Title: Primary biliary cholangitis has causal effects on systemic rheumatic diseases: A
Mendelian randomization study
Version: 2 Date: 11 Jun 2024
Reviewer's report:
In this study, the authors aimed to valuate the causal effects of primary biliary cholangitis (PBC)
on systemic rheumatic diseases (SRDs) through Mendelian randomization (MR).
They used the genome-wide association study (GWAS) summary data obtained from MRC IEU
OpenGWAS and FinnGen databases. Independent genetic variants for PBC were selected as
instrumental variables. Inverse variance weighted was used as the main approach to evaluate the
causal effects of PBC on the following SRDs: Sjögren syndrome (SS), rheumatoid arthritis (RA),
systemic lupus erythematosus (SLE), systemic sclerosis (SSc), mixed connective tissue disease
(MCTD) and polymyositis (PM). Horizontal pleiotropy and heterogeneity were measured by
MR#Egger intercept test and Cochran's Q value, respectively. The MR results demonstrated a
positive causal effects of PBC on SRDs, indicating casual effects on various SRDs.
This study is of interest and of clinical significance. However, the following points should
be addressed to further improve the clinical impact: 1) As reported, all PBC cases fulfilled
the American Association for the Study of Liver Disease criteria for PBC. However, SRDs
diagnostic criteria are not reported, but only ICD codes. The authors should reported the
diagnostic criteria of SS, RA, SLE, SSc, MCTD, and PM; 2)  Discussion: to further support the
study results, the authors should recall important previous literature data supporting the concept
that PBC represents on overlap condition between autoimmune hepatology and rheumatology
since PBC patients are characterized by serum positivity of autoantibodies classically detected
in rheumatological patients such as SS-A/Ro-52kD and centromere as previously demonstrated
(Aliment Pharmacol Ther. 2007 Sep 15;26(6):831-8. doi: 10.1111/j.1365-2036.2007.03433.x. )
and the so-called PBC-specific antinuclea r antibodies such as ANA exhibiting the Multiple
Nuclear Dots (MND) or the Rim-Like immunofluorescence patters are detected in SLE, SSc
and SjS, as previously demonstrated (Alimentary Pharmacology and Therapeutics 2006;24
(11-12):1575 - 1583; DOI 10.1111/j.1365-2036.2006.03172.x). Importantly, autoantibodies
directed against nuclear body component such as sp140 protein, have been indentified in
PBC patients , as previously demonstrated (Am J Gastroenterol. 2010 Jan;105(1):125-31. doi:
10.1038/ajg.2009.596.) and may have a pathogenetic significance on both rheumatological
patients and PBC patients, thus supporting the immunological link between rheumatological
disorders and PBC.
Title: Primary biliary cholangitis has causal effects on systemic rheumatic diseases: A
Mendelian randomization study
Version: 2 Date: 11 Jun 2024
Reviewer's report:
In this study, the authors aimed to valuate the causal effects of primary biliary cholangitis (PBC)
on systemic rheumatic diseases (SRDs) through Mendelian randomization (MR).
They used the genome-wide association study (GWAS) summary data obtained from MRC IEU
OpenGWAS and FinnGen databases. Independent genetic variants for PBC were selected as
instrumental variables. Inverse variance weighted was used as the main approach to evaluate the
causal effects of PBC on the following SRDs: Sjögren syndrome (SS), rheumatoid arthritis (RA),
systemic lupus erythematosus (SLE), systemic sclerosis (SSc), mixed connective tissue disease
(MCTD) and polymyositis (PM). Horizontal pleiotropy and heterogeneity were measured by
MR#Egger intercept test and Cochran's Q value, respectively. The MR results demonstrated a
positive causal effects of PBC on SRDs, indicating casual effects on various SRDs.
