Primary biliary cirrhosis(PBC) is a slowly progressive autoimmune disease of the liver
which mainly affects women aged between 35 and 45 years.Prolonged liver inflammation can
cause scarring, leading to cirrhosis. Although 50 to 60 percent of patients are asymptomatic at
diagnosis, they will develop symptoms later. PBC can be associated with arthralgia and other
non-hepatic autoimmune diseases, such as Sjögren’s syndrome, sicca syndrome, thyroiditis and
scleroderma. PBC and rheumatoid arthritis (RA) have been suggested to coexist in 1.8 to 5.6% of
patients with PBC, but data supporting this association are scarce. We report two cases of such an
association and discuss how to improve threapy

Fan, Daiming

Han, Ying

Liu, Jingmei

Wang, Jingbo

Yan, Li

Zhou, Xinmin

Eldorado - Ressourcen aus und für Lehre, Studium und Forschung

EXCLI Journal 2007;6:183-186 – ISSN 1611-2156 
Received: July 29, 2007, accepted: August 14, 2007, published: August 17, 2007 
 
183 
Case report: 
 
Primary Biliary Cirrhosis associated with rheumatoid arthritis : 
two case reports in China 
 
Jingmei Liu1,2, Xinmin Zhou1,2, Ying Han1,2, Li Yan1, Jingbo Wang1, Daiming Fan1,* 
 
1 State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital, The 
Fourth Military Medical University, Xi'an, Shaanxi Province, China. E-mail: fan-
daim@fmmu.edu.cn; Phone: 86-29-84773974; Fax: 86-29-82539041 (*corresponding author) 
2 Jingmei Liu, Xinmin Zhou and Ying Han contribute equally to this paper. 
 
ABSTRACT 
Primary biliary cirrhosis(PBC) is a slowly progressive autoimmune disease of the liver 
which mainly affects women aged between 35 and 45 years.Prolonged liver inflammation can 
cause scarring, leading to cirrhosis. Although 50 to 60 percent of patients are asymptomatic at 
diagnosis, they will develop symptoms later. PBC can be associated with arthralgia and other 
non-hepatic autoimmune diseases, such as Sjögren’s syndrome, sicca syndrome, thyroiditis and 
scleroderma. PBC and rheumatoid arthritis (RA) have been suggested to coexist in 1.8 to 5.6% of 
patients with PBC, but data supporting this association are scarce. We report two cases of such an 
association and discuss how to improve threapy. 
 
Keywords: primary biliary cirrhosis, rheumatoid arthritis, ursodeoxycholic acid, methotrexate 
 
 
INTRODUCTION 
 
Primary biliary cirrhosis is a slowly 
progressive autoimmune disease of the liver 
that primarily affects women. Its peak inci-
dence occurs in the fifth decade of life, and it 
is uncommon in persons under 25 years of 
age (Kaplan and Gershwin, 2005). 
50 to 60 percent of patients are asymp-
tomatic at diagnosis (Pares and Rodes, 2003; 
Prince et al., 2004). However, most asymp-
tomatic patients, over time, will develop 
symptoms and hepatic disease will progress 
(Metcalf et al., 1997). Fatigue and pruritus 
are the most common presenting symptoms 
(Bergasa et al., 2003).  
Other common findings in PBC include 
Sjögren’s syndrome, sicca syndrome, thy-
roiditis and scleroderma (Watt et al., 2004). 
The co-existence of PBC and RA is well 
known with a frequency ranging from 1.8 % 
to 5.6 % (Pares and Rodes, 2003; Marasini et 
al., 2001). As far as we know there is no data 
of PBC frequency in large cohort of patients 
with RA.  
Ursodeoxycholic acid (UDCA) is the 
only approved drug for PBC. However, the 
beneficial effect of UDCA in PBC patients is 
uncertain. 
As we know the co-existence is rare and 
may occur concomitantly or serially. Clini-
cians must be aware of the possibility of liver 
disease so that it can be treated as soon as 
possible. We report two cases of such an as-
sociation in China. 
 
