Methotrexate (MTX) is a chemotherapy agent and immune system suppressant that can cause liver fibrosis in long-term usage. This study aimed to investigate the relationship between the dose of MTX and the incidence of liver fibrosis in patients with rheumatoid arthritis (RA).

This cohort study was conducted on RA patients with normal liver function who took MTX. Liver FibroScan and laboratory tests, including α2-macroglobulin, total bilirubin, g-glutamyltransferase, apolipoprotein A1, haptoglobin, and alanine transaminase was performed. The patients were divided into 2 groups regarding their cumulative dose of MTX and the rate of liver fibrosis incidence was compared between the 2 groups.

In total, 60 RA patients with the mean age of 55.2 ±11.8 years were enrolled. The mean duration of MTX use in patients was 6.9 ±3.8 years, and it was higher in the higher cumulative dose MTX group (> 2 g) than in the lower cumulative dose group (< 2 g; p < 0.0001). The overall prevalence of grade 3 fibrosis was 3.33%. The prevalence of second- and third-degree liver fibrosis in patients receiving a lower cumulative dose was respectively 9 (28.1%) and 1 (3.1%), and in patients receiving a higher cumulative dose it was 7 (25%) and 1 (3.6%), respectively. There was no statistically significant difference between the 2 groups regarding the prevalence of liver fibrosis (p = 0.88). Both aspartate aminotransferase to platelet ratio index and Fibrosis Index Based on 4 Factors indices showed no significant difference between the 2 groups (p = 0.594, p = 0.232).

These results suggest that long-term treatment with a higher cumulative dose of MTX is not associated with a higher incidence of liver fibrosis in RA patients.

Methotrexate (MTX) and leflunomide (LEF) play fundamental roles in rheumatoid arthritis (RA) treatment and require proper monitoring of side effects. Concerns about MTX/LEF-related liver fibrosis (LF) in patients with RA remain unclear. This study investigated liver stiffness using two-dimensional shear wave elastography (2D-SWE) in RA patients undergoing disease-modifying antirheumatic drug (DMARD) therapy. Moreover, 2D-SWE was employed to evaluate the correlations between liver stiffness, cumulative MTX and LEF doses and risk factors for substantial LF.

We recruited 222 participants from the Department of Rheumatology. The participants were divided into healthy controls (n = 78) and patients with RA (n = 144). Pearson's correlation analysis was performed to assess the correlations between liver stiffness and the cumulative dose of MTX/LEF and other clinical and laboratory variables.

The mean elasticity modulus was 4.79 ± 0.92 kPa, excluding the presence of significant fibrosis. Mean 2D-SWE values were significantly lower in healthy controls than in RA treated with MTX and LEF. The cut-off ≥3.8 kPa 2D-SWE values with the sensitivity of 86.1%, specifity of 83.3%. 2D-SWE values were not significantly different across the strata of the cumulative MTX subgroups.

MTX and LEF increase liver stiffness but may be considered low risk for the development of LF.

A high prevalence of steatotic liver disease has been described in psoriasis. However, the influence of genetic polymorphisms has yet to be investigated in this scenario. This study aims to determine the frequency of steatosis, advanced liver fibrosis and PNPLA3/TM6SF2 genotypes in individuals with psoriasis and to evaluate the impact of genetic polymorphisms, metabolic parameters and cumulative methotrexate dose on steatosis and fibrosis.

Cross-sectional study that prospectively included psoriasis outpatients, submitted to clinical and laboratory analysis, transient elastography (FibroScan®, Fr) and PNPLA3/TM6SF2 genotyping. Steatosis was defined by CAP ≥275 dB/m and advanced liver fibrosis as transient elastography ≥10 kPa. Logistic regression analysis evaluated the independent variables related to steatosis and fibrosis; p-value< 0.05 was considered significant.

One hundred and ninety-nine patients were enrolled (age 54.6 ± 12.6 years, 57.3% female). Metabolic syndrome (MetS), steatosis and advanced liver fibrosis prevalence were 55.8%, 54.8% and 9%, respectively. PNPLA3 and TM6SF2 genotypes frequencies were CC 42.3%/CG 49.5%/GG 8.2% and CC 88.7%/ CT 11.3%/ TT 0%. MetS (OR3.01 95%CI 1.51-5.98; p = 0.002) and body mass index (OR1.17 95%CI 1.08-1.26; p < 0.01) were independently associated with steatosis. Diabetes Mellitus (T2DM) (OR10.76 95%CI 2.42-47.87; p = 0.002) and harboring at least one PNPLA3 G allele (OR5.66 95%CI 1.08-29.52; p = 0.039) were associated with advanced fibrosis, but not TM6SF2 polymorphism or cumulative MTX dose.

MetS and T2DM confer higher odds for steatosis and advanced fibrosis in individuals with psoriasis. PNPLA3 G allele, but not TM6SF2 polymorphism, impacts a 5-fold odds of advanced liver fibrosis.

