Title: High neutrophil-lymphocyte ratio indicates a worse response to ursodeoxycholic acid in
primary biliary cholangitis: a retrospective cohort study
Version: 2 Date: 05 Oct 2023
Reviewer's report:
In this study, Huiling Zhu and colleagues, aimed to elucidate the changes in Neutrophil-to-
lymphocyte (NLR)  in response to one-year UDCA treatment of  primary biliary cholangitis
(PBC) patients. Overall,  they studied 257 PBC patients treated with UDCA (13–15 mg/kg/
d). The response to treatment was evaluated based on alkaline phosphatase levels < 1.67 times
the upper limit of the normal value after 12 months of UDCA treatment. Multivariable logistic
regression analysis was performed to investigate the association between NLR at baseline and
the response to 12- month UDCA treatment after adjusting for important confounding variables.
The quartiles of increased baseline NLR was assessed as a predictor of future nonresponse to
UDCA treatment.
By multiple regression analysis, they found that NLR at baseline was positively associated with
the nonresponse to UDCA treatment after adjustments for potential confounders (age, sex, BMI,
hypertension, arterial plaque, thyroid disease, jaundice, albumin, globulin, total bile acid, ALP,
GGT, LDLC, total cholesterol, hemoglobin, and APTT) (OR = 1.370, 95% CI 1.066-1.761).
Whether NLR was translated into a categorical variable, the OR and 95% CI in the fourth quartile
versus the first quartile was OR = 3.782, 95% CI 1.094-13.073, respectively (P for trend = 0.036).
Thus, they concluded that study results show that NLR is an independent risk factor of UDCA
treatment nonresponse.
The study has clinical interest, however some adjunctive informations are required and should
be provided.
-Enrolled patients: the authors stated that patients could be diagnosed with PBC when two of
the following three criteria were fulfilled: (1) elevated ALP in the liver biochemical indicators;
(2) positive serum AMA or the AMA-M2 subtype; and (3) manifestations of nonsuppurative
cholangitis and intrahepatic interlobular bile duct destruction established through liver biopsy.
However,  according to EASL guidelines, the diagnosis of PBC may be done also in the absence
of AMA when some antinuclear antibodies (the so-called ANA-PBC specific), in particular anti-
Sp10O and anti-gp210 antibodies are positive since these autoantibodies displyed a very high
PBC-specificity in a pivotal study addressing the PBC specificity of anti-Sp10O and anti-gp210
antibodies in more than 4000 sera, as previousle described (Antinuclear antibodies giving the
'multiple nuclear dots' or the 'rim-like/membranous' patterns: diagnostic accuracy for primary
biliary cirrhosis. Aliment Pharmacol Ther. 2006 Dec;24(11-12):1575-83.). This point is of
major clinical relevance because anti-gp210 antibodies display also a prognostic significance,
in particular are signifcantly associated to a lower response rate to UDCA therapy and risk of
disease progression as well-described in a comprehensive review addressing the role of ANA
in PBC ( Antinuclear antibodies as ancillary markers in primary biliary cirrhosis. Expert Rev
Mol Diagn. 2012 Jan;12(1):65-74.).
-discussing the prognostic factors associated to UDCA treatment response, the authors should
also evaluate the rate of theri patients who presented fatigue and pruritus at the diagnosis
since these two symptoms have a negative prognostic significance as previously demonstrated
(Fatigue and pruritus at onset identify a more aggressive subset of primary biliary cirrhosis.
Liver Int. 2015 Feb;35(2):636-41. ). The authors should discuss this important literature study.
-the last point worth mentioning and discussing, is the presence of PBC patients displaying
features suggestive for an overla AIH-PBC syndrome. In this regard, as recalled by the EASL
guidelines, PBC patients displaying the concomitant seropositivity of AMA and anti-double
stranded DNA antibodies (anti-ds-DNA) are those with concomitant clinical and histological
features of AIH-PBC overla syndrome, as previousle demonstrated (The serological profile of
the autoimmune hepatitis/primary biliary cirrhosis overlap syndrome. Am J Gastroenterol. 2009
Jun;104(6):1420-5. ). The authors should exclude this condition in their patients and recall this
important literature study.
