Methotrexate (MTX) is an effective immunosuppressive drug for moderate to severe psoriasis and psoriatic arthritis.1 2 It is considered relatively safe and cost-effective for long-term use. However, prolonged used of MTX can potentially cause liver fibrosis and fatty changes without alterations in liver enzymes. The mechanism of MTX-induced liver fibrosis is suspected to involve the production of extracellular adenosine, a pro-fibrotic agent.3

Although liver fibrosis can be evaluated by imaging or biochemical parameters, liver biopsy remains the gold standard for diagnosing liver fibrosis.4 However, it has limitations such as sampling error and poor feasibility for serial assessments. The rates of liver biopsy–associated morbidity and mortality are approximately 1% and 0.01% to 0.1%, respectively.5 6 The Roenigk scale is generally used to grade MTX-induced liver fibrosis,7 but other systems (eg, Ishak and METAVIR) have also been used for fibrosis assessment.8 9

The measurement of serum level of specific biomarkers such as the amino terminal of type III procollagen peptide can be used as alternative methods to assess liver fibrosis.10 11 12 13 However, these measurements are not widely available in many regions. Therefore, a sensitive and specific non-invasive technique is required to detect MTX-induced liver injury.

Transient elastography (TE) is a non-invasive method for assessing liver ‘hardness’ or stiffness that involves measuring the velocity of a vibration wave (ie, a shear wave) when travelling to a particular depth inside the liver, based on the principle that the wave velocity is greater in fibrotic tissue than in normal liver tissue. This technique has been used as a screening tool for liver cirrhosis in various conditions.14 15 16 17 In contrast to liver biopsy, TE allows the simultaneous assessment of a larger sampling area, is easily reproducible, and has low inter-observer variability and a low failure rate (<5%).15 Generally, a liver stiffness (LS) of ≤5 kilopascals (kPa) suggests a low probability of fibrosis, whereas a value of ≥7 kPa suggests a high likelihood of advanced fibrosis in patients with various chronic liver disorders.14 15 16 17 18 Thus far, there are limited data regarding TE accuracy and cut-off threshold in terms of detecting MTX-induced liver injury among Chinese psoriasis patients.

This study aimed to evaluate the performance (reliability) of TE in detecting significant liver fibrosis among psoriasis patients in the Chinese population, compared with gold-standard liver biopsy assessment using the Roenigk classification.

This cross-sectional single-centre study was conducted from 1 December 2019 to 31 March 2021. Patients with psoriasis and/or psoriatic arthritis undergoing regular follow-up in the dermatological clinic at a major tertiary hospital in Hong Kong were consecutively screened for inclusion (Fig 1). The inclusion criteria were as follows: age ≥18 years, clinical diagnosis of psoriasis with or without arthritis, and current use of MTX with a cumulative dosage of ≥150 mg or minimum duration of 6 months. Patients were excluded if they had known liver cirrhosis or concomitant chronic liver disease (including chronic hepatitis B or C infection, alcohol use disorder, Wilson’s disease, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and a history of hepatocellular carcinoma), had a condition that could influence TE accuracy (eg, ascites, severe renal disease, peritoneal dialysis, or severe cardiovascular insufficiency),14 15 16 17 18 refused to give consent, were pregnant, or had not been receiving MTX. After the acquisition of informed consent, all participants provided a thorough history and underwent a comprehensive examination.

Upon recruitment, clinical and metabolic measurements, including body weight, body mass index (BMI), systolic and diastolic blood pressure, and waist circumference, were recorded. The duration and cumulative dosage of MTX treatment, disease severity (measured by the Psoriasis Area and Severity Index), and body surface area (BSA) were documented. Laboratory parameters assessed included hepatitis B/C infection status, complete blood count, serum fasting glucose level, glycated haemoglobin (HbA1c) level, triglyceride level, low- and high-density lipoprotein cholesterol levels, liver enzyme levels (eg, aspartate aminotransferase and alanine aminotransferase), and renal function. Patient demographic data, co-morbidities (hypertension, diabetes, cardiovascular disease, chronic liver/renal disease, and alcoholic liver disease), and concomitant medications were collected from electronic medical records.

