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High frequency of anti-ribosomal P antibody in patients with systemic lupus erythematosus-associated hepatitis
Hepatology Research 28 (2004) 137–139
Preliminary notes
High frequency of anti-ribosomal P antibody in patients with systemic lupus erythematosus-associated hepatitis Hiromasa Ohira a,∗ , Junko Takiguchi b , Tsuyoshi Rai a , Kazumichi Abe a , Junko Yokokawa a , Yukio Sato a , Isao Takeda a , Takashi Kanno b a
Department of Internal Medicine II, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan b Division of Rheumatology, Ohta Nishinouchi Hospital, Koriyama, Japan
Received 30 June 2003; received in revised form 24 October 2003; accepted 19 November 2003
Abstract Hepatic manifestations are a common phenomenon in patients with systemic lupus erythematosus (SLE). However, their cause may be difficult clinically to determine. A significantly increased frequency of anti-ribosomal P antibody has recently been found in patients with SLE-associated hepatitis. Thus, we examined the prevalence of anti-ribosomal P antibody and clinical differences between anti-ribosomal P antibody positive and negative SLE patients with liver dysfunction using ELISA kits against recombinant ribosomal P0 protein. Sera of 61 patients with SLE and 20 patients with autoimmune hepatitis (AIH) were assayed. Of 34 SLE patients with liver dysfunction, anti-ribosomal P antibody was detected in 15 (44.1%), consisting of 11 (68.8%) of 16 patients with SLE-associated hepatitis, 2 (28.6%) of 7 patients with fatty liver, 1 (16.7%) of 6 patients with drug-induced hepatitis, and 1 (20.0%) of 5 patients with SLE complicated by AIH. This antibody was not detected in patients with AIH. Except for those with SLE-associated hepatitis, anti-ribosomal P antibody positive patients were complicated by renal dysfunction and CNS lupus. The positive rate of anti-ribosomal P antibody was significantly higher in patients with SLE-associated hepatitis (68.8%) than in patients with SLE complicated by AIH (20%) (P < 0.05) and AIH (0%) (P < 0.01). These findings suggest that anti-ribosomal P antibody may be a useful marker of SLEassociated hepatitis to differentiate it from AIH and other liver dysfunctions in SLE patients without renal dysfunction or CNS lupus. © 2003 Elsevier B.V. All rights reserved. Keywords: Autoimmune hepatitis; CNS lupus; dsDNA
1. Introduction Systemic lupus erythematosus (SLE) is a diverse multisystem disorder with various degrees of major involvement of different organs and tissues. Hepatic manifestations are a common phenomenon in patients with SLE. Subclinical liver disease, characterized by mild to moderate elevations in serum liver transaminases, has been found in 25–50% of patients with SLE [1,2]. However, it is not clear whether such damage is caused by a primary liver disease such as autoimmune hepatitis (AIH) or is a hepatic manifestation of
∗ Corresponding author. Tel.: +81-24-547-1202; fax: +81-24-547-2055. E-mail address: [email protected] (H. Ohira).
1386-6346/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.hepres.2003.11.008
SLE. Differentiation of SLE-associated hepatitis from AIH with extrahepatic manifestations is usually not easy [3]. Autoantibody to ribosomal P proteins, first described in 1985 [4], is found in approximately 16% of serum samples from patients with SLE and have been associated with psychosis and nephritis. A significantly increased frequency of SLE-associated hepatitis has recently been found in patients positive for anti-ribosomal P antibody [5,6]. However, there are few reports on this antibody in patients with SLE-associated hepatitis [7,8]. Because ELISA kits that easily enable detection of anti-ribosomal P antibody is now commercially available, we examined both the frequency of anti-ribosomal P antibody detected by using these kits in sera of SLE patients with liver dysfunction and the usefulness of anti-ribosomal P antibody as a marker of SLE-associated hepatitis.
