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Maybury CM, Porter HF, Kloczko E, et al. Prevalence of Advanced Liver Fibrosis in Patients With Severe Psoriasis. JAMA Dermatol. Published online June 05, 2019. doi:10.1001/jamadermatol.2019.0721
Which clinical factors are associated with advanced liver fibrosis in severe psoriasis?
In a cohort study of 333 patients with severe psoriasis, results of cross-sectional analysis indicated that 14.1% (47 patients) of the cohort had advanced liver fibrosis. Clinical factors significantly associated with advanced fibrosis were increased central obesity, insulin resistance, and severity of psoriasis disease.
This study suggests that people with severe psoriasis should be screened for advanced liver fibrosis irrespective of which systemic medication they are receiving; obesity and insulin resistance should be proactively managed to prevent the potential poor prognosis associated with advanced liver fibrosis in this population.
Advanced liver fibrosis is a precursor to cirrhosis, a leading cause of mortality. People with severe psoriasis are at risk for liver disease, but our understanding of advanced fibrosis in individuals with psoriasis is limited.
To describe the prevalence of and evaluate the clinical factors associated with advanced liver fibrosis in people with severe psoriasis.
Design, Setting, and Participants
The Co-morbidities in Severe Psoriasis study, a prospective observational cohort study in a large center serving London and Southeast England, was conducted from October 18, 2012, to April 2, 2015; 400 adults with severe psoriasis (Psoriasis Area Severity Index score, ≥10) were recruited from outpatient clinics. Statistical analysis was conducted from October 2, 2016, to March 3, 2017.
Main Outcomes and Measures
The primary outcome was a diagnosis of advanced liver fibrosis determined by transient elastography, a noninvasive criterion standard test. Clinical factors evaluated included psoriasis-specific and metabolic indices, alcohol use, and methotrexate exposure.
Of 400 patients recruited (108 women and 289 men; mean [SD] age, 49.5  years), 333 had a successful transient elastography scan and were included in final analysis. Forty-seven patients (14.1%; 95% CI, 10.4%-17.9%) had advanced liver fibrosis as diagnosed by transient elastography. The clinical factors that produced the best-fit model for advanced fibrosis were central obesity (waist circumference), insulin resistance, aspartate aminotransferase level, platelet count, psoriasis disease severity, and reduced alcohol use (R2 = 0.54).
Conclusions and Relevance
Findings from this study suggest that advanced fibrosis is common in severe psoriasis. Abdominal obesity (by waist circumference) and insulin resistance were associated with the presence of advanced fibrosis. Longitudinal work to characterize the hepatic sequelae of central obesity, insulin resistance, and inflammation as well as the influence of systemic drugs (methotrexate and biologics) will inform future personalized therapeutic decision-making.
ClinicalTrials.gov identifier: NCT02174367
Liver disease is a leading cause of global morbidity and mortality.1 When liver fibrosis reaches an advanced stage, progression to cirrhosis and hepatocellular carcinoma increases.1 People with psoriasis are more likely than matched controls in the general population to have advanced fibrosis.2 Historically, the cause of liver fibrosis in psoriasis was attributed to methotrexate. Methotrexate has remained the focus of attention in dermatological research and practice. Awareness of other clinical factors that cause liver fibrosis in psoriasis and how best to identify them is limited, which has hindered progress in clinical management.
People with psoriasis have high rates of obesity, insulin resistance, and diabetes,3 all independent risk factors for advanced liver fibrosis in the general population. The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)4 is an algorithm of fasting glucose and insulin levels used to measure insulin resistance. The HOMA-IR is associated with advanced liver fibrosis in people with nonalcoholic fatty liver disease (NAFLD)5 but to date has not been prospectively investigated in psoriasis in the context of liver fibrosis. Other potential factors associated with advanced fibrosis include alcohol use6 and severity of psoriasis.
Our aim was to describe the prevalence of advanced fibrosis in a population with severe psoriasis and to explore factors associated with advanced fibrosis in this cohort.
