A meta-analysis was performed of RCTs comparing therapies that combine UDCA and corticosteroids with UDCA monotherapy. In this paper, we found that the combination therapy of UDCA and corticosteroids was more effective for PBC-AIH.
Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) are two autoimmune diseases that have major effects on the liver. Each disease has its own clinical manifestations and immunological and histological features [
The relevant studies were identified and selected by searching the databases PubMed, Cochrane Library, EMBASE, CINAHL, and the Science Citation Index (updated to June 2013) [
The following selection criteria were applied: (i) study design: RCT comparing combination therapy with UDCA/corticosteroids and monotherapy with UDCA; and (ii) study population: patients with PBC with features of AIH identified according to the Paris criteria [
The data were independently abstracted from each study by the two researchers (Yan Zhang and Jie Lu) and any disagreement was resolved by consensus. The following data were extracted from each included article: name of the first author, year of publication, number of patients, daily dose of oral therapy, duration of treatment, method used to deal with missing data, liver biochemistry (AP, ALT, aspartate aminotransferase (AST), GGT, IgG, IgM), symptoms, liver histology, death, liver transplantation, death and/or transplantation, and adverse events.
The methodological quality of the studies included in the meta-analysis was scored with the Jadad composite scale (Table
Criteria used to grade the quality of RCTs: the Jadad scores.
Each study was given one point for each “yes” and 0 points for each “no” in response to each of the following questions. | |
---|---|
(1) Was the study described as randomized using the words “randomly”, “random”, or “randomization”? | |
(a) An additional point was given if the method of randomization was described and was appropriate (e.g., table of random numbers, computer generated). | |
(b) A point was deducted if the method of randomization was inappropriate (e.g., patients allocated alternately, by birth date, or by hospital number). | |
(2) Was the study described as “double blind”? | |
(a) A point was given if the method of blinding was described and it was appropriate (e.g., identical placebo). | |
(b) An additional point was deducted if the method of blinding was inappropriate (e.g., comparing placebo tablet with injection). | |
(3) Was there a description of the patients who withdrew or dropped out? | |
The maximum number of points was 5. |
All analyses were performed with RevMan5.2 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). The odds ratio (OR) for each clinical event was presented with its 95% confidence interval (CI). We tested heterogeneity by using the
From 1237 studies, we finally selected seven RCTs (Figure
Baseline characteristics of the trials included in the meta-analysis.
Authors | Mean age (years) | Monotherapy ( |
Combination therapy ( |
UDCA dose (mg·kg−1·d−1) | Corticosteroids dose (mg·kg−1·d−1) | Duration of treatment | Publication type |
---|---|---|---|---|---|---|---|
Chazouillères et al. [ |
50 | 5 | 6 | 13–15 | 0.5 | 23 m | Full text |
Günsar et al. [ |
44 | 13 | 7 | 13 | 0.5 | 28 m | Full text |
Chazouillères et al. [ |
41 | 11 | 6 | 13–15 | 0.5 | 90 m | Full text |
Heurgué et al. [ |
44 | 9 | 4 | 11–14.7 | 0.5–1 | 60 m | Full text |
Ozaslan et al. [ |
44 | 3 | 9 | 13–15 | 0.5 | 31 m | Full text |
Tanaka et al. [ |
54 | 15 | 10 | 10 | 0.5 | 73 m | Full text |
Zhu et al. [ |
50 | 11 | 8 | 13–15 | 0.5–1 | 10 m | Full text |
Jadad quality scores of the trials included in the meta-analysis.
Study | Randomization method | Double blinding | Withdrawals dropouts | Total |
---|---|---|---|---|
Chazouillères et al. [ |
2 | 2 | 1 | 5 |
Günsar et al. [ |
1 | 2 | 1 | 4 |
Chazouillères et al. [ |
2 | 2 | 1 | 5 |
Heurgué et al. [ |
2 | 1 | 1 | 4 |
Ozaslan et al. [ |
1 | 2 | 1 | 4 |
Tanaka et al. [ |
1 | 1 | 0 | 2 |
Zhu et al. [ |
2 | 2 | 1 | 5 |
Descriptive results of the randomized trials.
Authors | Symptoms improved | Liver-biochemistry improved | Histology progression | Death | Death or liver transplantation | Adverse events | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
UDCA | COM. | UDCA | COM. | UDCA | COM. | UDCA | COM. | UDCA | COM. | UDCA | COM. | |
Chazouillères et al. [ |
2/5 | 3/6 | 2/5 | 6/6 | 3/5 | 0/2 | 1/5 | 0/6 | 1/5 | 0/6 | 1/5 | 2/6 |
Günsar et al. [ |
1/16 | 0/7 | 8/16 | 7/7 | 5/8 | 1/7 | 0/16 | 1/7 | 0/16 | 1/7 | 1/16 | 0/7 |
Chazouillères et al. [ |
3/11 | 0/6 | 4/11 | 6/6 | 4/8 | 0/4 | NR | NR | 0/11 | 1/6 | NR | NR |
Heurguè et al. [ |
1/6 | 1/4 | 3/6 | 3/4 | 3/6 | 1/4 | NR | NR | 0/6 | 0/4 | NR | NR |
Ozaslan et al. [ |
3/3 | 3/9 | 3/3 | 3/9 | 0/3 | 6/9 | 0/3 | 2/9 | 0/3 | 3/9 | NR | NR |
Tanaka et al. [ |
3/15 | 1/10 | 8/15 | 10/10 | 7/15 | 0/10 | 0/15 | 1/10 | 0/15 | 1/10 | NR | NR |
Zhu et al. [ |
0/11 | 0/8 | 6/11 | 8/8 | 3/3 | 0/3 | NR | NR | 0/11 | 0/8 | 2/11 | 1/8 |
UDCA: monotherapy with ursodeoxycholic acid; COM: combination therapy with UDCA and corticosteroids; NR: not reported.
