Evaluation of GLOBE and UK-PBC Scores and Long- Term Outcomes in Primary Biliary Cholangitis Complicated with CREST Syndrome

doi:10.21203/rs.3.rs-3573666/v1

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Evaluation of GLOBE and UK-PBC Scores and Long- Term Outcomes in Primary Biliary Cholangitis Complicated with CREST Syndrome

https://doi.org/10.21203/rs.3.rs-3573666/v1

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Aim

Primary biliary cholangitis (PBC) is frequently associated with autoimmune disease. Although there have been some reports of PBC complicated with CREST syndrome (PBC-CREST), the long-term prognosis of these patients has not been fully investigated. Herein, the long-term prognosis of PBC-CREST was compared with that of PBC alone using GLOBE and UK-PBC scores.

Methods

A total of 302 patients diagnosed with PBC between December 1990 and August 2021 at our hospital and related institutions were included. The survival rates without liver transplantation (LT) were compared between patients with PBC-CREST (n = 57) and those with PBC alone (n = 245). Moreover, 173 patients were divided into two groups (PBC-CREST (n = 26) and PBC alone (n = 147)), excluding those with LT/liver-related death within 1 year after ursodeoxycholic acid administration; GLOBE and UK-PBC scores were compared.

Results

The survival rates without LT (3/5/10 years) were 98%/96%/96% for the PBC-CREST group and 92%/87%/80% for the PBC-alone group, with a significantly better prognosis in the PBC-CREST group (log-rank, P = 0.0172). The predicted liver-related death and LT risk (5/10/15 years) based on the UK-PBC score was significantly lower in the PBC-CREST group (2.4%/7.6%/13.2%) than in the PBC-alone group (4.8%/11.8%/18.8%; P < 0.05). The predicted LT-free survival (3/5 years) based on the GLOBE score was significantly higher in the PBC-CREST group (93%/88%) than in the PBC-alone group (88%/81%; P < 0.05). Multivariate analysis revealed that the presence of CREST syndrome is an independent protective factor for the presence of cirrhosis.

Conclusions

PBC-CREST may have a better long-term prognosis than PBC alone.

Biological sciences/Immunology

Health sciences/Gastroenterology

Health sciences/Rheumatology

primary biliary cholangitis

CREST syndrome

prognosis

UK-PBC risk score

GLOBE score

Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease characterized by portal inflammation, immune-mediated destruction of the intrahepatic bile ducts, and the presence of highly specific anti-mitochondrial antibodies (AMAs) in the serum ⁽¹⁾. Patients with PBC occasionally suffer complications from other autoimmune diseases ^(2–5), such as Sjögren’s syndrome, rheumatoid arthritis, Hashimoto’s thyroiditis or scleroderma caused by either systemic sclerosis (SSc) or limited cutaneous SSc (lcSSc), which was previously called CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly and telangiectasias) syndrome. LcSSc is accompanied by CREST symptoms, although CREST cases that involve all of these symptoms are rare, with a high prevalence of Raynaud’s phenomenon, sclerodactyly and telangiectasia and a lower prevalence of calcinosis and esophageal dysmotility ⁽⁶⁾. The association of PBC with CREST syndrome (PBC-CREST) was first described by Murray-Lyon et al. in 1970. These authors reported two patients with PBC complicated with scleroderma, of whom one patient had CREST syndrome, and suggested that the association of the two diseases may be due to a common autoimmune mechanism. In 1971, Reynolds et al. reported six patients with PBC and CREST syndrome. Although many cases have been reported since then, the etiology and outcome of this combined disorder remain largely unknown ^(7–14).

Tojo et al. reported that the survival rate 10 years after diagnosis of the disease was higher in patients with PBC-CREST (87.5%) than in patients with PBC alone (45.5%) ⁽¹³⁾. Similarly, a better prognosis in terms of survival was found by Remmel et al. for PBC patients who had anti-nuclear antibodies (ANAs) and anti-centromere antibodies (ACAs) ⁽¹⁵⁾. Other studies have demonstrated that combined PBC-SSc has a significantly better outcome in terms of 10-year survival but not in terms of overall survival and that the rates of jaundice progression and liver transplantation are significantly lower in patients with combined PBC and CREST syndrome than in patients with PBC alone ^{(13, 16)}. Given that ACA-positive PBC is associated with an increased risk of portal hypertension, the early control of gastroesophageal varices may lead to an improved outcome.