CASE 1 
 
In 2004, a 62-year-old woman presented 
with inflammatory arthralgia of the meta- 
carpophalangeal,interphalangeal and left knee 
joints. She was negative for rheumatoid fac-
EXCLI Journal 2007;6:183-186 – ISSN 1611-2156 
Received: July 29, 2007, accepted: August 14, 2007, published: August 17, 2007 
 
184 
tor. She was treated with Tripterygium wil-
fordii (Chinese crude drug). 
In 2006, the disease flared up with pru-
ritus and jaundice. Her urine presents dark 
brown. She was treated with amino acids 
drugs. 
Three months later, the patient devel-
oped fatigue. Jaundice and pruritus became 
active again. Laboratory findings on admis-
sion are summerized in Table 1. Alkaline 
phosphatase (ALP), γ-glutamyltranspeptidase 
(GGT), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), γ-globulin, 
IgG, and IgM were elevated, but the level of 
serum bilirubin was normal. Viral markers 
were still negative. Liver ultrasound was 
normal, showing no biliary duct dilatation 
and no biliary sludge. The presence of 
anti-mitochondrial antibodies (AMA M2 type, 
1/320) led to the diagnosis of PBC. A liver 
biopsy confirmed the diagnosis and revealed 
stage II histology. 
X-ray revealed bilateral and symmetrical 
erosion of the metacarpophalangeal joints. 
She was positive for rheumatoid factor and 
anti-CCP antibodies. She received 10 mg/kg 
of ursodeoxycholic acid per day, which im-
proved the pruritus and biological hepatic 
abnormalities. 
 
Table 1 
Patients characteristics and laboratory data on admission 
 Case 1 Case 2 
Age 62 41 
Sex Female Male  
Histologic stage of PBC II IV 
ALP (IU/L) 767 598 
GGT (IU/L) 172 562 
ALT (IU/L) 68 25 
AST (IU/L) 104 98 
TBIL (mmol/L) 7.8 51.5  
ANA Positive (1:640) Positive (1:320) 
AMA Positive (1:320) Positive (1:640) 
Ig G (g/L)  18.5 11.0 
Ig M (g/L) 2.42 0.685 
Anti-HAV antibody Negative Negative 
Anti-HBV antibody Negative Negative 
Anti-HCV antibody Negative Negative 
RF (IU/mL) 17.4 20.4 
hs-CRP (mg/L) 15 19 
ESR (mm/hr) 25 50 
ALP: Alkaline Phosphatase, GGT: gamma-glutamyl transferase, ALT: alanine aminotrans-
ferase, AST: aspartate aminotransferase, TBIL: Total Bilirubin, AMA: antimitochondrial anti-
bodies, ANA: antinuclear antibodies, Ig: immunoglobulin, RF: rheumatoid factor, ESR: eryth-
rocyte sedimentation rate, CRP: C-reactive protein 
 
CASE 2 
 
In 2001, a 41-year-old man presented 
with fatigue all of the body. Hepatic tests 
showed elevated aminotransferase. He was 
not taking any drugs. 
In 2002, he developed symmetrical ar-
thritis of the knees. He was treated with peni-
cilin, but the disease got worse and worse. 
The patient got fever and jaundice quickly. 
He was negative for rheumatoid factor and 
hand X-rays were normal. Serological tests 
EXCLI Journal 2007;6:183-186 – ISSN 1611-2156 
Received: July 29, 2007, accepted: August 14, 2007, published: August 17, 2007 
 
185 
were negative for hepatitis A, B and C. Bio-
logical investigations revealed that he was 
negative for other antibodies such as antinu-
clear antibodies (ANA), anti-neutrophil cyto-
plasmic antibodies (ANCA), smooth muscle 
and liver-kidney microsomal antibodies 
(LKM1). He was treated prednisone (30 mg 
per day). 
In 2004, he presented symmetrical in-
flammatory arthralgia of the hands and knees 
(metacarpophalangeal and proximal inter-
phalangeal joints) once again. X-ray showed 
bilateral femoral heads aseptic necrosis. Then 
the disease was controlled with prednisone 
(30 mg per day) and methotrexate (15 mg per 
week). 
In 2005, he was diagnosed with PBC. 
The diagnosis was based on the discovery of 
elevated ALP and GGT level, but normal 
values for transaminase and bilirubin during a 
blood test (Table1). The liver ultrasound re-
vealed hepatic cirrhosis and hypersplenotro-
phy. Further biological  investigations re-
vealed that she was positive for AMA type. A 
liver biopsy revealed signs of non-sup-
purative cholangitis with fibrosis or cirrhosis. 
X-ray showed bilateral femoral head aseptic 
necrosis. She was positive for rheumatoid 
factor and anti-CCP antibodies; she was 
treated with ursodeoxycholic acid (10 mg/kg 
per day) and methotrexate (15 mg per week). 
Methotrexate and ursodeoxycholic acid re-
leased the symptoms and hepatic tests’ value. 
 