Psoriasis has been related to metabolic dysfunction-associated fatty liver disease and, liver fibrosis. This study aimed to evaluate the prevalence of liver fibrosis in psoriasis and identify predictors for fibrosis. This is a cross-sectional study conducted from December 2012 to June 2016 assessing psoriasis and psoriatic arthritis patients attended at four centers in Mexico City. Data regarding history of the skin disease, previous and current medication, and previously diagnosed liver disease was collected. Liver fibrosis was assessed with four different non-invasive methods (FIB4, APRI, NAFLD score and elastography). We compared data based on the presence of fibrosis. Adjusted-logistic regression models were performed to estimate OR and 95% CI. A total of 160 patients were included. The prevalence of significant fibrosis using elastography was 25% (n = 40), and 7.5% (n = 12) for advanced fibrosis. Patients with fibrosis had higher prevalence of obesity (60% vs 30.8%, P = 0.04), type 2 diabetes (40% vs 27.5%, P = 0.003), gamma-glutamyl transpeptidase levels (70.8±84.4 vs. 40.1±39.2, P = 0.002), and lower platelets (210.7±58.9 vs. 242.8±49.7, P = 0.0009). Multivariate analysis showed that body mass index (OR1.11, 95%CI 1.02-1.21), type 2 diabetes (OR 3.44, 95%CI 1.2-9.88), and gamma-glutamyl transpeptidase (OR 1.01, 95%CI1-1.02) were associated with the presence of fibrosis. The use of methotrexate was not associated. Patients with psoriasis are at higher risk of fibrosis. Metabolic dysfunction, rather than solely the use of hepatotoxic drugs, likely plays a major role; it may be beneficial to consider elastography regardless of the treatment used. Metabolic factors should be assessed, and lifestyle modification should be encouraged.

There are conflicting findings on the link between liver fibrosis and cumulative methotrexate dosages. We aimed to determine the frequency of liver fibrosis in rheumatoid arthritis patients treated with methotrexate and to identify its associated factors.

We conducted a cross-sectional study over 9 months (April-December 2021), including rheumatoid arthritis patients treated with methotrexate. Demographic and clinical data were collected. Liver stiffness was assessed by FibroScan. Fibrosis and significant liver fibrosis were defined as liver stiffness higher than 6 and 7.2 kPa, respectively. Liver tests, albuminemia, lipid profile, and blood glycemia were measured. Metabolic syndrome was also evaluated. Statistical analyses were performed using SPSS.

We included 21 men and 47 women. The mean age was 51.60 ± 1.82 years. The mean disease duration was 8.29 ± 6.48 years. The mean weekly intake of methotrexate was 13.76 ± 3.91 mg. The mean methotrexate duration was 4.67 ± 4.24 years. The mean cumulative dose was 3508.87 ± 3390.48 mg. Hypoalbuminemia and metabolic syndrome were found in 34% and 25% of cases. We noted increased alkaline phosphatase levels in four cases. The mean liver stiffness was 4.50 ± 1.53 kPa. Nine patients had liver fibrosis, and four had significant fibrosis. Associated factors with liver fibrosis were as follows: age ≥ 60 years (OR:22.703; 95%CI [1.238-416.487]; p = 0.035), cumulated dose of methotrexate ≥ 3 g (OR: 76.501; 95%CI [2.383-2456.070]; p = 0.014), metabolic syndrome (OR: 42.743; 95%CI [1.728-1057.273]; p = 0.022), elevated alkaline phosphatase levels (OR: 28.252; 95%CI [1.306-611.007]; p = 0.033), and hypoalbuminemia (OR: 59.302; 95%CI [2.361-1489.718]; p = 0.013).

Cumulating more than 3 g of methotrexate was associated with liver fibrosis in rheumatoid arthritis patients. Having a metabolic syndrome, higher age, hypoalbuminemia, and elevated alkaline phosphatase levels were also likely to be independently associated with liver fibrosis. Key points • Rheumatoid arthritis patients require monitoring hepatic fibrosis when the cumulated dose of methotrexate is above 3 g. • Metabolic syndrome is a risk factor for liver fibrosis, suggesting that its management is necessary to prevent this complication. • Hypoalbuminemia and elevated alkaline phosphatase levels (twice the upper limit) in rheumatoid arthritis patients treated with methotrexate were associated with liver fibrosis.

To assess the liver stiffness in patients with rheumatoid arthritis treated with methotrexate monotherapy using non-invasive, ultrasound-based elastography (acoustic radiation force impulse (ARFI) imaging) in a longitudinal approach.

In total, 23 MTX-naive patients were longitudinally assessed using acoustic radiation force impulse (ARFI) imaging. Baseline assessments were carried out between July 2018 and April 2019, and the follow-up evaluations took place after an average of 2.6 years. The main outcome variable was the mean shear wave velocity as measured by the ARFI method. It was calculated from 10 valid ARFI measurements for each patient. Inferential statistical analyses (within-group comparisons) were performed using t-tests for dependent samples or suitable nonparametric procedures.

The main finding was that observed ARFI shear wave velocities did not increase during the observation period. In fact, this parameter decreased over time from 1.07 m/s (SD = 0.23) at baseline without MTX exposure to 0.97 m/s (SD = 0.16) at follow-up after a mean of 2.6 years (P = 0.013). Moreover, the magnitude of the change in shear wave velocity could not be predicted by indicators of inflammation or disease activity, BMI, age, sex or NSAR intake (corresponding regression analysis: corrected R2 = 0.344; P = 0.296).

No increased risk of liver fibrosis was found in RA patients treated with MTX monotherapy during observation period.

This study aimed to assess the prevalence and identify predictors of hepatic steatosis and fibrosis in patients with juvenile idiopathic arthritis (JIA) during methotrexate treatment.