Ursodeoxycholic acid (UDCA) is the only accepted first-line agent for the treatment of PBC ^(17–20). UDCA improves liver biochemistry and slows histologic progression to liver cirrhosis ^(21–22). Recently, two newly validated scoring systems, the GLOBE score ⁽²³⁾ and UK-PBC risk score ⁽²⁴⁾, were established to predict the long-term outcomes of PBC patients treated with UDCA. Several previous reports have demonstrated that the GLOBE score and the UK-PBC risk score can be used to assess risk reduction in patients who were treated with UDCA, bezafibrate (BF), fenofibrate and obeticholic acid ^(25–28). However, these two scoring systems have not yet been validated in patients with PBC-CREST. In this study, we compared the long-term prognosis of PBC-CREST with that of PBC alone using GLOBE and UK-PBC scores.

STUDY DESIGN AND PATIENT POPULATION

In this retrospective cohort study, we reviewed the clinical records of patients with PBC who were diagnosed at Fukushima Medical University Hospital (Fukushima, Japan) between December 1990 and August 2021. The inclusion criteria were a diagnosis of PBC confirmed by liver biopsy and/or an available blood sample obtained before biopsy. Patients were diagnosed with PBC features if they met at least two of the following three criteria: (i) chronic elevation of the cholestatic liver enzymes alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (GGT) for at least 6 months; (ii) the presence of serum AMAs detected by either indirect immunofluorescence or enzyme-linked immunosorbent assay (ELISA) using commercially available kits; and (iii) typical histological findings in biopsied liver specimens ⁽¹⁷⁾. The patients were treated with UDCA (13–15 mg/kg/day) after biopsy. The exclusion criteria included evidence of other liver diseases, such as chronic hepatitis C, chronic hepatitis B, and alcoholic liver disease (> 20 g alcohol/day). Patients with an overlapping syndrome, active systemic disorders and active malignancies were also excluded. Liver cirrhosis was diagnosed based on morphologic changes in the liver, such as hypertrophy of the left lateral and caudate lobes or atrophy of the right posterior haptic lobe, identified by ultrasonography (US), computed tomography (CT), and/or magnetic resonance imaging (MRI); a finding of pseudolobule formation on histopathologic examination; or the presence of portal hypertension indicated by varices. Findings supporting a CREST syndrome diagnosis included the following: calcinosis on X-ray images of the extremities; Raynaud's phenomenon based on medical history; esophageal dysmotility shown on barium examination or endoscopy; and sclerodactyly and telangiectasia based on objective observations ⁽²⁹⁾. The diagnosis of CREST syndrome was based on the presence of positivity for ACAs and at least 2 out of the 5 clinical symptoms of CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly and telangiectasias) in accordance with a previous report ⁽¹³⁾.

We initially enrolled 483 patients, but 181 patients were excluded (inadequate follow-up data) (Fig. 1). A total of 302 patients with follow-up were included in this study. The survival rate without liver transplantation was compared between PBC-CREST (n = 57) and PBC alone (n = 245). Thirty-one of the 57 patients with PBC-CREST have been reported in a previous study ⁽¹³⁾. In addition, 173 patients were divided into two groups, PBC-CREST (n = 26) and PBC alone (n = 147), excluding patients who had liver transplantation/liver-related death within 1 year after diagnosis and patients who were not evaluable after 1 year of UDCA administration and those with concomitant use of BF within 1 year of initiation of UDCA treatment. GLOBE scores and UK-PBC scores were compared.

LIVER HISTOLOGY

Liver biopsies were carried out with an 18-G needle and percutaneous ultrasound guidance. Routine hematoxylin–eosin staining was used to evaluate inflammation and fibrosis. The biopsy specimens were assessed by pathologists without knowledge of prior clinical data. The histological findings were graded according to the Scheuer staging system ⁽³⁰⁾.