This study is of interest and of clinical significance. However, the following points should
be addressed to further improve the clinical impact: 1) As reported, all PBC cases fulfilled
the American Association for the Study of Liver Disease criteria for PBC. However, SRDs
diagnostic criteria are not reported, but only ICD codes. The authors should reported the
diagnostic criteria of SS, RA, SLE, SSc, MCTD, and PM; 2)  Discussion: to further support the
study results, the authors should recall important previous literature data supporting the concept
that PBC represents on overlap condition between autoimmune hepatology and rheumatology
since PBC patients are characterized by serum positivity of autoantibodies classically detected
in rheumatological patients such as SS-A/Ro-52kD and centromere as previously demonstrated
(Aliment Pharmacol Ther. 2007 Sep 15;26(6):831-8. doi: 10.1111/j.1365-2036.2007.03433.x. )
and the so-called PBC-specific antinuclea r antibodies such as ANA exhibiting the Multiple
Nuclear Dots (MND) or the Rim-Like immunofluorescence patters are detected in SLE, SSc
and SjS, as previously demonstrated (Alimentary Pharmacology and Therapeutics 2006;24
(11-12):1575 - 1583; DOI 10.1111/j.1365-2036.2006.03172.x). Importantly, autoantibodies
directed against nuclear body component such as sp140 protein, have been indentified in
PBC patients , as previously demonstrated (Am J Gastroenterol. 2010 Jan;105(1):125-31. doi:
10.1038/ajg.2009.596.) and may have a pathogenetic significance on both rheumatological
patients and PBC patients, thus supporting the immunological link between rheumatological
disorders and PBC.
Please review this paper.
user
Title: Primary biliary cholangitis has causal effects on systemic rheumatic diseases: A
Mendelian randomization study
Version: 2 Date: 11 Jun 2024
Reviewer's report:
In this study, the authors aimed to valuate the causal effects of primary biliary cholangitis (PBC)
on systemic rheumatic diseases (SRDs) through Mendelian randomization (MR).
They used the genome-wide association study (GWAS) summary data obtained from MRC IEU
OpenGWAS and FinnGen databases. Independent genetic variants for PBC were selected as
instrumental variables. Inverse variance weighted was used as the main approach to evaluate the
causal effects of PBC on the following SRDs: Sjögren syndrome (SS), rheumatoid arthritis (RA),
systemic lupus erythematosus (SLE), systemic sclerosis (SSc), mixed connective tissue disease
(MCTD) and polymyositis (PM). Horizontal pleiotropy and heterogeneity were measured by
MR#Egger intercept test and Cochran's Q value, respectively. The MR results demonstrated a
positive causal effects of PBC on SRDs, indicating casual effects on various SRDs.
This study is of interest and of clinical significance. However, the following points should
be addressed to further improve the clinical impact: 1) As reported, all PBC cases fulfilled
the American Association for the Study of Liver Disease criteria for PBC. However, SRDs
diagnostic criteria are not reported, but only ICD codes. The authors should reported the
diagnostic criteria of SS, RA, SLE, SSc, MCTD, and PM; 2)  Discussion: to further support the
study results, the authors should recall important previous literature data supporting the concept
that PBC represents on overlap condition between autoimmune hepatology and rheumatology
since PBC patients are characterized by serum positivity of autoantibodies classically detected
in rheumatological patients such as SS-A/Ro-52kD and centromere as previously demonstrated
(Aliment Pharmacol Ther. 2007 Sep 15;26(6):831-8. doi: 10.1111/j.1365-2036.2007.03433.x. )
and the so-called PBC-specific antinuclea r antibodies such as ANA exhibiting the Multiple
Nuclear Dots (MND) or the Rim-Like immunofluorescence patters are detected in SLE, SSc
and SjS, as previously demonstrated (Alimentary Pharmacology and Therapeutics 2006;24
(11-12):1575 - 1583; DOI 10.1111/j.1365-2036.2006.03172.x). Importantly, autoantibodies
directed against nuclear body component such as sp140 protein, have been indentified in
PBC patients , as previously demonstrated (Am J Gastroenterol. 2010 Jan;105(1):125-31. doi:
10.1038/ajg.2009.596.) and may have a pathogenetic significance on both rheumatological
patients and PBC patients, thus supporting the immunological link between rheumatological
disorders and PBC.
assistant