This cross-sectional study included JIA patients who had received methotrexate for > 1 year. Laboratory data including liver chemistry and lipid profiles were collected. Liver stiffness measurements (LSM) and controlled attenuation parameters (CAP) were determined by transient elastography. Significant hepatic fibrosis was defined as LSM > 7 kilopascal (kPa), and hepatic steatosis was defined as CAP > 225 decibel/meter (dB/m). Logistic regression analysis was performed to identify predictors associated with hepatic steatosis and fibrosis.

Of 60 patients, 66.7% were female, and the median age (IQR) was 12.8 (10.6-15.0) years. The median duration of methotrexate usage (IQR) was 45 (22-85) months, and the median cumulative dose of methotrexate (IQR) was 3768 (1806-6466) mg. The median LSM (IQR) and CAP (IQR) were 4.1 (3.4-4.6) kPa and 191.0 (170.3-223.8) dB/m, respectively. No patients had transient elastography-defined hepatic fibrosis, whereas 21.7% had hepatic steatosis. A body mass index Z-score > 1 (OR 5.71 [95%CI 1.31-24.98], p = 0.021) and higher cumulative dose of methotrexate (OR 1.02 [95%CI 1.00-1.04], p = 0.041) were associated with hepatic steatosis, whereas the cumulative dose of steroids was not (OR 1.00 [95%CI 1.00-1.01], p = 0.097).

Hepatic steatosis is common among JIA patients receiving methotrexate, but none had transient elastography-defined hepatic fibrosis. Overweight/obese JIA adolescents and patients with a high cumulative dose of methotrexate are at risk for hepatic steatosis. Key Points •Long-term low-dose methotrexate usage and the concomitant use of other DMARDs did not increase the risk of hepatic fibrosis in JIA patients. •The prevalence of hepatic steatosis in JIA patients receiving methotrexate was higher than in a healthy pediatric population. •Overweight/obesity and a higher cumulative dose of methotrexate were predictors of hepatic steatosis.

To study the prevalence of liver fibrosis (LF) measured by FibroScan and APRI index in patients with rheumatoid arthritis (AR) undergoing treatment with methotrexate (MTX).

We included 59 patients with RA on MTX. Medical records, FibroScan measures and serological markers of liver damage were compared on the basis of cumulative methotrexate dose.

Mean treatment duration was 82.4±65.1 months and mean cumulative dose was 5214.5±4031.9mg. Five patients met LF criteria by fibroscan, while only one patient had a suggestive APRI score. No statistically significant differences were found in terms of LF measured by both APRI and fibroScan between patients with cumulative doses above and below 4000mg. There was also no relationship between LF and treatment duration.

The occurrence of LF in patients with RA on MTX is a multifactorial process that does not seem directly related to its cumulative dose. FibroScan may be a useful technique in clinical practice to screen for this complication.

Background and Objectives: Methotrexate (MTX) is routinely prescribed for rheumatoid arthritis (RA) patients, but high cumulative doses may lead to hepatic fibrosis. Additionally, a high proportion of RA patients suffer from metabolic syndrome, which also increases the risk of hepatic fibrosis. This cross-sectional study aimed to explore the association between a cumulative MTX dose, metabolic syndrome, and hepatic fibrosis in patients diagnosed with RA. Materials and Methods: RA patients undergoing treatment with MTX were examined using transient elastography (TE). All patients, regardless of having hepatic fibrosis, were compared to identify the risk factors. Results: Two hundred and ninety-five rheumatoid arthritis patients were examined using FibroScan. One hundred and seven patients (36.27%) were found to have hepatic fibrosis (TE > 7 kPa). After multivariate analysis, only BMI (OR = 14.73; 95% CI 2.90-74.79; p = 0.001), insulin resistance (OR = 312.07; 95% CI 6.19-15732.13; p = 0.04), and cumulative MTX dosage (OR 1.03; 95% CI 1.01-1.10; p = 0.002) were associated with hepatic fibrosis. Conclusions: While the cumulative MTX dose and metabolic syndrome are both the risk factors of hepatic fibrosis, metabolic syndrome, including a high BMI and insulin resistance, poses a greater risk. Therefore, MTX-prescribed RA patients with metabolic syndrome factors should be attentively monitored for signs of liver fibrosis.

After decades of use, methotrexate displays an established safety and efficacy profile in both in-hospital and outpatient settings. Despite its widespread use, there is surprisingly little clinical evidence to guide daily practice with methotrexate in dermatology.

To provide guidance for clinicians in daily practice for areas in which there is limited guidance.

A Delphi consensus exercise on 23 statements was carried out on the use of methotrexate in dermatological routine settings.

Consensus was reached on statements that cover six main areas: (1) pre-screening exams and monitoring of therapy; (2) dosing and administration in patients naïve to methotrexate; (3) optimal strategy for patients in remission; (4) use of folic acid; (5) safety; and (6) predictors of toxicity and efficacy. Specific recommendations are provided for all 23 statements.

In order to optimize methotrexate efficacy, it is essential to optimize treatment using appropriate dosages, carrying out a rapid drug-based step-up on a treat-to-target strategy and preferably using the subcutaneous formulation. To manage safety aspects appropriately, it is essential to evaluate patients' risk factors and carry out proper monitoring during the course of treatment.