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H. Ohira et al. / Hepatology Research 28 (2004) 137–139
that the causes of liver dysfunction were SLE-associated hepatitis in 16, fatty liver in 7, drug-induced hepatitis in 6 and overlap with AIH in 5 (Table 1). Histological examination of the 16 patients with SLE-associated hepatitis revealed that 14 had nonspecific reactive hepatitis (NSRH) and 2 acute hepatitis (AH). Serum anti-ribosomal P antibody was detected in 23 (37.7%) of the 61 patients with SLE but not in any of the patients with AIH. Anti-ribosomal P antibody-positive patients with SLE showed significantly (P < 0.05) higher titers of anti-dsDNA antibody (231 ± 616.3 IU/L) than negative patients (59.0 ± 120.5 IU/L) and significantly lower titers of CH50 (21.0 ± 11.2 IU/L) than negative patients (30.4 ± 11.9 IU/L), indicating that serum anti-ribosomal P antibody is present at a higher frequency in patients with active SLE. Of the 34 SLE patients with liver dysfunction, serum anti-ribosomal P antibody was detected in 15 (44.1%) consisting of 11 (68.8%) of the 16 patients with SLE-associated hepatitis, 2 (28.6%) of the 7 patients with fatty liver, 1 (16.7%) of the 6 patients with drug-induced hepatitis, and 1 (20.0%) of the 5 patients with SLE complicated by AIH (Table 1). However, among patients with fatty liver, drug-induced hepatitis, and SLE complicated by AIH, anti-ribosomal P antibody was detected only in those with renal dysfunction and CNS lupus. The positive rate of anti-ribosomal P antibody was significantly higher in patients with SLE-associated hepatitis (68.8%) than in patients with AIH (0%) (P < 0.01) (Table 1). On the other hand, there was no significant difference in the level of ALT or ALP between patients with SLE-associated hepatitis and AIH. These findings suggest that anti-ribosomal P antibody may be a useful marker of SLE-associated hepatitis to differentiate it from AIH and other liver dysfunctions in SLE patients without renal dysfunction or CNS lupus. In this study, only one of the patient with SLE complicated by AIH was positive for anti-ribosomal P antibody. Renal dysfunction may have been involved in the positive reaction. Anti-ribosomal P antibody may serve to differentiate
2. Materials and methods 2.1. Patients The patients in this study were 12 men and 49 women, aged 37.5 ± 14.8 years, who had been diagnosed as having SLE on the basis of the criteria of the American College of Rheumatology (ACR) [9]. Twenty patients with AIH (20 women, aged 27–70 years) were used as controls. Diagnosis of AIH was based on the criteria established by the International Autoimmune Hepatitis Group (IAHG) in 1999 [10]. All cases of AIH were diagnosed as definite AIH by the IAHG criteria. SLE complicated by AIH was diagnosed on the basis of both ACR criteria and histological findings in liver biopsy samples from patients with chronic active hepatitis. Liver biopsy samples were also obtained from all patients with SLE-associated hepatitis. SLE-associated hepatitis was reflecting SLE disease activity without showing histologically chronic active hepatitis, which excluded other causes of liver disease such as viral hepatitis, drug-induced hepatitis and fatty liver [2,3]. Blood was taken from the cubical vein of each patient, and sera were prepared by clotting each specimen. The sera were stored at −20 ◦ C until use. 2.2. ELISA for detection of anti-ribosomal P antibodies All sera were assessed for reactivity against recombinant ribosomal P0 using commercially available ELISA kits (MBL Co., Ltd, Nagoya, Japan) according to the manufacturer’s instructions. 2.3. Statistical analysis The results are expressed as means ± S.D.. Differences were compared by the χ2 -test and Fisher’s exact probability test, and a value of P < 0.05 was considered significant. 3. Results and discussion Liver dysfunction was found in 34 (55.7%) of the 61 patients with SLE. Clinicopathological examinations showed