Transient elastography assessments were conducted within 1 month after recruitment. Liver stiffness was evaluated using the FibroScan ultrasonic imaging device (Echosens, Paris, France) and expressed as the median value (in kPa) after at least 10 successful acquisitions. Measurements were considered reliable if the success rate was ≥60%, combined with an interquartile range (IQR) of ≤30%.15 16 For patients with a BMI of <30 kg/m², an M probe was used; for those with a BMI of ≥30 kg/m², an XL probe was used. The controlled attenuation parameter (CAP) was also recorded to estimate liver steatosis, expressed in decibels per metre (dB/m).16 The investigators (senior research assistants trained to perform TE) were blinded to the patients’ clinical characteristics, MTX dosage, and previous liver ultrasound or biopsy results. Patients were instructed to fast for 4 hours prior to LS measurements. In previous studies involving Asian populations, significant liver fibrosis or cirrhosis was indicated by LS values of ≥7.1 kPa19 and >14.0 kPa,20 respectively. Therefore, in our study, significant liver fibrosis on TE was defined as LS ≥7.1 kPa.

A liver biopsy (to assess the degree of liver fibrosis by histology) was performed within 3 months after TE in patients who had significant liver fibrosis (ie, LS ≥7.1 kPa on TE) or a total cumulative dose (TCD) of MTX ≥3.5 g, with or without additional risk factors. This protocol was adopted based on international guidelines1 2 18 19 20 21 22 and previous studies in Asian populations.21 22 Ultrasound-guided core-needle liver biopsy procedures were performed by an experienced radiologist using a percutaneous approach.5 6

Histological assessments were conducted by a pathologist with expertise in hepatobiliary disorders, who was blinded to the TE results. The Roenigk scale was used to grade liver fibrosis/cirrhosis, defined as grade 1 (no fibrosis, no or mild fatty infiltration, no or mild nuclear variability, and no or mild portal inflammation), grade 2 (no fibrosis, but moderate to severe fatty infiltration, nuclear pleomorphism, and portal inflammation), grade 3a (mild fibrosis, moderate to severe fatty infiltration, portal tract enlargement, and lobular necrosis), grade 3b (moderate to severe fibrosis), and grade 4 (cirrhosis).7 For patients with MTX-induced liver injury (Roenigk grade 3a), MTX could be continued, with follow-up liver biopsy repeated in 6 months. For those with significant liver fibrosis or cirrhosis (Roenigk grades 3b or 4), MTX was discontinued and alternative treatment was initiated.2

For statistical analysis, continuous variables were expressed as median (range or IQR, as specified) or mean (± standard deviation) values, as appropriate. Receiver operating characteristic (ROC) curves were used to determine the predictive ability of TE-based LS relative to histopathology (Roenigk grade ≥3a), with 95% confidence intervals (CIs). Correlations between two variables were calculated using Pearson or Spearman rank correlation coefficients. The Chi squared test or Fisher’s exact test was used for comparisons of categorical variables, as appropriate. Quantitative variables were subjected to normality assessment via the Shapiro–Wilk test; non–normally distributed variables were compared between groups using the Wilcoxon rank-sum test. Statistical analyses were conducted using SPSS software (Windows version 26.0; IBM Corp, Armonk [NY], United States). P values <0.05 were considered statistically significant.

In total, 785 psoriasis patients were recruited into the study; 234 fulfilled the screening criteria and were included in the analysis. Six patients subsequently withdrew their consent (Fig 1).