Title: High neutrophil-lymphocyte ratio indicates a worse response to ursodeoxycholic acid in
primary biliary cholangitis: a retrospective cohort study
Version: 2 Date: 05 Oct 2023
Reviewer's report:
In this study, Huiling Zhu and colleagues, aimed to elucidate the changes in Neutrophil-to-
lymphocyte (NLR)  in response to one-year UDCA treatment of  primary biliary cholangitis
(PBC) patients. Overall,  they studied 257 PBC patients treated with UDCA (13–15 mg/kg/
d). The response to treatment was evaluated based on alkaline phosphatase levels < 1.67 times
the upper limit of the normal value after 12 months of UDCA treatment. Multivariable logistic
regression analysis was performed to investigate the association between NLR at baseline and
the response to 12- month UDCA treatment after adjusting for important confounding variables.
The quartiles of increased baseline NLR was assessed as a predictor of future nonresponse to
UDCA treatment.
By multiple regression analysis, they found that NLR at baseline was positively associated with
the nonresponse to UDCA treatment after adjustments for potential confounders (age, sex, BMI,
hypertension, arterial plaque, thyroid disease, jaundice, albumin, globulin, total bile acid, ALP,
GGT, LDLC, total cholesterol, hemoglobin, and APTT) (OR = 1.370, 95% CI 1.066-1.761).
Whether NLR was translated into a categorical variable, the OR and 95% CI in the fourth quartile
versus the first quartile was OR = 3.782, 95% CI 1.094-13.073, respectively (P for trend = 0.036).
Thus, they concluded that study results show that NLR is an independent risk factor of UDCA
treatment nonresponse.
The study has clinical interest, however some adjunctive informations are required and should
be provided.
-Enrolled patients: the authors stated that patients could be diagnosed with PBC when two of
the following three criteria were fulfilled: (1) elevated ALP in the liver biochemical indicators;
(2) positive serum AMA or the AMA-M2 subtype; and (3) manifestations of nonsuppurative
cholangitis and intrahepatic interlobular bile duct destruction established through liver biopsy.
However,  according to EASL guidelines, the diagnosis of PBC may be done also in the absence
of AMA when some antinuclear antibodies (the so-called ANA-PBC specific), in particular anti-
Sp10O and anti-gp210 antibodies are positive since these autoantibodies displyed a very high
PBC-specificity in a pivotal study addressing the PBC specificity of anti-Sp10O and anti-gp210
antibodies in more than 4000 sera, as previousle described (Antinuclear antibodies giving the
'multiple nuclear dots' or the 'rim-like/membranous' patterns: diagnostic accuracy for primary
biliary cirrhosis. Aliment Pharmacol Ther. 2006 Dec;24(11-12):1575-83.). This point is of
major clinical relevance because anti-gp210 antibodies display also a prognostic significance,
in particular are signifcantly associated to a lower response rate to UDCA therapy and risk of
disease progression as well-described in a comprehensive review addressing the role of ANA
in PBC ( Antinuclear antibodies as ancillary markers in primary biliary cirrhosis. Expert Rev
Mol Diagn. 2012 Jan;12(1):65-74.).
-discussing the prognostic factors associated to UDCA treatment response, the authors should
also evaluate the rate of theri patients who presented fatigue and pruritus at the diagnosis
since these two symptoms have a negative prognostic significance as previously demonstrated
(Fatigue and pruritus at onset identify a more aggressive subset of primary biliary cirrhosis.
Liver Int. 2015 Feb;35(2):636-41. ). The authors should discuss this important literature study.
-the last point worth mentioning and discussing, is the presence of PBC patients displaying
features suggestive for an overla AIH-PBC syndrome. In this regard, as recalled by the EASL
guidelines, PBC patients displaying the concomitant seropositivity of AMA and anti-double
stranded DNA antibodies (anti-ds-DNA) are those with concomitant clinical and histological
features of AIH-PBC overla syndrome, as previousle demonstrated (The serological profile of
the autoimmune hepatitis/primary biliary cirrhosis overlap syndrome. Am J Gastroenterol. 2009
Jun;104(6):1420-5. ). The authors should exclude this condition in their patients and recall this
important literature study.