Table 1 Prevalence of anti-ribosomal P antibody and laboratory data in patients with systemic lupus erythematosus Ribosomal P antibody positive ratio (%) Systemic lupus erythematosus (n = 61) SLE-associated hepatitis (n = 16) Fatty liver (n = 7) Drug-induced hepatitis (n = 6) With autoimmune hepatitis (n = 5) No liver dysfunction (n = 27) Autoimmune hepatitis (n = 20)
11 2 1 1 8
(68.8)a (28.6)b (16.7) (20.0)c,e (29.6)d,f
0 (0)
Renal dysfunction (positive number)
CNS lupus (positive number)
T-Bil (mg/dl)
2 4 1 3 11
0 2 4 1 1
1.0 0.8 0.6 3.9 0.5
(0) (2) (1) (1) (2)
0 (0)
(0) (0) (1) (0) (0)
0 (0)
± ± ± ± ±
0.9 0.4 0.3 6.7∗ 0.3
5.9 ± 10.9∗
ALT (IU/l)
476.1 53.3 57.8 362.0 22.3
± ± ± ± ±
1382.4 25.5 62.6 404.3 15.7∗
522.9 ± 1382.4
ALP (IU/l)
485.5 231.5 515.5 383.2 178.4
± ± ± ± ±
470.4 98.8 361.4 133.2 76.1∗
411.1 ± 242.7
IgG (mg/dl)
1941.3 1764.2 1495.3 3266.6 1978.5
± ± ± ± ±
641.7 220.1 926.6 1187.5∗ 849.2
3139.0 ± 1002.9∗
a P < 0.01, b P < 0.05, c P < 0.05, d P < 0.01 compared with autoimmune hepatitis; e P < 0.05, f P < 0.01, and ∗ P < 0.05 compared with SLE-associated hepatitis.
H. Ohira et al. / Hepatology Research 28 (2004) 137–139 Table 2 Comparison of clinicolaboratory findings in anti-ribosomal P antibodypositive and -negative patients with systemic lupus erythematosus-associated hepatitis
Sex (M:F) Age ALT (IU/L) ALP (IU/L) IgG (mg/dl) ANA (median titer) dsDNA (IU/L) CH50 (IU/L) Renal dysfunction (cases) CNS lupus (cases) Liver histology (cases)
Positive (n = 11)
Negative (n = 5)
P
1:10 36.9 ± 16.9 647.0 ± 1661.4 442.2 ± 375.6 1982.4 ± 714.5 640 125.3 ± 133.2 19.8 ± 10.7 4 0 9 NSRH, 2 AH
2:3 51.0 ± 10.1 100.0 ± 88.9 572.2 ± 665.6 1850.8 ± 503.1 320 65.2 ± 96.6 31.1 ± 12.2 3 0 5 NSRH
NS NS NS NS NS NS NS NS NS NS
NSRH: nonspecific reactive hepatitis; AH: acute hepatitis.
SLE-related hepatitis from SLE-AIH overlap, but the final diagnosis seems to be established by histological evidence. The pathogenesis of SLE-associated hepatitis has not been clarified yet. This study revealed no significant difference in clinicolaboratory findings between anti-ribosomal P antibody-positive and -negative patients with SLE-associated hepatitis (Table 2). However, the fact that anti-ribosomal P antibody was not detected in patients with AIH indicates that this antibody does not participate in the pathogenesis of AIH. Koren et al. showed that the ribosomal P protein is present on the surface of liver cells [11], and in vitro studies have shown that anti-ribosomal P antibody can directly injure hepatic cells in a compliment-independent fashion [12]. Although we did not confirm the presence of ribosomal P protein on the surfaces of hepatic cells in patients with SLE-associated hepatitis, anti-ribosomal P antibody may react with ribosomal P protein on liver cells. The finding of an association of anti-ribosomal P antibody with SLE-associated hepatitis
139
may be useful for future studies aimed at clarification of the mechanism underlying the pathogenesis of SLE-associated hepatitis.