Among 228 patients who underwent TE evaluation, 140 were diagnosed with psoriasis and 88 were diagnosed with psoriatic arthritis (Table 1). Fifty-eight patients, who either had LS ≥7.1 kPa or received a TCD of MTX ≥3.5 g, were advised to undergo liver biopsy; 24 patients who refused or had contraindications to liver biopsy were excluded from the study (Fig 1). Thus, 34 patients (24 fulfilling the TE criteria and 15 fulfilling the TCD criteria of MTX) who had undergone both TE and liver biopsies were included in further analyses. The clinical and demographic details of the study participants are summarised in Table 1.

Among the 34 patients, the median values of LS and CAP were 8.80 kPa (IQR, 7.1-12.4; range, 3.5-30.4) and 321.0 dB/m (IQR, 262-357; range, 200-400), respectively. Furthermore, 24 patients (70.6%) had a high LS value (ie, ≥7.1 kPa, indicative of significant fibrosis); 24 patients (70.6%) had a CAP value of ≥268 dB/m, indicative of moderate to severe steatosis.

Histology evaluation revealed liver fibrosis in nine of 34 (26.5%) patients: six had Roenigk grade 3a, three had Roenigk grade 3b, and none had Roenigk grade 4 (cirrhosis).

Liver stiffness measurements via TE showed moderate correlations with BMI (r=0.441; P=0.009), waist circumference (r=0.437; P=0.01), and body weight (r=0.456; P=0.007); there were no correlations with the TCD of MTX or duration of MTX use (Table 2).

Patients with LS ≥7.1 kPa had a higher BMI (P=0.01), body weight (P=0.01), and waist circumference (P=0.03). They also exhibited greater disease severity with a higher Psoriasis Area and Severity Index score (P=0.02) and more extensive BSA involvement (P=0.03). Furthermore, patients with LS ≥7.1 kPa had higher fasting glucose (P=0.03) and HbA1c levels (P=0.02), but they did not show significant differences in serum lipid levels (Table 3).

In terms of histology findings, patients with a Roenigk grade ≥3a had significantly greater BMI (P=0.01), waist circumference (P=0.04), BSA (P=0.04), and HbA1c values (P=0.03), compared with those who exhibited lower stages of histological fibrosis. Notably, there were no significant differences in the TCD of MTX, lipid profiles, or liver and renal biochemistries between the two groups. Patients with Roenigk grade ≥3a (LS: 11.7 kPa; range, 7.8-15.7) had higher LS values than those with Roenigk grade <3a (LS: 8.6 kPa; range, 5.9-11) [P=0.018] (Table 3).

Comparison of TE-based LS values (in kPa) with histopathology revealed an area under the ROC curve of 0.76 (95% CI=0.59-0.93; P=0.021) [Fig 2], which demonstrated the satisfactory performance of TE in detecting significant liver fibrosis. An LS cut-off value of 7.1 kPa yielded 100% sensitivity and 68% specificity for diagnosing Roenigk grade ≥3a.

In a subgroup analysis of patients with LS ≥7.1 kPa, excluding patients who only met the TCD criteria of MTX (n=24), the area under the ROC curve with reference to Roenigk grade ≥3a was 0.702 (95% CI=0.47-0.94); an LS cut-off value of 10.7 kPa yielded 86% sensitivity and 59% specificity. In contrast, when ROC analysis was focused on the subgroup of patients with a TCD of MTX ≥3.5 g (n=14, excluding patients who only met the TE criteria), the area under the ROC curve was 0.622 (95% CI=0.31-0.94); an LS cut-off value of 8.2 g yielded 60% sensitivity and 67% specificity.

International guidelines recommend using TE for routine monitoring of MTX therapy.2 4 According to the Australasian position statement, TE monitoring is recommended every 3 years if initial LS is <7.5 kPa and yearly if LS is ≥7.5 kPa; liver biopsy is recommended if LS is >9.5 kPa.23

Currently, there is no guideline for monitoring MTX-induced liver fibrosis among Chinese psoriasis patients in Hong Kong. On the basis of previous studies,2 4 23 the present study utilised a modified approach that reflects our department’s routine practice of conducting liver biopsy for patients who have TE-based LS ≥7.1 kPa or a TCD of MTX ≥3.5 g, with or without abnormal liver biochemistry.