ETHICS STATEMENT

All patients agreed to serum and histological testing and provided written informed consent. The study protocol conformed to the ethical guidelines of the Declaration of Helsinki and was approved for the use of opt-out consent by the ethics committee of Fukushima Medical University (no. 2427). This study was performed in accordance with the relevant guidelines and regulations, and all patients and control subjects agreed to undergo serum and histological testing and have their blood stored for future research.

CALCULATION OF THE GLOBE SCORE

The GLOBE score for each patient was calculated using their age, levels of bilirubin, ALP and albumin, and platelet count ⁽²³⁾ after UDCA monotherapy. Liver transplant-free survival at 3, 5, 10, and 15 years was predicted using the GLOBE score ⁽²³⁾. The score and prediction of the liver transplant-free survival of each patient were also calculated using data obtained 12 months after the start of UDCA therapy.

CALCULATION OF THE UK-PBC RISK SCORE

The UK-PBC risk score reflects the risk of occurrence of liver transplant or liver-related death within 5, 10, or 15 years. It is calculated using the levels of bilirubin, ALP, alanine transaminase (ALT) and albumin and the platelet count ⁽²⁴⁾. We determined the risk scores of each patient 12 months after the start of UDCA therapy.

STATISTICAL ANALYSIS

Continuous variables are described as the medians (interquartile ranges [IQRs]). Differences were compared using the Mann‒Whitney U test and Wilcoxon matched-pairs signed-rank test. To determine the optimal cutoff level for factors that could distinguish between liver-related death or liver transplantation (LRD/LT) and non-LRD/LT, receiver operating characteristic (ROC) curves were used. The cutoff levels for the parameters were defined as the points closest to 100% sensitivity and specificity. Confounders with a threshold value lower than 0.05 in the univariate analysis were selected a priori based on their known associations with UDCA treatment and OS. The survival rates were calculated using the Kaplan‒Meier method, and the log-rank test was used to evaluate the differences between the curves. Univariate and multivariate Cox proportional hazards regression analyses were performed to analyze the factors related to the development of LRD/LT. Multivariate logistic regression analysis was performed to identify factors associated with the presence of liver cirrhosis. All statistical analyses were performed using Prism 6.0 software (GraphPad Software, Inc.) and Excel Statistics (2011, Esumi Co. Ltd., Tokyo, Japan). P < 0.05 was considered significant.

BASELINE CHARACTERISTICS

The clinicolaboratory data from the patients with PBC-CREST are given in Table 1. The median age at diagnosis of all 302 PBC patients was 59 years, and there were 49 males and 253 females. These patients had a higher prevalence of ACAs and a lower prevalence of AMAs than patients with PBC alone. Moreover, the patients with PBC-CREST had significantly fewer cirrhosis cases and lower values of ALT, γ-GTP, and TB than the patients with PBC alone. Although there was no significant difference in the frequency of varices between the patients with PBC-CREST and PBC alone, more varices patients with PBC alone progressed to cirrhosis than those with PBC-CREST. The median observation period was 5.4 years, and there were 6 cases of liver transplantation and 37 cases of liver-related death. Among 245 patients with PBC alone, 207 received UDCA monotherapy, 4 received UDCA monotherapy but it was discontinued, and 34 patients underwent combination therapy with UDCA and BF. Among 57 patients with PBC-CREST, 56 received UDCA monotherapy, and 1 patient underwent combination therapy with UDCA and BF.