References [1] Miller MH, Urowitz MB, Gladman DD, Blendis LM. The liver in systemic lupus erythematosus. Q J Med 1984;53:401–9. [2] van Hoek B. The spectrum of liver disease in systemic lupus erythematosus. Neth J Med 1996;48:244–53. [3] Youssef WI, Tavill AS. Connective tissue disease and the liver. J Clin Gastroenterol 2002;35:345–9. [4] Elkon KB, Parnassa AP, Foster CL. Lupus autoantibodies target ribosomal P proteins. J Exp Med 1985;162:459–71. [5] Arnett FC, Reichlin M. Lupus hepatitis: an under-recognized disease feature associated with autoantibodies to ribosomal P. Am J Med 1995;99:465–72. [6] Hulsey M, Goldstein R, Scully L, Surbeck W, Reichlin M. Anti-ribosomal P antibodies in systemic lupus erythematosus: a casecontrol study correlating hepatic and renal disease. Clin Immunol Immunopathol 1995;74:252–6. [7] Yoshio T, Masuyama JI, Minota S, et al. A close temporal relationship of liver disease to antiribosomal P0 protein antibodies and central nervous system disease in patients with systemic lupus erythematosus. J Rheumatol 1998;25:681–8. [8] Massardo L, Burgos P, Martinez ME, et al. Antiribosomal P protein antibodies in Chilean SLE patients: no association with renal disease. Lupus 2002;11:379–83. [9] Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7. [10] Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group Report: review of criteria for dignosis of autoimmune hepatitis. J Hepatol 1999;31:929–38. [11] Koren E, Reichlin MW, Koscec M, Fugate RD, Reichlin M. Autoantibodies to the ribosomal P proteins react with a plasma membrane-related target on human cells. J Clin Invest 1992;89:1236– 41. [12] Koscec M, Koren E, Wolfson-Reichlin M, et al. Autoantibodies to ribosomal P proteins penetrate into live hepatocytes and cause cellular dysfunction in culture. J Immunol 1997;159:2033–41.
Preliminary notes
High frequency of anti-ribosomal P antibody in patients with systemic lupus erythematosus-associated hepatitis Hiromasa Ohira a,∗ , Junko Takiguchi b , Tsuyoshi Rai a , Kazumichi Abe a , Junko Yokokawa a , Yukio Sato a , Isao Takeda a , Takashi Kanno b a
Department of Internal Medicine II, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan b Division of Rheumatology, Ohta Nishinouchi Hospital, Koriyama, Japan
Received 30 June 2003; received in revised form 24 October 2003; accepted 19 November 2003
Abstract Hepatic manifestations are a common phenomenon in patients with systemic lupus erythematosus (SLE). However, their cause may be difficult clinically to determine. A significantly increased frequency of anti-ribosomal P antibody has recently been found in patients with SLE-associated hepatitis. Thus, we examined the prevalence of anti-ribosomal P antibody and clinical differences between anti-ribosomal P antibody positive and negative SLE patients with liver dysfunction using ELISA kits against recombinant ribosomal P0 protein. Sera of 61 patients with SLE and 20 patients with autoimmune hepatitis (AIH) were assayed. Of 34 SLE patients with liver dysfunction, anti-ribosomal P antibody was detected in 15 (44.1%), consisting of 11 (68.8%) of 16 patients with SLE-associated hepatitis, 2 (28.6%) of 7 patients with fatty liver, 1 (16.7%) of 6 patients with drug-induced hepatitis, and 1 (20.0%) of 5 patients with SLE complicated by AIH. This antibody was not detected in patients with AIH. Except for those with SLE-associated hepatitis, anti-ribosomal P antibody positive patients were complicated by renal dysfunction and CNS lupus. The positive rate of anti-ribosomal P antibody was significantly higher in patients with SLE-associated hepatitis (68.8%) than in patients with SLE complicated by AIH (20%) (P < 0.05) and AIH (0%) (P < 0.01). These findings suggest that anti-ribosomal P antibody may be a useful marker of SLEassociated hepatitis to differentiate it from AIH and other liver dysfunctions in SLE patients without renal dysfunction or CNS lupus. © 2003 Elsevier B.V. All rights reserved. Keywords: Autoimmune hepatitis; CNS lupus; dsDNA
1. Introduction Systemic lupus erythematosus (SLE) is a diverse multisystem disorder with various degrees of major involvement of different organs and tissues. Hepatic manifestations are a common phenomenon in patients with SLE. Subclinical liver disease, characterized by mild to moderate elevations in serum liver transaminases, has been found in 25–50% of patients with SLE [1,2]. However, it is not clear whether such damage is caused by a primary liver disease such as autoimmune hepatitis (AIH) or is a hepatic manifestation of
∗ Corresponding author. Tel.: +81-24-547-1202; fax: +81-24-547-2055. E-mail address: [email protected] (H. Ohira).