Our study confirmed the robust performance of TE in detecting significant liver fibrosis among Chinese psoriasis patients receiving MTX; the LS cut-off value of 7.1 kPa yielded 100% sensitivity and 68% specificity. These findings are consistent with a recent review and studies in other countries (Table 4).7 19 20 According to these published data, TE demonstrated fair to good performance in detecting liver fibrosis, with high negative predictive values (NPVs) [83% to 96%] but generally low positive predictive values (PPVs),19 20 21 22 23 24 which might be explained by the overall low prevalence of significant liver fibrosis in this population and the higher rate of TE failure among patients with obesity. Obesity might also influence diagnostic performance; a recent review noted that obesity could substantially reduce TE accuracy.19 Lee et al25 showed that, compared with control participants, independent risk factors for liver fibrosis included diabetes mellitus (odds ratio [OR]=30.4), obesity with high BMI (OR=8.3), and overweight (OR=6.3). Our results supported previous observations that TE-based LS measurements were not correlated with the TCD of MTX, although they were associated with BMI, diabetes mellitus, and obesity.19 24 Rongngern et al19 analysed 41 Asian psoriasis patients receiving MTX; they demonstrated that TE had good performance in detecting MTX-induced liver injury, with an area under the ROC curve of 0.78.19

In this same study,19 using an LS cut-off value of 7.1 kPa, for detecting MTX-induced liver injury, defined as Roenigk grade ≥3a, TE provided a sensitivity and specificity of 50% and 83.9%, respectively, and a PPV of 50% and a NPV of 84%; in addition, the use of TE values ≥7.1 yielded 50% sensitivity and 76.9% specificity for detecting significant liver fibrosis, defined as METAVIR stage ≥F2; and giving a PPV of 10% and a NPV of 96.8%. Similarly, our study showed a PPV of 26.7% and a NPV of 100%. In the study of 53 psoriasis patients receiving MTX, Khandpur et al20 identified median LS values of 5.3 kPA (range, 2.7-17.8); TE could only detect 4 (21%) of 19 patients with liver fibrosis (Ishak stage ≥F1).20

Because the median LS for our patients with significant liver fibrosis (Roenigk grade ≥3a) was 11.7 kPa (IQR, 7.8-15.7), we recommend yearly TE monitoring for patients with LS ≥7.1 kPa. Liver biopsy should be considered for patients with LS ≥11.7 kPa, instead of a TCD ≥3.5 g or LS ≥7.1 kPa; earlier biopsy is suggested for high-risk patients (eg, patients with high BMI, abdominal obesity, or diabetes mellitus).

The median LS in this study (n=228) was 6.91 kPa (IQR, 4.5-7.1). Among the 34 patients who underwent liver biopsy, the median LS was 8.80 kPa (IQR, 7.1-12.4). Overall, 9 of 34 patients (26.5%) had Roenigk grade 3a (mild)/3b (moderate to severe) liver fibrosis, whereas 14 (41.2%) patients had moderate to severe fatty infiltration (Roenigk grade 2) [Table 1]. The prevalences of liver fibrosis and steatotic changes in our study were higher than the rates reported in a 2015 review, where histology showed that only 5% of patients (range, 0%-33%) receiving MTX had developed significant liver fibrosis.14