Methotrexate is a key component of the treatment of inflammatory rheumatic diseases and the mainstay of therapy in rheumatoid arthritis. Hepatotoxicity has long been a concern for prescribers envisaging long-term treatment with methotrexate for their patients. However, the putative liver toxicity of methotrexate should be evaluated in the context of advances in our knowledge of the pathogenesis and natural history of liver disease, especially non-alcoholic fatty liver disease (NAFLD). Notably, patients with NAFLD are at increased risk for methotrexate hepatotoxicity, and methotrexate can worsen the course of NAFLD. Understanding the mechanisms of acute hepatotoxicity can facilitate the interpretation of elevated concentrations of liver enzymes in this context. Liver fibrosis and the mechanisms of fibrogenesis also need to be considered in relation to chronic exposure to methotrexate. A number of non-invasive tests for liver fibrosis are available for use in patients with rheumatic disease, in addition to liver biopsy, which can be appropriate for particular individuals. On the basis of the available evidence, practical suggestions for pretreatment screening and long-term monitoring of methotrexate therapy can be made for patients who have (or are at risk for) chronic liver disease.

The risk of significant liver fibrosis from prolonged methotrexate (MTX) exposure has been estimated at around 5%, prompting intensive monitoring strategies. However, the evidence is derived from retrospective studies that under-reported risk factors for liver disease. We evaluated the risk of long-term MTX therapy on liver fibrosis in a longitudinal cohort study using two non-invasive markers.

Between 2014-2021, adult patients diagnosed with rheumatoid arthritis (RA) or psoriasis for ≥2 years were recruited prospectively from six UK sites. The MTX group included patients who received MTX for ≥6 months, whereas the unexposed group included those who never received MTX. All patients underwent full liver profiling, with transient elastography (TE) and enhanced liver fibrosis (ELF) marker measurements.

A total of 999 patients (mean age 60.8 ± 12 years, 62.3% females) were included. Of 976 with valid TE values, 149 (15.3%) had liver stiffness ≥7.9 kPa. Of 892 with a valid ELF, 262 (29.4%) had ELF ≥9.8. Age and BMI were independently associated with elevated liver stiffness and ELF. Neither MTX cumulative dose nor duration was associated with elevated liver stiffness. Diabetes was the most significant risk factor associated with liver stiffness ≥7.9 kPa (adjusted odds ratio = 3.19; 95% CI 1.95-5.20; p <0.001). Regular use of non-steroidal anti-inflammatory drugs showed the strongest association with ELF ≥9.8 (odds ratio = 1.76; 95% CI 1.20-2.56; p = 0.003), suggesting the degree of joint inflammation in RA may confound ELF as a non-invasive marker of liver fibrosis.

The risk of liver fibrosis attributed to MTX itself might have been previously overestimated; there is a need to consider modifying current monitoring guidelines for MTX.

Current guidelines recommend intensive (2-3 monthly) monitoring strategies for patients on long-term methotrexate therapy due to the potential risk of liver fibrosis. Evaluation of the association using two validated non-invasive markers of liver fibrosis, liver stiffness and enhanced liver fibrosis score, in a large cohort of patients with rheumatoid arthritis or psoriasis shows that the reported risk has previously been overestimated. The clinical focus should be to improve patients' metabolic risk factors, diabetes and BMI, that are independently associated with liver stiffness. There is a need to consider modifying current treatment monitoring guidelines for methotrexate.

Patients with psoriasis are more likely than matched controls in the general population to have advanced liver fibrosis; however, our understanding of these patients is limited. There is currently no systematic evaluation of the prevalence and risk factors of liver fibrosis in psoriasis patients.

To evaluate the prevalence of psoriasis patients who are at high or low risk for advanced liver fibrosis and determine the risk factors for developing liver fibrosis.

Electronic searches were conducted using the PubMed, Embase, Scopus, and Cochrane Library databases from the dates of their inception till May 2022, using the PubMed, Embase, Scopus, and Cochrane Library databases. Any observational study describing the prevalence and/or risk factors for liver fibrosis in patients with psoriasis was included.

Patients with psoriasis at high risk for advanced liver fibrosis had a pooled prevalence of 9.66% [95% confidence interval (CI): 6.92-12.75%, I ² = 76.34%], whereas patients at low risk for advanced liver fibrosis had a pooled prevalence of 77.79% (95% CI: 73.23-82.05%, I ² = 85.72%). Studies that recruited methotrexate (MTX)-naïve patients found a lower prevalence of advanced liver fibrosis (4.44, 95% CI: 1.17-9.22%, I ² = 59.34%) than those that recruited MTX-user cohorts (12.25, 95% CI: 6.02-20.08%, I ² = 82.34%). Age, sex, BMI, PASI score, psoriasis duration, MTX cumulative dose, and the prevalence of obesity, MTX users, diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome were not identified as sources of heterogeneity by meta-regression analysis. The pooled odds ratios for age >50 years, BMI > 30, diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome were 2.20 (95% CI: 1.42-3.40, I ² = 0%), 3.67 (95% CI: 2.37-5.68, I ² = 48.8%), 6.23 (95% CI: 4.39-8.84, I ² = 42.4%), 2.82 (95% CI: 1.68-4.74, I ² = 0%), 3.08 (95% CI: 1.90-4.98, I ² = 0%), and 5.98 (95% CI: 3.63-9.83, I ² = 17%), respectively.

Approximately 10% of the population with psoriasis is at high risk for advanced liver fibrosis, while 78% are at low risk. Patients over the age of 50 with obesity, diabetes, hypertension, dyslipidemia, and/or metabolic syndrome have an increased risk of developing liver fibrosis, necessitating monitoring.