DISCUSSION 
 
Primary biliary cirrhosis is a chronic 
cholestatic disease, which leads to progres-
sive fibrosis of the liver and sometimes to 
cirrhosis. Most cases are currently diagnosed 
in asymptomatic patients (Pares and Rodes, 
2003). Primary biliary cirrhosis (PBC) and 
rheumatoid arthritis (RA) are chronic medical 
conditions in which, although the etiology is 
uncertain, autoimmune features predominate. 
Both of these conditions are fairly rare, with 
RA being found in approximately 1 % of the 
population and PBC being found in approxi-
mately 20/100,000 women and 2/100,000 
men (Gabriel et al., 1999; Kim et al., 2000). 
The likelihood of these uncommon condi-
tions occurring in the same patient is very 
rare and unusual. 
It has been well established that patients 
with PBC (case 2) may have musculoskeletal 
complaints and patients with RA (case 1) 
may have evidence of hepatic dysfunction. 
RA did not show specificity in our two pa-
tients; in one patient, articular involvement 
occurred before PBC and in the other, it oc-
curred subsequently. Interestingly, it is re-
ported that most of patients were diagnosed 
with RA years before PBC was diagnosed 
(Siegel et al., 2003). More data are required 
to determine which one is the predominant 
disease. It should be noticed in case 2 that the 
destructive arthropathy of the bilateral femo-
ral heads contrasted with other mild erosive 
lesions of the wrist. Such rapidly destructive 
arthropathies have already been described in 
PBC, involving notably the hip (Bourgeois et 
al., 1981). Our findings, together with previ-
ous findings, suggest that the discovery of 
abnormal hepatic tests (mainly elevated ALP 
concentrations) should lead to AMA meas-
urement in patients with RA and that patients 
with PBC presented joints erosion should 
consider RA. 
Ursodeoxycholic acid (UDCA) is the 
only approved drug for PBC. However, the 
beneficial effect of UDCA in PBC patients is 
uncertain. An updated systematic review did 
not demonstrate any benefit of UDCA on 
mortality and mortality or liver transplanta-
tion in patients with PBC (Gong et al., 2007). 
Articular involvement occurred before 
PBC in case 1,which raised questions about 
hepatotoxicity of RA drugs. In fact, metho-
trexate (MTX) has been tested as a treatment 
for PBC, especially when classical UDCA 
monotherapy is ineffective (Lindor et al., 
1995; Kaplan et al., 2004). Conflicting data 
have been reported, but a recent ten-year fol-
low-up study suggested that MTX plus 
UDCA was not more effective than UDCA 
alone in terms of survival free of liver trans-
EXCLI Journal 2007;6:183-186 – ISSN 1611-2156 
Received: July 29, 2007, accepted: August 14, 2007, published: August 17, 2007 
 
186 
plantation. In addition, adverse events asso-
ciated with methotrexate treatment have been 
reported in 24.5 % of PBC patients (Lindor et 
al., 1995). Other data showed that the coex-
istence of these two diseases does not seem to 
modify the course of either disease and we 
can suggest that methotrexate can be choosen 
as a treatment of both of them without scare 
of hepatotoxicity, in association with ursode-
oxycholic acid (Siegel et al., 2003). 
In conclusion, if PBC patients can be 
controlled with ursodeoxycholic acid, we 
recommend UDCA monotherapy. However, 
if UDCA is ineffective, MTX plus UDCA 
may be an alternative. A high risk of 
drug-induced hepatotoxicity should be con-
sidered, when PBC is associated with RA. 
The association between PBC and RA is rare. 
However, recognition of the correct diagnosis 
can have a tremendous impact on therapy and 
possibly on prognosis of such patients. 
 
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Primary biliary cirrhosis associated with rheumatoid arthritis

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