The Co-morbidities in Severe Psoriasis (CORE) study is a prospective observational cohort study conducted from October 18, 2012, to April 2, 2015. Patients were recruited during dermatology outpatient visits in a large specialist center (Guy’s and St Thomas’ Hospital) serving London and Southeast England. Transient elastography (TE) (Fibroscan) and a fasting blood collection were performed during a single study visit. This study was approved by the National Research Ethics Service (NRES London Bridge Committee). All participants provided written informed consent.
Adults 18 years or older with a diagnosis of severe chronic plaque psoriasis made by a dermatologist were eligible to participate in this study. Disease severity was determined by a current or previous Psoriasis Area Severity Index score (PASI) of 10 or more. Patients were enrolled irrespective of their current psoriasis treatment (eg, methotrexate and biologics).
The primary outcome was advanced fibrosis as determined by TE (≥8.7 kPa). Transient elastography is an accurate method to detect advanced fibrosis: the area under the receiver operating characteristic curve for advanced fibrosis using TE compared with biopsy in NAFLD is 0.93 (95% CI, 0.86-0.96). Transient elastography is recommended in recent US guidelines for the detection of advanced fibrosis in people with NAFLD.7 Using TE rather than biopsy enabled us to sample a larger proportion of our cohort. Other outcomes were any liver fibrosis (TE, ≥7 kPa) and NAFLD diagnosed by ultrasonography. We recorded potentially relevant covariates including demographics, psoriasis-specific factors, systemic medications, metabolic factors, alcohol use, and smoking status.
Statistical analysis was conducted from October 2, 2016, to March 3, 2017. Statistical analyses were performed using SPSS, version 22.0 (SPSS Inc) and R, version 3.3.2 (R Foundation for Statistical Computing). Descriptive statistics were performed on all covariates. Continuous variables with normal distribution were summarized using means and SDs and analyzed using t tests. Continuous variables with nonnormal distributions were summarized using medians and interquartile ranges and analyzed using Mann-Whitney tests. We computed categorical variables as frequencies and percentages and compared them with χ2or Fisher exact tests. All P values were from 2-sided tests and results were deemed statistically significant at P < .05.
First, we assessed all variables associated with the outcome of advanced fibrosis by univariate analysis. We further assessed all variables with P ≤ .05 and with missingness of 20% or less using stepwise variable selection to identify the best fitting model as determined by Bayesian Information Criterion.
To determine whether our cohort is representative of a wider population of individuals with severe psoriasis, we obtained permission to evaluate The Biomarkers of Systemic Treatment Outcomes in Psoriasis (BSTOP) database. The BSTOP study has recruited more than 4000 patients from more than 70 centers in the United Kingdom and Ireland (BSTOP study ethics reference 11/H0802/7). We compared demographics from participants in our study (CORE participants at Guy’s and St Thomas’ Hospital enrolled in BSTOP) with those of all other BSTOP participants.
Of the 400 patients recruited (108 women and 289 men; mean [SD] age, 49.5  years), 333 had an evaluable TE and were included in the analysis. There was a significant difference in mean waist measurement in those who completed TE (101 cm) compared with those who failed TE (113 cm), suggesting that our results may underestimate the prevalence of advanced fibrosis in this cohort.
A total of 135 patients (37%) were overweight (body mass index, 25 to <30 [calculated as weight in kilograms divided by height in meters squared]), 135 of 363 (37.2%) were obese (body mass index, >30), 247 (79%) had a raised waist circumference (https://www.idf.org), 184 (53%) were insulin resistant (HOMA-IR score,3 ≥2), 79 (22%) had type 2 diabetes, and 163 (50%) had NAFLD. Low levels of alcohol consumption were reported (see Table 1 for participant demographics). At enrollment, 66.6% of patients (251 of 377) were taking a biologic (adalimumab, 107 of 377 [28%]; etanercept, 77 of 377 [20%]; infliximab, 14 of 377 [4%]; ustekinumab, 52 of 377 [14%]; and secukinumab, 1 of 377 [0.27%]). A total of 85 patients (21%) were taking methotrexate, and according to patients’ history, 340 (85%) had been exposed to methotrexate. The mean methotrexate dosage was 15 mg weekly (interquartile range, 13.6-15.5 mg). Median duration of methotrexate exposure was 0.6 years (interquartile range, 0.0-2.4 years).
