any significant deterioration in the hepatic architecture o f our patients. Despite the relatively prolonged therapy (up to 7 89 years), there was no severe fibrosis or cirrhosis in any of our patients. N o association between liver histology and the presence of secondary Sj6gren's syndrome, transaminase level elevations or other accompanying diseases could be found, nor was any correlation observed between H L A type and hepatic histologic grade. Most authors recommend that routine pre-treatment liver biopsies be done only in those patients with a history of liver disease or heavy alcohol intake [8, 9, 17]. Whether R A patients should have serial liver biopsies is still a matter for debate. This issue can be solved only when enough material on biopsies in patients taking M T X for prolonged periods has accumulated.
References 1. Weinblatt ME, Coblyn JS, Fraser PA, Holdsworth DE, Falchuk KR, Trentham DE (1988) Long term prospective study of methotrexate in rheumatoid arthritis. Arthritis Rheum 31:167-t75 2. Kremer JM, Lee JK (1988) A long term prospective study of methotrexate in rheumatoid arthritis: An update after a mean of 53 months. Arthritis Rheum 31:577--584 3. Tishler M, Caspi D, Rosenbach TO, Fishel B, Wigler I, Gazit E, Yaron M (1988) Methotrexate in rheumatoid arthritis: a prospective study in Israeli patients with immunogenetic correlations. Ann Rheum Dis 47:654-659
4. Gispen JG, Alarcon GS, Johnson J J, Acton RT, Barger BO, Koopman WJ (1987) Toxicity to methotrexate in rheumatoid arthritis. J Rheumatol 14:74-79 5. Nyfors A, Poulson H (1976) Liver biopsies from psoriatics related to methotrexate therapy. 2. Findings before and after methotrexate therapy in 88 patients: a blind study. Aeta Pathol Microbiol Scand 84:262-270 6. Lefkowitz AM, Farrow IJ (1955) The liver in rheumatoid arthritis. Ann Rheum Dis 14:162-168 7. Hoffmeister RT (1983) Methotrexate therapy in rheumatoid arthritis. 15 years experience. Am J Med 75:69-73 8. Kremer JM, Lee RG, Tolman KG (1989) Liver histology in rheumatoid arthritis patients receiving long term methotrexate therapy. Arthritis Rheum 32:121-127 9. Brick JE, Moreland LW, A1-Kawas F, Chang W, Layne RD, DiBartolomeo AG (1989) Prospective analysis of liver biopsies before and after methotrexate therapy in rheumatoid arthritis. Semin Arthritis Rheum 19:31-44 10. Loo AP, MacKenzie AH, Tutrill RJ, Leatherman JR (1985) Liver histology in rheumatoid arthritis before and after prolonged methotrexate therapy. Arthritis Rheum 28:$14 II. Roenigh HH, Auerbach R, Marbach AI, Weinstein GD (1982) Methotrexate guidelines: revised. J Am Acad Dermatol 6:145155 12. Colsky J, Greenspan EM, Warren TN (1955) Hepatic fibrosis in children with acute leukemia after therapy with folic acid antagonists. Arch Pathol Lab Med 59:198-206 13. Roenigk HH, Bergfeld WF, St Jaques R, Owens FJ, Hawk WA (1971) Hepatotoxicity of methotrexate in the treatment of psoriasis. Arch Dermatol 103:250-261 14. Aponte J, Petrelli M (1988) Histopathologic findings in the liver of rheumatoid arthritis patients treated with long term bolus methotrexate. Arthritis Rheum 31:1457-1464 15. Mackenzie AH (1985) Hepatotoxicity of prolonged methotrexate therapy for rheumatoid arthritis. Clev Clin Q 52:129-135 16. Hoyumpa AM, Greene HL, Dunn GD, Schenker S (1975) Fatty liver: biochemical and clinical characteristics. Am J Dig Dis 20:1142-1170 17. Bridges SL, Alarcon GS, Koopman WJ (1989) Editorial: Methotrexate induced liver abnormalities in rheumatoid arthritis. J Rheumataol 16:1180-1182 18. Willkens RF, Leonard PA, Clegg DO, Tolman KG, Ward JR, Marks CR, Greene ML, Roth GH, Jackson CG, Cannon GW, Lee RG (1990) Liver histology in patients receiving low dose pulse methotrexate for the treatment of arthritis. Ann Rheum Dis 49:591-593
Announcement 1st International Workshop on Hypertrophic Osteoarthropathy. Florence, Italy, June 21-24, 1992 Information: Fiorino Viaggi- Congress Department, Via Antonio Gramsci, 333-335, 50019 Sesto Fiorentino, I-Florence, Italy, Tel. 39 55 4493431; Fax 3955 442907