The aetiology of liver fibrosis can be multifactorial. Previous studies have shown that obesity, combined with other metabolic risk factors, is associated with liver fibrosis in non-alcoholic fatty liver disease (NAFLD) patients and psoriasis patients.26 27 28 The potential contributions of coexisting non-alcoholic steatohepatitis or NAFLD and metabolic syndrome to liver fibrosis have been suggested. In our cohort, >40% of psoriasis patients had a CAP of ≥268 dB/m, indicative of moderate to severe steatosis. The liver fibrosis could be attributed to coexisting non-alcoholic steatohepatitis or NAFLD, in addition to MTX-induced changes. The work of Wong et al26 demonstrated that NAFLD patients with BMI ≥30 kg/m² had higher LS compared with normal healthy individuals. Our findings corroborate these observations; we found that BMI, body weight, and waist circumference were moderately correlated with TE-based LS measurements (all r>0.40; all P<0.05) [Table 2]. Intriguingly, although 70.6% of our biopsy cohort had moderate to severe hepatic steatosis (Table 1), CAP values were not significantly associated with LS >7.1 kPa or Roenigk grade ≥3a (Table 3). Therefore, the adverse effect of BMI on LS cannot be explained by concomitant hepatic steatosis alone.

In our study, patients with clinically significant liver fibrosis more frequently displayed characteristics of metabolic syndrome compared with patients lacking histologically confirmed liver fibrosis, as evidenced by significantly greater BMI (33.5 ± 0.68 kg/m² vs 29.4 ± 6.18 kg/m²; P=0.01), waist circumference (138.0 ± 52.0 cm vs 101.2 ± 14.9 cm; P=0.04), and HbA1c values (7.86 ± 2.02% vs 6.15 ± 1.16%; P=0.03) [Table 3]. Sub-analysis showed that all patients with histologically confirmed liver fibrosis had a BMI ≥25 kg/m² (Table 5), suggesting that psoriasis patients should maintain a normal BMI to decrease the risk of liver fibrosis.

Despite the recommendation to perform a screening liver biopsy for exclusion of possible liver cirrhosis among patients receiving long-term MTX therapy (with a TCD >3.5 g),1 2 our study did not identify a positive correlation between significant liver fibrosis and the TCD of MTX. Similarly, a study involving 420 patients with inflammatory arthritis receiving MTX revealed no significant correlation between cumulative MTX dosage and TE-based LS measurements.24 In the present study, although the TCD of MTX was higher in patients with liver fibrosis (5.23 g vs 4.79 g in those without), the difference was not statistically significant. In this context, LS measurements may be superior to the TCD of MTX when considering the need for liver biopsy to rule out advanced liver fibrosis.

Contrary to concerns about hepatotoxicity during long-term MTX therapy, we did not find a correlation between LS values and the duration of MTX use. The duration of MTX use in patients without liver fibrosis was nearly 10 years, indicating that the drug is generally well-tolerated in psoriasis patients. Patients who tended to continue MTX treatment belonged to an MTX-responsive group without significant adverse events, such as liver derangement identified via blood tests. In contrast, patients experiencing liver derangement or other adverse events might have discontinued MTX treatment earlier and were thus excluded from the study. Although we excluded patients with chronic hepatitis B, TE-based LS measurement is a widely validated non-invasive tool for real-world assessments of liver fibrosis in such patients; it allows the prediction of advanced fibrosis and disease progression.29 Therefore, TE should also be considered a valuable tool in guiding treatment for psoriasis patients with chronic hepatitis B who are receiving MTX.

In addition to LS measurement, TE can assess the degree of steatosis through CAP. This assessment was beneficial among patients with psoriasis in the present study; 26.5% (9 of 34) of the patients had metabolic syndrome and were predisposed to concomitant hepatic steatosis, regardless of MTX use. The median CAP value in our study was 321 ± 95 dB/m (range, 200-400). The area under the ROC curve of TE was 0.783 (95% CI=0.61-0.95; P<0.01); the cut-off of 254 dB/m for detecting steatosis yielded 91% sensitivity and 60% specificity. However, the presence of simple hepatic steatosis alone does not warrant liver biopsy, and management decisions should follow appropriate clinical guidelines.30 31 32

This study had some limitations. Notably, its sample size was small. Although liver fibrosis is generally uncommon in patients with psoriasis receiving MTX therapy, a larger sample size may be required for more definitive conclusions. Additionally, sampling error and inter- and intra-observer variabilities in histological assessment of liver tissue may have influenced the findings.