Table 1

**COMPARISON OF CLINICOLABORATORY FINDINGS BETWEEN PATIENTS WITH PBC-CREST AND PATIENTS WITH PBC ALONE (N = 302).**
	PBC alone	PBC-CREST	P
n Age (years), median (IQR)	245	57
n Age (years), median (IQR)	59.0 (51–68)	61.5 (52–70)	0.6958
Sex (male/female)	48/197	1/56	0.0009^*
Symptomatic/asymptomatic	56/189	8/49	0.1421
AMA-positive, n (%)	214 (87)	42 (74)	0.0097^*
ACA-positive, n (%)	46 (19)	57 (100)	< 0.0001^*
Scheuer’s stage, 1/2/3/4 (n = 159)	57/41/19/14	16/8/2/2	0.1726
Liver cirrhosis, n (%)	51 (21)	4 (7)	0.0150^*
At the time of diagnosis	42	3
During the follow up period	9	1
Esophagogastric varices, n (%)	46 (19)	6 (11)	0.0951
Varices without cirrhosis, n (%) Hepatocellular carcinoma, n (%)	4 (1.6) 6 (2.4)	4 (7.0) 0 (0)	0.0226^* 0.2327
Pulmonary hypertension, n (%)	1 (0.4)	1 (1.8)	0.2590
Calcinosis, n (%)	NA	14 (25)	-
Raynaud’s phenomenon, n (%)	NA	51 (89)	-
Esophageal dysmotility, n (%)	NA	16 (28)	-
Sclerodactyly, n (%)	NA	35 (61)	-
Telangiectasia, n (%)	NA	42 (74)	-
Complete type of CREST, n (%)	NA	6 (11)	-
Observation Period (years), median (IQR)	5.2 (2.4–9.9)	7.0 (3.0-10.8)	0.1284
ALT (U/l), median (IQR)	41 (25–75)	34 (22–50)	0.0376^*
ALP (U/l), median (IQR)	158 (123–230)	141 (115–201)	0.1384
γGTP (U/l), median (IQR)	140 (71–284)	75 (44–146)	0.0002^*
TB (mg/dl), median (IQR)	0.8 (0.6–1.2)	0.6 (0.5–0.9)	0.0021^*
ALB (g/dl), median (IQR)	4.1 (3.6–4.3)	4.1 (3.8–4.3)	0.5802
PLT (x10⁴/µl), median (IQR)	20.0(13.5–24.9)	20.5 (17.5–23.9)	0.5530
IgG (mg/dl), median (IQR)	1792 (1444–2189)	1640 (1420–1966)	0.1464
IgM (mg/dl), median (IQR)	321 (183–550)	336 (252–444)	0.7658
Liver-related death, n (%)	34 (13.9)	3 (5.3)	0.0740
Liver transplantation, n (%)	6 (2.4)	0 (0)	0.2327
Liver-related death or liver transplantation, n (%)	40 (16.3)	3 (5.3)	0.0313^*
SSc-related death, n (%) UDCA monotherapy, n (%) Combination therapy with BF	NA 207 (84.5) 34 (13.9)	2 (3.5) 56 (98.2) 1 (1.2)	- 0.0053^* 0.01^*
NA, not applicable. ^*P < 0.05. Abbreviations: ACA, anticentromere antibody; AMA, antimitochondrial antibody; BF, bezafibrate; UDCA, ursodeoxycholic acid.

ANALYSIS OF SURVIVAL AFTER UDCA TREATMENT

The median follow-up time was 6.3 years from diagnosis. The survival rate without liver transplantation (3/5/10 years) was 98%/96%/96% for the PBC-CREST group and 92%/87%/80% for the PBC-alone group, with a significantly better prognosis in the PBC-CREST group (log-rank, P = 0.0172) (Fig. 2).

UNIVARIATE AND MULTIVARIATE ANALYSIS OF RISK AND PROTECTIVE FACTORS ASSOCIATED WITH LIVER-RELATED DEATH OR LIVER TRANSPLANTATION IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS

The results of univariate and multivariate Cox proportional hazards regression analyses of the risk and protective factors significantly associated with LRD/LT are shown in Table 2 and Supporting Table 1. Univariate analysis revealed that the following factors were significantly associated with LRD/LT: positivity for ACAs, presence of liver cirrhosis, presence of CREST syndrome, ALT > 46 U/L, ALP > 499 U/L, TB > 0.97 mg/dL, ALB ≤ 3.6 g/dL and PLT ≤ 12.8 x10⁴/µl. Multivariate analysis was performed using the significant factors identified by univariate analysis, and liver cirrhosis and ALB levels were found to be independent factors. The hazard ratio (HR) of LRD/LT with a serum ALB level ≤ 3.6 g/dl was 3.62 (95% CI, 1.71–7.69), and the HR of liver cirrhosis was 12.6 (95% CI, 5.01–31.49).