Please review this paper.
user
Title: High neutrophil-lymphocyte ratio indicates a worse response to ursodeoxycholic acid in
primary biliary cholangitis: a retrospective cohort study
Version: 2 Date: 05 Oct 2023
Reviewer's report:
In this study, Huiling Zhu and colleagues, aimed to elucidate the changes in Neutrophil-to-
lymphocyte (NLR)  in response to one-year UDCA treatment of  primary biliary cholangitis
(PBC) patients. Overall,  they studied 257 PBC patients treated with UDCA (13–15 mg/kg/
d). The response to treatment was evaluated based on alkaline phosphatase levels < 1.67 times
the upper limit of the normal value after 12 months of UDCA treatment. Multivariable logistic
regression analysis was performed to investigate the association between NLR at baseline and
the response to 12- month UDCA treatment after adjusting for important confounding variables.
The quartiles of increased baseline NLR was assessed as a predictor of future nonresponse to
UDCA treatment.
By multiple regression analysis, they found that NLR at baseline was positively associated with
the nonresponse to UDCA treatment after adjustments for potential confounders (age, sex, BMI,
hypertension, arterial plaque, thyroid disease, jaundice, albumin, globulin, total bile acid, ALP,
GGT, LDLC, total cholesterol, hemoglobin, and APTT) (OR = 1.370, 95% CI 1.066-1.761).
Whether NLR was translated into a categorical variable, the OR and 95% CI in the fourth quartile
versus the first quartile was OR = 3.782, 95% CI 1.094-13.073, respectively (P for trend = 0.036).
Thus, they concluded that study results show that NLR is an independent risk factor of UDCA
treatment nonresponse.
The study has clinical interest, however some adjunctive informations are required and should
be provided.
-Enrolled patients: the authors stated that patients could be diagnosed with PBC when two of
the following three criteria were fulfilled: (1) elevated ALP in the liver biochemical indicators;
(2) positive serum AMA or the AMA-M2 subtype; and (3) manifestations of nonsuppurative
cholangitis and intrahepatic interlobular bile duct destruction established through liver biopsy.
However,  according to EASL guidelines, the diagnosis of PBC may be done also in the absence
of AMA when some antinuclear antibodies (the so-called ANA-PBC specific), in particular anti-
Sp10O and anti-gp210 antibodies are positive since these autoantibodies displyed a very high
PBC-specificity in a pivotal study addressing the PBC specificity of anti-Sp10O and anti-gp210
antibodies in more than 4000 sera, as previousle described (Antinuclear antibodies giving the
'multiple nuclear dots' or the 'rim-like/membranous' patterns: diagnostic accuracy for primary
biliary cirrhosis. Aliment Pharmacol Ther. 2006 Dec;24(11-12):1575-83.). This point is of
major clinical relevance because anti-gp210 antibodies display also a prognostic significance,
in particular are signifcantly associated to a lower response rate to UDCA therapy and risk of
disease progression as well-described in a comprehensive review addressing the role of ANA
in PBC ( Antinuclear antibodies as ancillary markers in primary biliary cirrhosis. Expert Rev
Mol Diagn. 2012 Jan;12(1):65-74.).
-discussing the prognostic factors associated to UDCA treatment response, the authors should
also evaluate the rate of theri patients who presented fatigue and pruritus at the diagnosis
since these two symptoms have a negative prognostic significance as previously demonstrated
(Fatigue and pruritus at onset identify a more aggressive subset of primary biliary cirrhosis.
Liver Int. 2015 Feb;35(2):636-41. ). The authors should discuss this important literature study.
-the last point worth mentioning and discussing, is the presence of PBC patients displaying
features suggestive for an overla AIH-PBC syndrome. In this regard, as recalled by the EASL
guidelines, PBC patients displaying the concomitant seropositivity of AMA and anti-double
stranded DNA antibodies (anti-ds-DNA) are those with concomitant clinical and histological
features of AIH-PBC overla syndrome, as previousle demonstrated (The serological profile of
the autoimmune hepatitis/primary biliary cirrhosis overlap syndrome. Am J Gastroenterol. 2009
Jun;104(6):1420-5. ). The authors should exclude this condition in their patients and recall this
important literature study.
assistant