S. Saarinen

OBJECTIVES: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin that mostly affects male patients with inflammatory bowel disease (IBD). The immune system is believed to be involved in the etiology/pathogenesis as these patients present with several immunological disturbances. Susceptibility to develop primary sclerosing cholangitis is partly determined by genes in the HLA complex. The aim of this study was to compare the prevalence of autoimmune disorders in IBD patients with and without PSC and to correlate the presence of autoimmune disorders in PSC to outcome and HLA association. METHODS: One hundred nineteen PSC patients were included in the study. Each PSC patient with IBD was matched to a IBD patient without PSC. The presence of autoimmune disorders was carefully evaluated in each group. Moreover, comparisons between PSC patients with and without autoimmune disorders were performed. RESULTS: Twenty-five percent of the PSC patients had at least one autoimmune disorder outside the liver and colon compared to 9% in the IBD group without PSC (p < 0.005). Nine of the PSC patients had two or more autoimmune diseases compared to only one patient in the IBD group (p < 0.02). The PSC patients with and without associated autoimmune disease did not differ in clinical presentation, outcome of PSC or HLA alleles. A significant overrepresentation of DRB1*03 was still present after excluding PSC patients with concomitant autoimmune diseases outside the liver and colon compared to a healthy Swedish control group. CONCLUSIONS: Autoimmune disorders are more frequent among PSC patients compared to IBD patients without liver disease. Associated autoimmune diseases in PSC patients does not influence the outcome or clinical presentation of PSC.

The association of primary sclerosing cholangitis (PSC) to HLA class II genes was studied by comparing patients from five different European populations. Deduced HLA-DRB1, DQA1, DQB1 haplotypes of 256 PSC patients from England, Italy, Norway, Spain and Sweden were compared to those observed in 764 ethnically-matched controls. Increased frequencies of the DRB1*03, DQA1*0501, DQB1*02 (RR=3.0, P<0.00001) and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes (RR=2.4, P<0.0001) were observed in all five patient groups. A total of 16% of the PSC patients were homozygous for the DRB1*03, DQA1*0501, DQB1*02 haplotype compared to 1% of the controls (RR=20, P<0.0001). The DRB1*04, DQA1*03, DQB1*0302 haplotype was significantly reduced in frequency(RR=0.4, P<0.00001). Among Norwegian, Swedish and British patients that did not carry neither the DRB1*03, DQA1*0501, DQB1*02 nor the DRB1*13, DQA1*0103, DQB1*0603 haplotype, an increased frequency of the DRB1*15, DQA1*0102, DQB1*0602 haplotype was observed (RR=2.0, P<0.0001). Thus, PSC was found to be positively associated to three different HLA class II haplotypes (i.e. the DRB1*03, DQA1*0501, DQB1*02, the DRB1*15, DQA1*0102, DQB1*0602 and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes) and negatively associated to one HLA class II haplotype (i.e. the DRB1*04, DQB1*0302 haplotype).

BACKGROUND: An improvement of prognostic models in primary sclerosing cholangitis (PSC) is needed. In particular, inclusion of prognostic markers that are independent of the disease stage would be advantageous. We investigated whether HLA class II genes associated with PSC are also related to disease progression. METHODS: The study included 265 PSC patients from five European countries with a median follow-up of 9.1 years. The end-points were death (n = 38) or liver transplantation (n = 52). Thirty patients developed cholangiocarcinoma during follow-up. RESULTS: The DRB1*03,DQA1*0501, DQB1*02 (i.e. DR3,DQ2) heterozygous genotype was associated with an increased risk of death or liver transplantation (hazard ratio = 1.63; 95% confidence interval (CI) = 1.06-2.52). The presence of a DQ6 encoding haplotype (DQB1*0603 or DQB1*0602) in DR3,DQ2 negative individuals was associated with a reduced risk of death or liver transplantation (hazard ratio = 0.57; 95% CI = 0.36-0.88). There was a trend towards an increased risk of developing cholangiocarcinoma among DR4,DQ8 positive patients, but this did not reach significance (odds ratio = 2.27; 95% CI = 0.78-6.62). CONCLUSION: The DR3,DQ2 heterozygous genotype is associated with a more rapid progression of PSC, whereas HLA-DQ6 is associated with a retarded disease progression. It is possible that the DR4,DQ8 haplotype is related to cholangiocarcinoma development.