Table 2

MULTIVARIATE ANALYSIS OF RISK AND PROTECTIVE FACTORS ASSOCIATED WITH LIVER-RELATED DEATH OR LIVER TRANSPLANTATION IN PATIENTS WITH PBC.
LRD/LT vs. Non-LRD/LT		HR (95% CI)	P
Age	≤ 58	0.86 (0.42–1.74)	0.666
	> 58	1 (Ref.)
Sex	Male	1.30 (0.55–3.08)	0.545
	Female	1 (Ref.)
Liver cirrhosis	Present	12.6 (5.01–31.49)	< 0.0001^*
	Absent	1 (Ref.)
CREST syndrome	Present	0.96 (0.27–3.36)	0.948
	Absent	1 (Ref.)
ALT (U/L)	> 46	0.92 (0.45–1.89)	0.827
	≤ 46	1 (Ref.)
ALP (U/L)	≤ 499	1.41 (0.67–2.94)	0.366
	> 499	1 (Ref.)
TB (mg/dL)	> 0.97	1.67 (0.74–3.76)	0.215
	≤ 0.97	1 (Ref.)
ALB (g/dL)	≤ 3.6	3.62 (1.71–7.69)	0.0008^*
	> 3.6	1 (Ref.)
PLT (x10⁴/µl)	≤ 12.8	1.70 (0.75–3.85)	0.203
	> 12.8	1 (Ref.)
*P < 0.05 was considered significant. Abbreviations: Ref., reference group; HR, hazard ratio; CI, confidence interval; LRD, liver-related death; LT, liver transplantation.

MULTIVARIATE ANALYSIS OF FACTORS ASSOCIATED WITH LIVER CIRRHOSIS IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS

A total of 302 PBC patients were included in the final analysis, of whom 245 did not have cirrhosis (Non-LC) and 55 had liver cirrhosis (LC). The patients’ baseline characteristics are shown in Supporting Table 2. Compared with Non-LC patients with PBC, PBC patients with LC had significantly higher levels of TB, AST, ALT, γ-GTP (GGT), IgG, and IgM and significantly lower ALB levels and PLT counts. As expected, the complication rate of CREST syndrome was higher in PBC patients with Non-LC than in those with LC. Multivariate analysis was performed using the significant factors for LC, and the presence of CREST syndrome was found to be a protective independent factor. The odds ratio (OR) of LC with the presence of CREST syndrome was 0.24 (95% CI, 0.07–0.83) (Table 3).

Table 3

MULTIVARIATE ANALYSIS OF FACTORS ASSOCIATED WITH LIVER CIRRHOSIS IN PATIENTS WITH PBC.
LC vs. Non-LC		OR (95% CI)	P
Age	≤ 58	1.41 (0.78–2.57)	0.259
	> 58	1 (Ref.)
Sex	Male	0.64 (0.26–1.55)	0.319
	Female	1 (Ref.)
AMAs	Positive	1.78 (0.65–4.92)	0.264
	Negative	1 (Ref.)
ACAs	Positive	1.22 (0.55–2.69)	0.622
	Negative	1 (Ref.)
CREST syndrome	Present	0.24 (0.07–0.83)	0.024^*
	Absent	1 (Ref.)
*P < 0.05 was considered significant. Abbreviations: ACA, anticentromere antibody; AMA, antimitochondrial antibody; Ref., reference group; OR, odds ratio; CI, confidence interval; LC, liver cirrhosis.

EFFECTS OF UDCA TREATMENT ON LIVER BIOCHEMISTRY

The clinicolaboratory data from the 173 patients with PBC-CREST and PBC alone at baseline, excluding patients who had LT/LRD within 12 months after diagnosis and patients who were not evaluable after 12 months of UDCA administration, are presented in Supporting Table 3. There were no significant differences between the two groups, except for sex. The effects of UDCA therapy on liver biochemistry are shown in Supporting Fig. 1. A comparison of liver biochemistry after 12 months of treatment with UDCA among patients with PBC-CREST and PBC alone showed that the TB, ALP and ALT levels in patients with PBC-CREST were significantly decreased after treatment. Although the ALP and ALT levels in patients with PBC alone were significantly decreased after treatment, TB levels in those with PBC alone were not significantly decreased after treatment.