[https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022303886], identifier [CRD42022303886].

Methotrexate (MTX), an antifolate agent, is recommended as the first-line disease-modifying antirheumatic drug (DMARD). In this systematic review, our goals were to assess liver fibrosis in methotrexate-treated patients, evaluate liver fibrosis in relation to treatment duration and cumulative dose, and identify differences based on the underlying disease. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to perform the systematic review. We thoroughly searched PubMed, PubMed Central (PMC), and Cochrane library databases to identify relevant articles based on predefined selection criteria. Studies were selected based on the following predefined eligibility criteria: English language, papers from the last 20 years, systematic reviews, observational studies, randomized controlled trials (RCTs), and clinical trials, which included papers on MTX playing roles in the development of liver fibrosis with the derived data transferred to a template. Following that, quality was assessed using the appropriate assessment tool for each study. The initial search yielded 512 results. Following a thorough review, 10 studies were chosen for final consideration: eight observational studies and two systematic reviews. Liver enzyme (LE) elevations during MTX therapy are a common but transient problem. Serial abnormal LE tests may be associated with liver pathology, but fibrosis development is uncommon. However, it is unclear from the literature how therapy should be adjusted in the case of elevated LE and to what extent MTX is linked to liver toxicity; definitive conclusions cannot be drawn because more research is needed.

Liver damage caused by drugs and other chemicals accounts for about 5% of all cases. Methotrexate (MTX), a folic acid analogue, is a first-line synthetic antimetabolite agent routinely used in the treatment of rheumatoid arthritis and other autoimmune and chronic inflammatory diseases. Polyethylene glycol (PEG) has antioxidant activity. In this study, we evaluated biochemically and histopathologically the antifibrotic effect of PEG 3350 administered intraperitoneally to prevent methotrexate-induced liver damage in rats.

A total of 30 male rats including 10 rats was given no drugs (normal group), and 20 rats received single-dose 20 mg/kg MTXfor induced liver injury in this study. MTX was given to 20 rats, which were divided in two groups. Group 1 rats was given PEG30 mg/kg/day (Merck) intraperitoneally, and Group 2 rats % 0.9 NaCl saline 1 mL/kg/day intraperitoneally daily for two weeks.

Transforming growth factor beta (TGF-β), plasma malondialdehyde (MDA), liver MDA, serum tumour necrosis factor alpha (TNF-α), alanine aminotransferase and plasma pentraxin-3 levels and, according to tissue histopathology, hepatocyte necrosis, fibrosis and cellular infiltration were significantly better in MTX+PEG group than in MTX+saline group.

PEG 3350 is a hope for toxic hepatitis due to other causes, since liver damage occurs through oxidative stress and cell damage, similar to all toxic drugs.

Methotrexate is an antineoplastic agent that is also used at lower doses for anti-inflammatory properties. Along with thiopurines (azathioprine and 6-mercaptopurine), it has historically been an important part of pharmacological treatment for patients with inflammatory bowel disease. Despite an increase in therapeutic options, these immunomodulators continue to play important roles in the management of inflammatory bowel disease, used either as a monotherapy in mild to moderate cases or in combination with monoclonal antibodies to prevent immunogenicity and maintain efficacy. In light of data linking the use of thiopurines with the risk of malignancies, methotrexate has regained attention as a potential alternative. In this article, we review data on the pharmacology, safety, and efficacy of methotrexate and discuss options for the positioning of methotrexate alone, or in combination, in therapeutic algorithms for Crohn's disease and ulcerative colitis.

The presence of serious toxicities is a major problem in the treatment of childhood acute lymphoblastic leukemia (ALL). The objective of this research is to evaluate drug-induced liver injury (DILI) during consolidation therapy in childhood ALL.

Clinical data of pediatric patients who received consolidation therapy between August 2012 and July 2018 were collected. Characteristics (incidences and patterns) of DILI at different stratifications were determined. Risks of DILI were evaluated using binary logistic regression analysis. Drug causality assessment was carried out by the updated Roussel Uclaf Causality Assessment Method (RUCAM).

Patients with high risk (HR) and standard risk (SR)/intermediate risk (IR) received 270 and 1539 courses of consolidation therapy, respectively; among these courses, 15 (5.6%) and 38 (2.5%) developed DILI. The occurrences of DILI in SR/IR patients were primarily associated with age (≤5.2 years), treatment course (≥5), and baseline serum parameters before treatment (cystatin C > 0.79 mg/L, albumin ≤45 g/L, and gamma-glutamyl transpeptidase (GGT) > 17 U/L). The ROC curve generated using the parameters assigned to specific values achieved an area under the curve (AUC) of 0.846 (95% CI 0.827-0.863) with a cutoff value of 3, and the sensitivity and specificity were 94.7% and 62.3%, respectively. For HR patients, a decrease in baseline albumin and elevation of baseline liver enzymes (GGT and aspartate aminotransferase) were observed in DILI cases compared with the non-DILI subjects. In the SR/IR group with DILI, the causality gradings for high-dose methotrexate (HD-MTX) were highly probable in 5 (13.2%) cases, probable in 31 (81.6%) cases, and possible in 2 (5.3%) cases. Among the DILI cases in HR-1, HR-2, and HR-3 groups, high causality gradings (probable + highly probable) were detected in "100% of HD-MTX + 57% of high-dose cytarabine (HD-Ara-C)," "100% of HD-MTX + 20% of pegylated asparaginase (PEG-ASP)," and "100% of HD-Ara-C + 33.3% of PEG-ASP," respectively.