1386-6346/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.hepres.2003.11.008
SLE. Differentiation of SLE-associated hepatitis from AIH with extrahepatic manifestations is usually not easy [3]. Autoantibody to ribosomal P proteins, first described in 1985 [4], is found in approximately 16% of serum samples from patients with SLE and have been associated with psychosis and nephritis. A significantly increased frequency of SLE-associated hepatitis has recently been found in patients positive for anti-ribosomal P antibody [5,6]. However, there are few reports on this antibody in patients with SLE-associated hepatitis [7,8]. Because ELISA kits that easily enable detection of anti-ribosomal P antibody is now commercially available, we examined both the frequency of anti-ribosomal P antibody detected by using these kits in sera of SLE patients with liver dysfunction and the usefulness of anti-ribosomal P antibody as a marker of SLE-associated hepatitis.
138
H. Ohira et al. / Hepatology Research 28 (2004) 137–139
that the causes of liver dysfunction were SLE-associated hepatitis in 16, fatty liver in 7, drug-induced hepatitis in 6 and overlap with AIH in 5 (Table 1). Histological examination of the 16 patients with SLE-associated hepatitis revealed that 14 had nonspecific reactive hepatitis (NSRH) and 2 acute hepatitis (AH). Serum anti-ribosomal P antibody was detected in 23 (37.7%) of the 61 patients with SLE but not in any of the patients with AIH. Anti-ribosomal P antibody-positive patients with SLE showed significantly (P < 0.05) higher titers of anti-dsDNA antibody (231 ± 616.3 IU/L) than negative patients (59.0 ± 120.5 IU/L) and significantly lower titers of CH50 (21.0 ± 11.2 IU/L) than negative patients (30.4 ± 11.9 IU/L), indicating that serum anti-ribosomal P antibody is present at a higher frequency in patients with active SLE. Of the 34 SLE patients with liver dysfunction, serum anti-ribosomal P antibody was detected in 15 (44.1%) consisting of 11 (68.8%) of the 16 patients with SLE-associated hepatitis, 2 (28.6%) of the 7 patients with fatty liver, 1 (16.7%) of the 6 patients with drug-induced hepatitis, and 1 (20.0%) of the 5 patients with SLE complicated by AIH (Table 1). However, among patients with fatty liver, drug-induced hepatitis, and SLE complicated by AIH, anti-ribosomal P antibody was detected only in those with renal dysfunction and CNS lupus. The positive rate of anti-ribosomal P antibody was significantly higher in patients with SLE-associated hepatitis (68.8%) than in patients with AIH (0%) (P < 0.01) (Table 1). On the other hand, there was no significant difference in the level of ALT or ALP between patients with SLE-associated hepatitis and AIH. These findings suggest that anti-ribosomal P antibody may be a useful marker of SLE-associated hepatitis to differentiate it from AIH and other liver dysfunctions in SLE patients without renal dysfunction or CNS lupus. In this study, only one of the patient with SLE complicated by AIH was positive for anti-ribosomal P antibody. Renal dysfunction may have been involved in the positive reaction. Anti-ribosomal P antibody may serve to differentiate