ANALYSIS OF GLOBE SCORES AFTER UDCA TREATMENT

The comparison of estimated survival rates calculated using the GLOBE score between patients with PBC-CREST and those with PBC alone is shown in Fig. 3. The mean GLOBE score of the patients with PBC alone after UDCA therapy was 0.88 ± 0.93 (range: -1.01 to 4.60), while the GLOBE score of those with PBC-CREST was decreased to 0.47 ± 0.78 (range: -1.12 to 2.09), and this difference was significant (P < 0.05) according to the Mann‒Whitney U test (Fig. 3A). GLOBE scores of > 0.3, defined as UDCA nonresponders with significantly shorter transplant-free survival than a matched healthy individual, were observed in 57.6% and 73.5% of patients with PBC-CREST and PBC alone, respectively. In addition, the 3-year and 5-year liver transplant-free survival rates calculated using the GLOBE score were significantly different after UDCA therapy (P < 0.05) (Fig. 3B-E).

ANALYSIS OF UK-PBC RISK SCORES AFTER UDCA TREATMENT

The risk of a liver transplant or liver-related death occurring within 5 years, 10 years and 15 years, as predicted using the UK-PBC risk score, was significantly decreased (P < 0.05) in patients with PBC-CREST compared to those with PBC alone after UDCA therapy (Fig. 4A-C).

This study is the first to report an evaluation of the long-term prognosis of PBC-CREST with that of PBC alone using GLOBE and UK-PBC scores. In this study, the survival rate without liver transplantation (3/5/10 years) was 98%/96%/96% for the PBC-CREST group and 92%/87%/80% for the PBC-alone group, with a significantly better prognosis for the PBC-CREST group. Moreover, the predicted risk of liver-related death and liver transplantation was significantly lower for PBC-CREST than for PBC alone. In addition, the liver transplant-free survival rates were significantly better after UDCA therapy for patients with PBC-CREST. Multivariate analysis of the prevalence of cirrhosis showed that the presence of CREST syndrome was a protective independent factor. Previous studies reported that the survival rate 10 years after diagnosis of the disease was higher in patients with PBC-CREST than in patients with PBC alone ⁽¹³⁾. Similarly, a better prognosis in terms of survival was found for PBC patients with ANAs and ACAs ⁽¹⁵⁾.

Recently, CREST syndrome has been considered to be a limited-form scleroderma, regardless of the number of symptoms present ⁽⁶⁾. In this study, most patients with sclerodactyly and at least one other symptom were diagnosed with CREST syndrome. Patients with Raynaud's phenomenon and telangiectasia only were included in this study because scleroderma symptoms often appear later, as described in a previous report ⁽¹³⁾.

The higher prevalence of AMAs and ACAs described in several reports on PBC-CREST patients. The prevalence of ACAs is also reported to be higher in PBC-CREST patients than in patients with PBC alone. Moreover, the positivity rate of ACAs shows a significant difference, with values of 30% in SSc patients and 70% in CREST patients. A previous study reported that ACA-positive PBC patients are more likely to develop portal hypertension ⁽³²⁾. Another study showed that the prevalence of esophageal varices is significantly higher in patients with PBC-CREST than in those with PBC alone in a cohort that excluded cirrhotic patients ⁽¹³⁾. In this study, although there was no significant difference in the frequency of varices between the patients with PBC-CREST and the patients with PBC alone, more varices patients with PBC alone than with PBC-CREST showed progression to cirrhosis.

Recently, two new scoring systems, the GLOBE score ⁽²³⁾ and the UK-PBC risk score ⁽²⁴⁾, have been developed and validated in PBC patients treated with UDCA in Western countries. The former can be used to estimate transplant-free survival, while the latter predicts the risk of liver transplantation or liver-related death occurring by a specific point in the future. The GLOBE score was established based on data collected after 12 months of UDCA treatment, but even using data collected 2–5 years after treatment, transplant-free survival rates have been accurately calculated ⁽²³⁾. Furthermore, these scoring systems have been validated in Asian PBC patients ⁽³³⁾. For these reasons, we decided to evaluate the validity of the GLOBE and UK-PBC risk scores in our retrospective cohort. In this study, the predicted risk of liver-related death and liver transplantation according to the UK-PBC score was significantly lower for PBC-CREST patients than for patients with PBC alone. Moreover, the number of patients defined as UDCA nonresponsive with a GLOBE score of 0.3 or higher was significantly lower in PBC-CREST patients than in patients with PBC alone. The liver transplant-free survival rates calculated using the GLOBE score were significantly better after UDCA therapy in PBC-CREST patients.