A total of 47 of 333 patients (14.1%; 95% CI, 10.4%-17.9%) had advanced fibrosis. In univariate analysis, there was a significant association between advanced fibrosis and age, severity of psoriasis, psoriatic arthritis, body mass index, waist circumference, metabolic syndrome, physical activity score, NAFLD, fasting glucose level, insulin resistance, and triglyceride, high-density lipoprotein, cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transferase levels. The best performing multivariate model for advanced fibrosis (R2 = 0.54) was a combination of increased central obesity (waist circumference), insulin resistance, psoriasis severity, aspartate aminotransferase level, platelet count, and reduced alcohol use (Table 2).
Receiver operating characteristic curve analysis determined that the best thresholds to detect advanced fibrosis were female waist measurement of 109 cm or above (area under the curve [AUC], 0.83), male waist measurement of 111 cm or above (AUC, 0.86), HOMA-IR (threshold, 3.65; AUC, 0.81), and aspartate aminotransferase level (threshold, 28.5 U/L [to convert to microkatals per liter, multiply by 0.0167]; AUC, 0.75). A total of 68 participants 20.4% (95% CI, 16.1%-24.8%) had any liver fibrosis. The best multivariate model for any liver fibrosis was a combination of waist measurement, HOMA-IR, and aspartate aminotransferase level.
Our population had equivalent waist circumference, body mass index, alcohol intake, and age to the wider UK and Ireland population with severe psoriasis (Table 3). The reference population had a higher median PASI score. The current study (CORE) recruited patients at any stage in therapy, whereas BSTOP study recruited patients at the initiation of systemic therapy. The difference in recruitment times may explain the discrepancy between the average PASI score at enrollment between Table 1 (CORE study) and Table 3 (BSTOP study).
To our knowledge, this is the largest data set published to prospectively evaluate the prevalence of and risk factors for advanced liver fibrosis in people with severe psoriasis. A total of 14.1% of our cohort had advanced liver fibrosis, a 7-fold increase compared with the prevalence in the general population8 and higher than the prevalence in overweight (2%) and obese (9%) populations in a Spanish study of 3076 individuals.2,9
Our data suggest that people with central obesity, insulin resistance, and active psoriasis are the most at risk for liver fibrosis. These parameters are not currently evaluated as part of routine care. In our study, most individuals with advanced fibrosis were not taking methotrexate and would not have been identified using current guidelines.
This study demonstrates the high prevalence of insulin resistance in a population with severe psoriasis and the association of insulin resistance with advanced liver fibrosis in this population, although smaller studies support these findings.10,11 It remains uncertain whether methotrexate contributes to advanced liver fibrosis in psoriasis, and if so, to what degree it contributes. In this study, methotrexate exposure was not associated with advanced liver fibrosis (consistent with other research12). However, a previous meta-analysis showed a small but significant progression of fibrosis after starting methotrexate.13 Methotrexate is a frequent cause of liver enzyme derangement,14 indicating hepatic inflammation; it is plausible this effect contributes to fibrosis over time. However, if use of methotrexate is a risk factor, it is not the only risk factor and for most patients it is unlikely to be the most important risk factor.
In our study low levels of alcohol use were reported, consistent with BSTOP. We acknowledge that this level of consumption is lower than in other studies of psoriasis.6 Use of a self-reported questionnaire introduces a risk of reporting bias.