Transient elastography is a reliable screening tool for detecting significant liver fibrosis in Chinese psoriasis patients receiving MTX. When considering liver biopsy to rule out the possibility of clinically significant liver fibrosis, TE-based LS measurements provide superior reference information, compared with the TCD of MTX. Patients with high BMI, body weight, and abdominal obesity have a higher risk of liver fibrosis. Therefore, these factors should be considered when monitoring MTX-related liver fibrosis in psoriasis patients.

Concept or design: CSM Wong, LLY Mak, CK Yeung, HHL Chan, MF Yuen.
Acquisition of data: CSM Wong, MMH Chung, LLY Mak.
Analysis or interpretation of data: CSM Wong, MMH Chung, LLY Mak.
Drafting of the manuscript: CSM Wong, LLY Mak, F Chu, VKH Lee, RCL Lo.
Critical revision of the manuscript for important intellectual content: CK Yeung, HHL Chan, MF Yuen.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

The authors thank Ms Rachael Yu, Ms Davis Wong, and Ms Ivy Cheng from Division of Dermatology, Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong for their assistance with patient recruitment, data acquisition, and analysis.

The preliminary data of this research were presented as ePoster presentation in the 31st European Academy of Dermatology and Venereology Congress 2022 (7-10 September 2022, Milan, Italy and online).

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This study was approved by the Institutional Review Board of The University of Hong Kong and Hong Kong West Cluster, Hospital Authority, Hong Kong (Ref No.: UW19-390) and was conducted in full compliance with the International Council for Harmonisation E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki. Patient consent has been obtained for all clinical information and images reported in this article. All participant information has been deidentified and remains anonymous.

1. Kalb RE, Strober B, Weinstein G, Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference. J Am Acad Dermatol 2009;60:824-37. Crossref

2. Warren RB, Weatherhead SC, Smith CH, et al. British Association of Dermatologists’ guidelines for the safe and effective prescribing of methotrexate for skin disease 2016. Br J Dermatol 2016;175:23-44. Crossref

3. Themido R, Loureiro M, Pecegueiro M, Brandão M, Campos MC. Methotrexate hepatotoxicity in psoriatic patients submitted to long-term therapy. Acta Derm Venereol 1992;72:361-4. Crossref

4. Kremer JM, Alarcón GS, Lightfoot RW Jr, et al. Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis Rheum 1994;37:316-28. Crossref

5. Howlett DC, Drinkwater KJ, Lawrence D, Barter S, Nicholson T. Findings of the UK national audit evaluating image-guided or image-assisted liver biopsy. Part II. Minor and major complications and procedure-related mortality. Radiology 2013;266:226-35. Crossref

6. Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;97:2614-8. Crossref

7. Berends MA, Snoek J, de Jong EM, et al. Biochemical and biophysical assessment of MTX-induced liver fibrosis in psoriasis patients: FibroTest predicts the presence and FibroScan predicts the absence of significant liver fibrosis. Liver Int 2007;27:639-45. Crossref

8. Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696-9. Crossref

9. Goodman ZD. Grading and staging systems for inflammation and fibrosis in chronic liver diseases. J Hepatol 2007;47:598-607. Crossref

10. Carneiro SC, Cássia FF, Lamy F, Chagas VL, Ramos-e-Silva M. Methotrexate and liver function: a study of 13 psoriasis cases treated with different cumulative dosages. J Eur Acad Dermatol Venereol 2008;22:25-9. Crossref

11. Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review. Ann Intern Med 2013;158:807-20. Crossref

12. Fung J, Lai CL, Fong DY, Yuen JC, Wong DK, Yuen MF. Correlation of liver biochemistry with liver stiffness in chronic hepatitis B and development of a predictive model for liver fibrosis. Liver Int 2008;28:1408-16. Crossref

13. Martyn-Simmons CL, Rosenberg WM, Cross R, Wong T, Smith CH, Barker JN. Validity of noninvasive markers of methotrexate-induced hepatotoxicity: a retrospective cohort study. Br J Dermatol 2014;171:267-73. Crossref

14. Brener S. Transient elastography for assessment of liver fibrosis and steatosis: an evidence-based analysis. Ont Health Technol Assess Ser 2015;15:1-45.