Incidence of DILI in HR patients was significantly higher than that in SR/IR patients. A number of potential risk factors were identified, among which the preexisting liver conditions were suggested as shared risk factors in all stratification groups. HD-MTX, HD-Ara-C, and PEG-ASP were the main causative agents of DILI. The knowledge generated from this study will be helpful for understanding characteristics of DILI during consolidation treatment in childhood ALL.

Several environmental factors have been implicated in the pathogenesis of inflammatory bowel diseases (IBD); however, the evidence for alcohol is sparse, as is its implications on disease activity and overall management. Here, we examine the available evidence for the effect of alcohol on IBD, including its association with the development of IBD, role in exacerbations, and potential medication interactions. Several mechanisms have been demonstrated to mediate the effects of ethanol in the gastrointestinal tract. Alcohol has been shown to alter the gut microbiome, disrupt intestinal barrier, and increase intestinal permeability, directly and indirectly promoting immune activation. Conversely, specific alcoholic beverages, notably red wine, may have anti-inflammatory properties capable of assisting in disease control and affecting disease monitoring. Nonetheless, most alcohol-mediated effects seem to facilitate intestinal inflammation and consequently impact disease onset, recurrence, and symptom control. Furthermore, alcohol use interferes with the metabolism of several medications leading to increased side effect profiles or even loss of effect. Notably, mesalamine, azathioprine, methotrexate, and biologic medications can all be affected by concomitant alcohol intake via a variety of mechanisms.

Methotrexate (MTX) is the first-choice disease-modifying drug in juvenile idiopathic arthritis (JIA) treatment. Methotrexate is metabolized in the liver and can cause liver toxicity and fibrosis with long-term use. Ultrasound shear wave elastography (SWE) is a non-invasive method and can detect liver fibrosis by evaluating the liver elasticity. The aim of this study was to assess liver stiffness and detect if there is an increase in liver stiffness or fibrosis findings with the non-invasive SWE method in JIA patients under MTX treatment.

The study included 49 JIA patients under MTX treatment and 48 healthy controls, matched for age and sex with a body mass index below the 95th percentile. The demographic data and clinical characteristics of patients were obtained from medical records. Liver function tests were evaluated, and liver tissue stiffness measurements were performed with SWE.

Of the 49 patients, 67.35% were girls and the mean age was 10.69 (±4.33) years. The duration of MTX treatment was 23.00 (1-80) months, and the cumulative dose of MTX was 1,280.867 mg (±934.2) in the patient group. There was no statistically significant difference in liver stiffness between patients receiving MTX and healthy controls (P = 0.313). There was no relationship between MTX duration, cumulative dose, route of administration, and liver stiffness. Only gamma glutamyl transferase values were weakly correlated with liver stiffness (P = 0.029).

We did not detect an increase in liver tissue stiffness in JIA patients using methotrexate in comparison with controls.

Inflammatory bowel disease (IBD) may show a wide range of extraintestinal manifestations. In this context, liver involvement is a focal point for both an adequate management of the disease and its prognosis, due to possible serious comorbidity. The association between IBD and primary sclerosing cholangitis is the most known example. This association is relevant because it implies an increased risk of both colorectal cancer and cholangiocarcinoma. Additionally, drugs such as thiopurines or biologic agents can cause drug-induced liver damage; therefore, this event should be considered when planning IBD treatment. Additionally, particular consideration should be given to the evidence that IBD patients may have concomitant chronic viral hepatitis, such as hepatitis B and hepatitis C. Chronic immunosuppressive regimens may cause a hepatitis flare or reactivation of a healthy carrier state, therefore careful monitoring of these patients is necessary. Finally, the spread of obesity has involved even IBD patients, thus increasing the risk of non-alcoholic fatty liver disease, which has already proven to be more common in IBD patients than in the non-IBD population. This phenomenon is considered an emerging issue, as it will become the leading cause of liver cirrhosis.

Methotrexate (MTX) is a first-line systemic psoriasis therapy with risk of liver fibrosis. Noninvasive tools for liver fibrosis screening are Fibroscan®, Fibrosis-4 (FIB-4) index, and aspartate aminotransferase-to-platelet ratio (APRI) index. To compare Fibroscan®, FIB-4, and APRI in detecting fibrosis, determine association of fibrosis with MTX cumulative dose, and explore risk factors for fibrosis. A case-control study involving psoriasis patients aged ≥18 years with MTX cumulative dose ≥1 g, with age and sex-matched MTX naïve psoriasis patients was performed. Noninvasive tools were used to assess liver fibrosis. Sixty-one patients on MTX and 54 controls participated. Fibroscan® detected fibrosis in 22 (36.1%) patients on MTX compared to 11 (19.6%) controls (p = 0.05). FIB-4 predicted fibrosis in 13 (21.3%) patients on MTX and in 10 (17.9%) controls (p = 0.64) while APRI diagnosed 7 (11.5%) versus 7 (12.5%), p = 0.65. No significant correlation between Fibroscan® assessed liver stiffness and MTX cumulative dose (p = 0.47). Independent risk factors for liver fibrosis were MTX use with raised alanine aminotransferase (OR = 68.56, 95% CI 8.26; 568.86, p < 0.001), diabetes mellitus (OR = 30.35, 95% CI 7.52; 122.42, p < 0.001), and raised BMI (obese patients OR = 8.26, 95% CI 1.73-39.43, p = 0.02; overweight patients OR = 6.29, 95% CI 1.28-30.99, p = 0.01). Liver fibrosis occurred in both MTX naïve and MTX-treated psoriasis patients. Fibroscan® detected higher prevalence of liver fibrosis compared to FIB-4 and APRI. Cumulative MTX does not correlate with fibrosis severity. Fibroscan® is recommended prior to MTX therapy and at regular intervals especially among patients with diabetes and increased BMI.