Limited findings have been reported regarding the etiology of combined PBC-SSc, including a higher expression level of T-cell receptor beta chain variable region 3 on CD8⁺ T cells and a higher prevalence of human leukocyte antigen (HLA)-DR9 expression in patients with combined PBC-SSc than in patients with either disorder alone ^{(13, 34)}. Both disorders are autoimmune fibrotic diseases characterized by increased levels of the profibrotic cytokines TGF-β and IL-6, which have recently been suggested to be involved in the production and function of Th17 cells and regulatory T cells (Tregs), which play a role in acquired immunity ^(35–39). Aberrant numbers and functions of natural killer (NK) cells have been reported in several different autoimmune disorders. A role of NK cells mediating direct or indirect biliary epithelial cell destruction in PBC pathogenesis has been supported by several studies ⁽⁴⁰⁾. Alterations in NK cell number and function were implicated in SSc pathogenesis ⁽⁴⁰⁾. B-cell abnormalities have also been reported in both disorders ^(41–44). To date, these immunological abnormalities have not been examined in patients with combined PBC-SSc and should be addressed in future studies.

Our study has several limitations. First, the limited sample size of this study does not allow solid conclusions to be drawn, necessitating further expansion of the sample size and further experimental research. Second, we used a retrospective design; thus, our results need confirmation in a prospective study.

In summary, patients with PBC-CREST manifested milder liver dysfunction associated with PBC and a lower prevalence of cirrhosis. A higher prevalence of ACA positivity, a lower prevalence of AMA positivity, and a better prognosis were found in patients with PBC-CREST than in patients with PBC alone.

ACA

anti-centromere antibody

ALB

albumin

ALP

alkaline phosphatase

ALT

alanine aminotransferase

AMA

anti-mitochondrial antibody

ANA

antinuclear antibody

AST

aspartate aminotransferase

bezafibrate

CMV

cytomegalovirus

EBV

Epstein‒Barr virus

ELISA

enzyme-linked immunosorbent assay

GGT

gamma-glutamyltransferase

H&E or HE

hematoxylin and eosin

HAV

hepatitis A virus

HBV

hepatitis B virus

healthy control

HCV

hepatitis C virus

HLA

human leukocyte antigen

IQRs

interquartile ranges

immunoglobulin

interleukin

lcSSc

limited cutaneous systemic sclerosis

LRD

liver-related death

liver transplantation

PBC

primary biliary cholangitis

PLT

platelet

PSL

prednisolone

prothrombin time

SSc

systemic sclerosis

total bilirubin

UDCA

ursodeoxycholic acid.

Acknowledgments

The authors thank Chikako Saito and Rie Hikichi for technical assistance.

Authors’ contributions

Conceived and designed the experiments: KA and HO. Analyzed the data: KA. Contributed materials: KA, AT, MF, MH, TS, NA, and YT. Wrote the paper: KA, KM and HO.

Competing interests

None to declare.

Funding

There was no additional external funding received for this study.

Data availability

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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No competing interests reported.

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Evaluation of GLOBE and UK-PBC Scores and Long- Term Outcomes in Primary Biliary Cholangitis Complicated with CREST Syndrome

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Version 1

Abstract

Aim

Methods

Results

Conclusions

Figures

Introduction

Methods

STUDY DESIGN AND PATIENT POPULATION

LIVER HISTOLOGY

ETHICS STATEMENT

CALCULATION OF THE GLOBE SCORE

CALCULATION OF THE UK-PBC RISK SCORE

STATISTICAL ANALYSIS

Results

BASELINE CHARACTERISTICS

ANALYSIS OF SURVIVAL AFTER UDCA TREATMENT

MULTIVARIATE ANALYSIS OF FACTORS ASSOCIATED WITH LIVER CIRRHOSIS IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS

EFFECTS OF UDCA TREATMENT ON LIVER BIOCHEMISTRY

ANALYSIS OF GLOBE SCORES AFTER UDCA TREATMENT

ANALYSIS OF UK-PBC RISK SCORES AFTER UDCA TREATMENT

Discussion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1