15. Foucher J, Castéra L, Bernard PH, et al. Prevalence and factors associated with failure of liver stiffness measurement using FibroScan in a prospective study of 2114 examinations. Eur J Gastroenterol Hepatol 2006;18:411-2. Crossref

16. Karlas T, Petroff D, Sasso M, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol 2017;66:1022-30. Crossref

17. Castéra L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005;128:343-50. Crossref

18. Friedrich-Rust M, Ong MF, Martens S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008;134:960-74. Crossref

19. Rongngern P, Chularojanamontri L, Wongpraparut C, et al. Diagnostic performance of transient elastography for detection of methotrexate-induced liver injury using Roenigk classification in Asian patients with psoriasis: a retrospective study. Arch Dermatol Res 2017;309:403-8. Crossref

20. Khandpur S, Yadav D, Jangid B, et al. Ultrasound liver elastography for the detection of liver fibrosis in patients with psoriasis and reactive arthritis on long-term methotrexate therapy: a cross-sectional study. Indian J Dermatol Venereol Leprol 2020;86:508-14. Crossref

21. Marsh RL, Kelly S, Mumtaz K, Kaffenberger J. Utility and limitations of transient elastography to monitor hepatic steatosis, hepatic fibrosis, and methotrexate-associated hepatic disease in psoriasis: a systematic review. J Clin Aesthet Dermatol 2021;14:24-8.

22. Cheng HS, Rademaker M. Monitoring methotrexate-induced liver fibrosis in patients with psoriasis: utility of transient elastography. Psoriasis (Auckl) 2018;8:21-9. Crossref

23. Rademaker M, Gupta M, Andrews M, et al. The Australasian Psoriasis Collaboration view on methotrexate for psoriasis in the Australasian setting. Australas J Dermatol 2017;58:166-70. Crossref

24. Darabian S, Wade JP, Kur J, Wade SD, Sayre EC, Badii M. Using FibroScan to assess for the development of liver fibrosis in patients with arthritis on methotrexate: a single-center experience. J Rheumatol 2022;49:558-65. Crossref

25. Lee JH, Loo CH, Tan WC, Lee CK, Jamil A, Khor YH. Comparison of noninvasive screening tools for hepatic fibrosis, association with methotrexate cumulative dose, and risk factors in psoriasis patients. Dermatol Ther 2022;35:e15203. Crossref

26. Wong GL, Chan HL, Choi PC, et al. Association between anthropometric parameters and measurements of liver stiffness by transient elastography. Clin Gastroenterol Hepatol 2013;11:295-302.e1-3. Crossref

27. Rodríguez-Zúñiga MJ, García-Perdomo HA. Systematic review and meta-analysis of the association between psoriasis and metabolic syndrome. J Am Acad Dermatol 2017;77:657-66.e8. Crossref

28. Malatjalian DA, Ross JB, Williams CN, Colwell SJ, Eastwood BJ. Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up. Can J Gastroenterol 1996;10:369-75. Crossref

29. Wong GL. Non-invasive assessments for liver fibrosis: the crystal ball we long for. J Gastroenterol Hepatol 2018;33:1009-15. Crossref

30. Cusi K, Isaacs S, Barb D, et al. American Association of Clinical Endocrinology Clinical Practice Guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocr Pract 2022;28:528-62. Crossref

31. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67:328-57. Crossref

32. European Association for the Study of the Liver; Clinical Practice Guideline Panel; Berzigotti A, et al. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis—2021 update. J Hepatol 2021;75:659-89. Crossref