To determine predictors of hepatic steatosis by the computed attenuation parameter (CAP) and fibrosis via transient elastography (TE) in persons on methotrexate (MTX) therapy with rheumatologic and dermatologic diseases.

A single-centred retrospective cohort study was performed. Patients on >6 months of MTX for a rheumatologic or dermatologic disease who had undergone TE from January 2015 to September 2019 were included. Multivariate analysis was performed to determine predictors of steatosis and fibrosis.

A total of 172 patients on methotrexate were included. Psoriasis was the most frequent diagnosis (n = 55), followed by rheumatoid arthritis (n = 45) and psoriatic arthritis (n = 34). Steatosis (CAP ≥245 dB/m) was present in 69.8% of patients. Multivariate regression analysis revealed that diabetes mellitus (OR 10.47, 95% CI 1.42-75.35), hypertension (OR 5.15, 95% CI 1.75-15.38), and BMI ≥30 kg/m2 (OR 16.47, 95% CI 5.56-45.56) were predictors of steatosis (CAP ≥245 dB/m). Predictors of moderate to severe fibrosis (Metavir ≥F2 = TE ≥8.0 kPa) by multivariate regression analysis included moderate to severe steatosis (CAP ≥270 dB/m) (OR 8.36, 95% CI 1.88-37.14), diabetes mellitus (OR 2.85, 95% CI 1.09-7.48), hypertension (OR 5.4, 95% CI 2.23-13.00), dyslipidemia (OR 3.71, 95% CI 1.50-9.18), and moderate alcohol use (OR 3.06, 95% CI 1.2-7.49).

In patients on MTX for rheumatologic and dermatologic diseases, hepatic steatosis as measured by CAP was common and moderate to severe steatosis predicted moderate to severe fibrosis.

Available data suggest that the prevalence of chronic liver disease (CLD) and primary liver cancer is rising in Europe and represents a major public health problem. Predictions are showing that these trends will continue to rise in the upcoming years.

Alcohol-related liver disease, nonalcohol fatty liver disease, and viral hepatitis B and hepatitis C are the leading causes of liver cirrhosis and primary liver cancer in Europe. Drug-induced liver injury represents a major cause of acute hepatitis, while liver transplantation is the second most common solid organ transplantation in the world. Patients with CLD have increasing rates of hospitalization, longer hospital stays, and more adverse outcomes compared to the other chronic conditions. Direct targeting of risk factors can prevent complications of advanced liver disease and improve outcome. Patients with CLD should be referred to a hepatologist for assessment of the stage of liver disease, for specific treatment and screening for hepatocellular carcinoma. Moreover, patients with unknown etiology of abnormal liver blood tests should be referred to a hepatologist for assessment of liver disease, as well as for prevention and treatment of complications of cirrhosis and/or portal hypertension. Key Messages: CLD is amenable to prevention and treatment, while disease management strategies need to improve in order to reduce the burden of liver disease and deaths due to end-stage liver diseases.

Methotrexate (MTX) is widely used in various medical specialties. However, hepatotoxicity is an ongoing concern and this is thought to be directly associated with cumulative dose. We sought to synthesise the published literature to evaluate the association between methotrexate hepatotoxicity and cumulative dose.

A systematic review of Medline (PubMed) EMBASE, CINAHL and The Cochrane Library was performed. Full texts of articles were examined, and excluded articles were recorded with reasons for exclusion. A meta-analysis of correlation coefficients was performed using Fisher's z-transformation and a random effects model. Cochran's Q-test and the I² statistic were calculated to assess heterogeneity.

A total of 35 studies met inclusion criteria. Measures of hepatotoxicity were highly varied and included liver biopsy, elastography, FibroTest, biochemical tests and scoring systems (Fib-4, APRI, AST:ALT). Some studies analysed for the association with MTX cumulative dose using more than one modality. Overall, 38 analyses found no significant association between MTX cumulative dose and hepatoxicity vs eight that identified a significant association. The pooled correlation coefficient from five studies which utilised elastography was 0.18 (95% CI, -0.09 to 0.42), with significant heterogeneity between studies (P < 0.0001), I²  = 92%).

Our synthesis of a large volume of studies in this review found no significant association between MTX cumulative dose and hepatotoxicity, both in terms of vote counting and with regard to the meta-analysis of correlation coefficients from studies that utilised elastography. This challenges the long-held belief that liver injury is a direct result of drug accumulation.

Only limited data are available on the risk of liver fibrosis in patients with rheumatoid arthritis on long-term methotrexate treatment. To assess the risk of liver fibrosis in patients with rheumatoid arthritis treated with methotrexate, non-invasive, ultrasound-based elastography [acoustic radiation force impulse (ARFI) imaging] was applied.