Increased severity of psoriasis was associated with the outcome of advanced fibrosis. Previous studies have demonstrated that inflammation (the interleukin 17 pathway in particular) is an important factor in the development and progression of liver fibrosis,15 which may explain why advanced fibrosis is more prevalent in individuals with severe psoriasis compared with other chronic inflammatory diseases.11
The strengths of this study are the systematic evaluation of clinical factors associated with advanced fibrosis in a population with severe psoriasis that has been accurately phenotyped. Demographics in our cohort are comparable with those of a reference population (BSTOP study; N = 3722) but also with phase 3 trial populations in North America and Europe,16 supporting the generalizability of our findings. This study had low levels of missing data. Limitations include single-center cross-sectional analysis. In the absence of longitudinal data, we cannot report incident advanced fibrosis or estimate the degree of risk for individual variables.
Subsequent work should involve replication of our findings and longitudinal analysis of the associated clinical factors identified in this study (including exposure to methotrexate and biologics) to delineate the causality of advanced liver fibrosis in severe psoriasis.
The data in this study highlight the significant burden of insulin resistance and advanced liver fibrosis in individuals with severe psoriasis. We suggest that clinicians managing patients with severe psoriasis, cognizant of psoriasis-associated complications, engage with their management to improve outcomes for patients.
Accepted for Publication: March 14, 2019.
Corresponding Author: Jonathan N. Barker, MD, FRCP, St John’s Institute of Dermatology, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King’s College London, Ninth Floor, Tower Wing, Guy’s Hospital, London SE1, United Kingdom (email@example.com).
Published Online: June 5, 2019. doi:10.1001/jamadermatol.2019.0721
Author Contributions: Drs Maybury and Barker had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Maybury, Crook, Natas, Wong, Smith, Barker.
Acquisition, analysis, or interpretation of data: Maybury, Porter, Kloczko, Duckworth, Cotton, Thornberry, Dew, Crook, Miquel, Lewis, Wong, Smith, Barker.
Drafting of the manuscript: Maybury, Porter, Crook, Wong, Smith, Barker.
Critical revision of the manuscript for important intellectual content: Maybury, Kloczko, Duckworth, Cotton, Thornberry, Dew, Crook, Natas, Miquel, Lewis, Wong, Smith, Barker.
Statistical analysis: Maybury, Porter, Kloczko, Lewis, Wong, Smith, Barker.
Administrative, technical, or material support: Kloczko, Duckworth, Cotton, Thornberry, Dew, Natas, Wong.
Supervision: Lewis, Wong, Smith, Barker.
Conflict of Interest Disclosures: Drs Maybury and Barker reported receiving grants from Siemens and the National Institute for Health Research during the conduct of the study. Dr Barker reported receiving an investigator-led grant from Pfizer and funding from the National Institute for Health Research/Biomedical Research Centres. No other disclosures were reported.
Funding/Support: This study was supported in part by an investigator-initiated research grant from Pfizer Ltd. Siemens UK provided funding for the enhanced liver fibrosis tests to be performed. Drs Maybury, Porter, Smith, Barker, and Lewis acknowledge funding by the National Institute for Health Research Biomedical Research Centres based at Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London, and at the South London and Maudsley National Health Service Foundation Trust and King’s College London.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health.
Additional Contributions: David Stowe, Echosens, provided training in transient elastography. Diane Feskanich, MD, Brigham and Women’s Hospital, provided guidance on the physical activity score. Mr Stowe and Dr Feskanish were not compensated for their contributions. We thank the patients attending Guy’s and St Thomas’ severe psoriasis service who participated in this study and the research and clinical nurses and physicians within the severe psoriasis service at St John’s Institute of Dermatology. We acknowledge the enthusiastic collaboration of all patients, dermatologists, and specialist nurses in the UK and the Republic of Ireland who provided the Biomarkers of Systemic Treatment Outcomes in Psoriasis data. The principal investigators at the participating sites at the time of data collection are listed at https://www.kcl.ac.uk/ContensisManagedLinks/BSTOP-Protocol-Version-5.pdf. We also acknowledge the National Institute for Health Research Biomedical Research Centre based at Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London.
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