2. Materials and methods 2.1. Patients The patients in this study were 12 men and 49 women, aged 37.5 ± 14.8 years, who had been diagnosed as having SLE on the basis of the criteria of the American College of Rheumatology (ACR) [9]. Twenty patients with AIH (20 women, aged 27–70 years) were used as controls. Diagnosis of AIH was based on the criteria established by the International Autoimmune Hepatitis Group (IAHG) in 1999 [10]. All cases of AIH were diagnosed as definite AIH by the IAHG criteria. SLE complicated by AIH was diagnosed on the basis of both ACR criteria and histological findings in liver biopsy samples from patients with chronic active hepatitis. Liver biopsy samples were also obtained from all patients with SLE-associated hepatitis. SLE-associated hepatitis was reflecting SLE disease activity without showing histologically chronic active hepatitis, which excluded other causes of liver disease such as viral hepatitis, drug-induced hepatitis and fatty liver [2,3]. Blood was taken from the cubical vein of each patient, and sera were prepared by clotting each specimen. The sera were stored at −20 ◦ C until use. 2.2. ELISA for detection of anti-ribosomal P antibodies All sera were assessed for reactivity against recombinant ribosomal P0 using commercially available ELISA kits (MBL Co., Ltd, Nagoya, Japan) according to the manufacturer’s instructions. 2.3. Statistical analysis The results are expressed as means ± S.D.. Differences were compared by the χ2 -test and Fisher’s exact probability test, and a value of P < 0.05 was considered significant. 3. Results and discussion Liver dysfunction was found in 34 (55.7%) of the 61 patients with SLE. Clinicopathological examinations showed
Table 1 Prevalence of anti-ribosomal P antibody and laboratory data in patients with systemic lupus erythematosus Ribosomal P antibody positive ratio (%) Systemic lupus erythematosus (n = 61) SLE-associated hepatitis (n = 16) Fatty liver (n = 7) Drug-induced hepatitis (n = 6) With autoimmune hepatitis (n = 5) No liver dysfunction (n = 27) Autoimmune hepatitis (n = 20)
11 2 1 1 8
(68.8)a (28.6)b (16.7) (20.0)c,e (29.6)d,f
0 (0)
Renal dysfunction (positive number)
CNS lupus (positive number)
T-Bil (mg/dl)
2 4 1 3 11
0 2 4 1 1
1.0 0.8 0.6 3.9 0.5
(0) (2) (1) (1) (2)
0 (0)
(0) (0) (1) (0) (0)
0 (0)
± ± ± ± ±
0.9 0.4 0.3 6.7∗ 0.3
5.9 ± 10.9∗
ALT (IU/l)
476.1 53.3 57.8 362.0 22.3
± ± ± ± ±
1382.4 25.5 62.6 404.3 15.7∗
522.9 ± 1382.4
ALP (IU/l)
485.5 231.5 515.5 383.2 178.4
± ± ± ± ±
470.4 98.8 361.4 133.2 76.1∗
411.1 ± 242.7
IgG (mg/dl)
1941.3 1764.2 1495.3 3266.6 1978.5
± ± ± ± ±
641.7 220.1 926.6 1187.5∗ 849.2
3139.0 ± 1002.9∗
a P < 0.01, b P < 0.05, c P < 0.05, d P < 0.01 compared with autoimmune hepatitis; e P < 0.05, f P < 0.01, and ∗ P < 0.05 compared with SLE-associated hepatitis.