Flow diagram of the studies included in the meta-analysis.
The seven RCTs reported the impact of the treatments on the patients’ symptoms, but only three studies [
Seven trials [
Effects of monotherapy versus combination therapy on pruritus and jaundice in patients with PBC-AIH.
Seven trials, including 117 patients, reported data regarding these endpoints. The symptoms improved in 34 of 67 patients in the monotherapy groups and in 43 of 50 patients in the combination therapy groups. There was no significant heterogeneity (
Biochemical parameters of patients treated with monotherapy versus combination therapy for PBC-AIH.
Seven trials, including 117 patients, reported data regarding these endpoints. The symptoms improved in 36 of 67 patients in the monotherapy groups and in 42 of 50 patients in the combination therapy groups. There was no significant heterogeneity (
IgG and IgM levels in patients treated with monotherapy versus combination therapy for PBC-AIH.
Of the 117 patients (seven trials) who underwent second biopsies, histology declined in 25 of 48 patients in the monotherapy groups and in eight of 39 patients in the combination therapy groups. There was no significant heterogeneity (
Histological progression in patients treated with monotherapy versus combination therapy for PBC-AIH.
Four trials [
Death in patients treated with monotherapy versus combination therapy for PBC-AIH.
Seven trials, including 117 patients, reported data regarding this endpoint. It was showen in one of 67 patients in the monotherapy groups and in six of 50 patients in the combination therapy groups. There was no significant heterogeneity (
Death or liver transplantation in patients treated with monotherapy versus combination therapy for PBC-AIH.
Three trials [
Adverse events in patients treated with monotherapy versus combination therapy for PBC-AIH.
A sensitivity analysis was performed of the six trials in which mid-dose UDCA (mean dose 13–15 mg kg−1 per day) was administered. The analysis indicated no differences in clinical events, histological liver changes, or the rate of death/liver transplantation between the UDCA monotherapy groups and the groups receiving a combination therapy of UDCA and corticosteroid. Only one study was a low-quality study (Jadad score ≤ 2). Thus, the meta-analytical results did not change after the exclusion of this study. A period of one year is commonly considered to be too short to evaluate the survival of PBC-AIH patients. Therefore, another sensitivity analysis was performed, including only those studies of long duration (≥24 months). Two trials [
Figure
Funnel plots for the meta-analysis.
Symptoms of fatigue and jaundice
Liver biochemical parameters (ALT and AP)
Histopathological assessment
Adverse events
The pathogenesis of PBC with features of AIH is unclear [
In this study, we applied stringent inclusion criteria so that the selected studies would have a tight design, good homogeneity, and high credibility. There were no significant differences in the baseline characteristics of the patients in any of the selected studies (e.g., age, sex, race, and serological markers) and little selection bias. However, our systematic review included only studies published in English or any unpublished studies (such as symposium conference records, conference papers, and literature-based evidence from nontraditional sources), which may have led to language bias and publication bias. The funnel plot analyses of symptoms, liver biochemistry, and histopathology showed asymmetry, indicating that there was a certain publication bias.
This study has shown that the combination therapy did not differ significantly from the monotherapy in improving fatigue, jaundice, mortality, death/liver transplantation, or adverse events, but was significantly superior to the monotherapy in reducing serum AP, ALT, and other biochemical liver markers. This may be attributable to the effects of corticosteroids in reducing cell edema and relieving the inflammation of the bile duct cells and liver cells [
Three of the included RCTs [
(1) The number of studies included in this analysis was small. Furthermore, allocation concealment and blinding will have affected the results [
(2) Although this research utilized important markers, including mortality, liver transplantation, symptom improvement, and biochemical indicators, quality of life is an equally important indicator. An improvement in the patient’s quality of life can determine whether the treatment is truly effective. The Cochrane Collaboration values quality of life as the major measure of treatment efficacy. However, none of the seven papers included in this study measured quality of life. Future studies should consider quality of life as an important indicator of treatment efficacy.
In summary, we recommend that patients diagnosed with the presymptomatic or symptomatic stages of PBC with features of AIH undertake early therapy combining UDCA and corticosteroids, even though there is currently no cure for the disease. This therapy is safe and effective for these patients and can improve their liver biochemistry indicators. Extended treatment may improve the pathological status of the liver, thereby delaying disease progression and improving the patient’s quality of life, prolonging his/her life, and reducing the burden on the patient. During treatment with corticosteroids, any opportunity to reduce the dose should be taken, and close observation of the adverse effects of corticosteroids is required, including bleeding, fractures, high blood sugar, high blood pressure, high cholesterol, pancytopenia, and severe infections. Naloxone can be given for itching. Proton pump inhibitors can cure acid reflux and can also prevent stress ulcer bleeding. Oral calcium and vitamin D supplementation can prevent osteoporosis. We suggest that an animal model of autoimmune liver disease should be established and improved in the near future to facilitate research into the pathogenesis of autoimmune liver diseases and target therapies [
The authors declare that they have no conflict of interests.
This study was supported by the National Natural Science Foundation of China (Grant nos. 81270515, 81300340); the Shanghai Science and Technology Foundation (Grant no. 11430702400); the Chinese Foundation for Hepatitis Prevention and Control (Grant nos. WBN20100021, TQ20120005); and the Shanghai Municipal Health Bureau Foundation (Grant no. 2011287, 2012107).