primary biliary cirrhosis ( pbc ) is an autoimmune disease in which the intrahepatic bile ducts are targeted by an immunemediated injury .
pbc is associated with a range of conditions , including sjgren 's syndrome in 70% of patients 2 , autoimmune thyroid disease in approximately 10% , and systemic sclerosis in 15% 3 .
however , pbc is suggested to only rarely be associated with rheumatoid arthritis ( ra ) , and the true prevalence of pbc in ra is not well known 4 . in this article
, we report an unusual case of a patient with pbc and ra , and discuss the association between these two diseases .
in 2013 , a 71yearold man with rheumatoid arthritis ( ra ) was admitted to our hospital with elevated transaminase levels .
he had been taking prednisone ( 6 mg / day ) and salazosulfapyridine ( 1000 mg / day ) for ra since 2012 ( fig .
1 ) . he reported no consumption of alcohol , recent travel , or sexual contact .
, he was icteric with mild pruritus . an abdominal ultrasound scan , computed tomography ( ct ) , and magnetic resonance cholangiopancreatography ( mrcp ) revealed neither biliary obstruction nor spaceoccupied lesions .
blood test results ( table 1 ) revealed the following : total bilirubin ( tbil ) , 3.76 mg / dl ; direct bilirubin ( dbil ) , 3.12 mg / dl ; aspartate aminotransferase ( ast ) , 167 iu / l ; alanine aminotransferase ( alt ) , 435 iu / l ; alkaline phosphatase ( alp ) , 2539 iu / l ; glutamyltranspeptidase ( gtp ) , 590 iu / l ; immunoglobulin g ( igg ) , 1322 mg / dl ; immunoglobulin m ( igm ) , 705 mg / dl ; antinuclear antibodies ( ana ) , 40 ; antimitochondrial antibodies ( ama ) , 20 ; amam2 antibodies , 34.1 ( normal ; < 6 ) ; antigp210 antibodies , 0.2 u / ml ( normal ; < 6 ) ; anticentromere antibodies , 55.6 u / ml ( normal ; < 9.9 ) . a liver biopsy at day 4 showed marked inflammatory cell infiltration surrounding and destroying the interlobular bile ducts in the portal area ( fig .
on the basis of these results , a diagnosis of pbc corresponding to sheuer 's stage i was confirmed .
treatment with ursodeoxycholic acid ( udca ) ( 600 mg / day ) was started 3 days after admission .
the patient 's clinical findings and biological data showed improvement and the patient was discharged 19 days after admission .
he has been followed up in our outpatient clinic . a second biopsy after 445 days of udca treatment showed marked improvement of inflammation in the portal area ( fig . 2b ) .
ast , aspartate aminotransferase ; alt , alanine aminotransferase ; alp , alkaline phosphatase ; gtp , glutamyltranspeptidase ; crp , creactive protein ; hbsag , hepatitis b surface antigen ; hcvab , hepatitis c virus antibody ; ebvvca , epstein  barr virus viral capsid antigen ; ebna , epstein  barr virus nuclear antigen ; ana , antinuclear antibodies ; asma , antismooth muscle antibodies ; ama , antimitochondrial antibodies ; antitg ab , antithyroglobulin antibody ; antitpo ab , anti thyroid peroxidase antibody .
( a ) a liver biopsy at day 4 . marked inflammatory cell infiltration is observed surrounding and destroying the interlobular bile ducts with ductular proliferation in the portal area .
hepatic involvement is common in rheumatic diseases and is usually related with nonspecific findings such as drugrelated liver dysfunction .
however , more serious hepatic involvement , including nodular regenerative hyperplasia , vasculitis , and pbc , have been observed in specific rheumatic diseases , such as ra 3 , 5 .
ra is present in about 1% of the population and pbc is even rarer , with an estimated prevalence of 0.02% in females and 0.002% in males .
however , there are some reports that describe their association with individuals or families 4 , 7 .
pbc patients often have concomitant autoimmune diseases , such as sjgren 's syndrome ( 70% ) , systemic sclerosis ( 15% ) , and thyroiditis ( 10% ) .
the association of pbc and ra is unclear , although previous studies on large series of pbc patients have suggested that the prevalence of ra in pbc is 1.85.6% 4 , 8 , 9 .
meanwhile , several previous studies have indicated the presence of pbcrelated features in ra patients .
one autopsy series of ra patients found that 65% of 182 ra cases had evident liver pathology , including chronic inflammatory infiltration of the portal tracts and small foci of necrosis , as well as steatosis 10 .
however , it is unclear whether any of these patients were diagnosed with pbc . a japanese study by takahashi et al .
furthermore , another study indicated ama positivity in ra patients to be 18% 12 . in our case
, ama testing was not performed at the diagnosis of ra because liver dysfunction was not observed . although the etiologic and pathologic mechanisms of these diseases are not yet understood , several factors have been suggested , such as genetic factors , epigenetic factors , and infectious agents .
genomewide association studies ( gwas ) have shed light on the genetic background of pbc and ra recently .
genetic studies have indicated that several genes implicated in pbc lay within nonhla and hla regions 13 , 14 .
several common genes have been identified in pbc and ra , although the majority of implicated genes in both diseases do not overlap .
overlapping genes include hladqb1 , ctla4 , mmel1 , irf5 , stat4 , and possibly cxcr5 . among these genes , stat4 is essential for il12 signal transduction via the il12 receptor ( il12r ) for ifn production and th1 polarization . in a gwas for pbc in the japanese population ,
15 reported that , in addition to possessing two significant susceptibility loci ( tnfsf15 and pou2af1 ) , stat4 showed a suggestive association with pbc in japanese and european patients . in our case
, we did not perform a genetic analysis ; however , individuals with a common genetic profile may be more susceptible to developing concomitant ra and pbc . assuming that several common genes exist in ra and pbc patients
, it has been suggested that common infectious triggers may be involved in the induction of both diseases .
most studied infection trigger of pbc is escherichia coli ( e. coli ) 16 ; due to the high incidence of recurrent urinary tract infections ( rutis ) in pbc patients 17 .
several infectious agents ( including e. coli ) have also been linked to ra 18 , 19 . of note , in rfpositive patients , antie .
no symptoms of bacterial infection , including rutis , were observed during the clinical course .
however , a possible role of e. coli has been suggested in the early pathogenesis of ra . in our case , the patients showed rapid elevation in alt as well as alp and gtp .
, druginduced liver injury ( dili ) and overlap syndrome between pbc and auto immune hepatitis ( aih ) were suspected at first .
however , the patient was finally diagnosed as pbc by laboratory data , histology findings , and clinical course . in our case ,
overlap syndrome between pbc and aih was also suspected , however , serum level of alt was normalized after 2 months of udca treatment .
for these findings , we thought that the diagnosis in our case was also closer to pbc than overlap syndrome . in conclusion ,
concomitant pbc in patients with ra is rare ; however , pbc should be ruled out in the differential diagnosis of any patients with ra having abnormal liver function tests . to determine the relationship between these two diseases ,
further studies are needed , in particular cohort studies related to pbc occurrence in a large cohort of ra patients .
 key clinical messagethe true prevalence of pbc in ra is not well known . 
 herein , we report an unusual case of a patient with pbc and ra , and discuss the association between these two diseases . 
 pbc should be ruled out in the differential diagnosis of patients with ra having abnormal liver function tests . 
Introduction
Case report
Discussion
Conflict of interest