H. Ohira et al. / Hepatology Research 28 (2004) 137–139 Table 2 Comparison of clinicolaboratory findings in anti-ribosomal P antibodypositive and -negative patients with systemic lupus erythematosus-associated hepatitis
Sex (M:F) Age ALT (IU/L) ALP (IU/L) IgG (mg/dl) ANA (median titer) dsDNA (IU/L) CH50 (IU/L) Renal dysfunction (cases) CNS lupus (cases) Liver histology (cases)
Positive (n = 11)
Negative (n = 5)
P
1:10 36.9 ± 16.9 647.0 ± 1661.4 442.2 ± 375.6 1982.4 ± 714.5 640 125.3 ± 133.2 19.8 ± 10.7 4 0 9 NSRH, 2 AH
2:3 51.0 ± 10.1 100.0 ± 88.9 572.2 ± 665.6 1850.8 ± 503.1 320 65.2 ± 96.6 31.1 ± 12.2 3 0 5 NSRH
NS NS NS NS NS NS NS NS NS NS
NSRH: nonspecific reactive hepatitis; AH: acute hepatitis.
SLE-related hepatitis from SLE-AIH overlap, but the final diagnosis seems to be established by histological evidence. The pathogenesis of SLE-associated hepatitis has not been clarified yet. This study revealed no significant difference in clinicolaboratory findings between anti-ribosomal P antibody-positive and -negative patients with SLE-associated hepatitis (Table 2). However, the fact that anti-ribosomal P antibody was not detected in patients with AIH indicates that this antibody does not participate in the pathogenesis of AIH. Koren et al. showed that the ribosomal P protein is present on the surface of liver cells [11], and in vitro studies have shown that anti-ribosomal P antibody can directly injure hepatic cells in a compliment-independent fashion [12]. Although we did not confirm the presence of ribosomal P protein on the surfaces of hepatic cells in patients with SLE-associated hepatitis, anti-ribosomal P antibody may react with ribosomal P protein on liver cells. The finding of an association of anti-ribosomal P antibody with SLE-associated hepatitis
139
may be useful for future studies aimed at clarification of the mechanism underlying the pathogenesis of SLE-associated hepatitis.
References [1] Miller MH, Urowitz MB, Gladman DD, Blendis LM. The liver in systemic lupus erythematosus. Q J Med 1984;53:401–9. [2] van Hoek B. The spectrum of liver disease in systemic lupus erythematosus. Neth J Med 1996;48:244–53. [3] Youssef WI, Tavill AS. Connective tissue disease and the liver. J Clin Gastroenterol 2002;35:345–9. [4] Elkon KB, Parnassa AP, Foster CL. Lupus autoantibodies target ribosomal P proteins. J Exp Med 1985;162:459–71. [5] Arnett FC, Reichlin M. Lupus hepatitis: an under-recognized disease feature associated with autoantibodies to ribosomal P. Am J Med 1995;99:465–72. [6] Hulsey M, Goldstein R, Scully L, Surbeck W, Reichlin M. Anti-ribosomal P antibodies in systemic lupus erythematosus: a casecontrol study correlating hepatic and renal disease. Clin Immunol Immunopathol 1995;74:252–6. [7] Yoshio T, Masuyama JI, Minota S, et al. A close temporal relationship of liver disease to antiribosomal P0 protein antibodies and central nervous system disease in patients with systemic lupus erythematosus. J Rheumatol 1998;25:681–8. [8] Massardo L, Burgos P, Martinez ME, et al. Antiribosomal P protein antibodies in Chilean SLE patients: no association with renal disease. Lupus 2002;11:379–83. [9] Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7. [10] Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group Report: review of criteria for dignosis of autoimmune hepatitis. J Hepatol 1999;31:929–38. [11] Koren E, Reichlin MW, Koscec M, Fugate RD, Reichlin M. Autoantibodies to the ribosomal P proteins react with a plasma membrane-related target on human cells. J Clin Invest 1992;89:1236– 41. [12] Koscec M, Koren E, Wolfson-Reichlin M, et al. Autoantibodies to ribosomal P proteins penetrate into live hepatocytes and cause cellular dysfunction in culture. J Immunol 1997;159:2033–41.