In total, 119 patients were assessed using acoustic radiation force impulse (ARFI) imaging between July 2018 and April 2019. In a cross-sectional, single-centre study design, ARFI scores were compared between patient subgroups with (n = 65) and without (n = 54) methotrexate exposure. The main outcome variable was the mean fibrosis score as measured by the ARFI method. The mean shear wave velocity was calculated from 10 valid ARFI measurements for each patient. Inferential statistical analyses (between group) were performed using ANOVA for independent samples in the case of continuous outcome variables.

Sixty-five patients with and fifty-four patients without MTX exposure were assessed using the ARFI elastography method. Participating patients on MTX medication (1.113 m/s) showed ARFI scores that were comparable to those of participants without MTX exposure (1.062 m/s); P = 0.228. The mean cumulative dose in the group of MTX-exposed patients was 3602 mg.

The mean value of the repeated determination of liver density using ARFI imaging did not differ significantly between the MTX-exposed and MTX-naive patients with RA. No increased rate of liver fibrosis was found among RA patients treated with MTX.

Up to 3% of methotrexate (MTX)-treated rheumatoid arthritis (RA) patients may develop liver fibrosis or cirrhosis, requiring effective screening algorithms.

To assess the utility of non-invasive liver fibrosis assessment in RA patients on MTX.

56 patients were recruited from rheumatology outpatient clinics in a public tertiary centre from July 2017 to October 2018. Clinical data was collected. Screening for hepatic fibrosis was performed utilising transient elastography (TE), aminoaspartate transaminase to platelet ratio index (APRI), Hepascore, and Fibrosis-4 index (FIB-4). Those with suspected significant liver fibrosis based on these screening tests were assessed by a hepatologist.

27 patients were suspected to have liver fibrosis on screening, including 10/56 (18%) by TE, 20/56 (36%) by Hepascore, 2/56 by APRI (4%) and 1/56 by FIB-4 (2%). Of these 27 patients, 11 were reviewed by a hepatologist and 1 diagnosed with significant liver fibrosis. TE, but not APRI, Hepascore or FIB-4, was found to have 100% sensitivity and 84% specificity (p=0.029) for hepatologist-diagnosed liver fibrosis.

Liver fibrosis develops in a minority of MTX-treated RA patients. This study suggests that TE is a more sensitive screening test than APRI, FIB-4 or Hepascore in the identification of people with RA at risk of hepatic fibrosis. This article is protected by copyright. All rights reserved.

Liver fibrosis is a common pathway shared by all progressive chronic liver diseases (CLD) regardless of the underlying etiologies. With liver biopsy being the gold standard in assessing fibrosis degree, there is a large unmet clinical need to develop non-invasive imaging tools that can directly and repeatedly quantify fibrosis throughout the liver for a more accurate assessment of disease burden, progression, and treatment response. Type I collagen is a particularly attractive target for molecular imaging as its excessive deposition is specific to fibrosis, and it is present in concentrations suitable for many imaging modalities. Novel molecular MRI contrast agents designed to bind with collagen provide direct quantification of collagen deposition, which have been validated across animal species and liver injury models. Collagen-targeted molecular imaging probes hold great promise not only as a tool for initial staging and surveillance of fibrosis progression, but also as a marker of fibrosis regression in drug trials.

Idiosyncratic drug-induced liver injury (IDILI) is an infrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs. Epimedii Folium (EF), the widely used herbal medicine, has shown to cause idiosyncratic liver injury, but the underlying mechanisms are poorly understood. Increasing evidence has indicated that most cases of IDILI are immune mediated. Here, we report that icariside Ⅱ (ICS Ⅱ), the major active and metabolic constituent of EF, causes idiosyncratic liver injury by promoting NLRP3 inflammasome activation. ICS Ⅱ exacerbates NLRP3 inflammasome activation triggered by adenosine triphosphate (ATP) and nigericin, but not silicon dioxide (SiO₂), monosodium urate (MSU) crystal or cytosolic lipopolysaccharide (LPS). Additionally, the activation of NLRC4 and AIM2 inflammasomes is not affected by ICS Ⅱ. Mechanistically, synergistic induction of mitochondrial reactive oxygen species (mtROS) is a crucial contributor to the enhancing effect of ICS Ⅱ on ATP- or nigericin-induced NLRP3 inflammasome activation. Importantly, in vivo data show that a combination of non-hepatotoxic doses of LPS and ICS Ⅱ causes the increase of aminotransferase activity, hepatic inflammation and pyroptosis, which is attenuated by Nlrp3 deficiency or pretreatment with MCC950 (a specific NLRP3 inflammasome inhibitor). In conclusion, these findings demonstrate that ICS Ⅱ causes idiosyncratic liver injury through enhancing NLRP3 inflammasome activation and suggest that ICS Ⅱ may be a risk factor and responsible for EF-induced liver injury.

We investigated the disease flare rate in patients with rheumatoid arthritis (RA) who achieved low disease activity following long-term methotrexate (MTX) treatment and the factors related to flare.

This retrospective longitudinal cohort study included patients with RA and low disease activity who were exposed to MTX for >10 years. Disease flare was defined as an increase in Disease Activity Score of 28 joints (DAS28) of >1.2 within 6 months of discontinuation of MTX. Logistic regression analysis was performed to identify the factors associated with flare.

In total, 97 patients with RA were included in the study. The mean baseline DAS28 was 1.96 ± 0.56. The median cumulative MTX dose was 11.7 g; the median duration of exposure to MTX was 19 years. Following MTX discontinuation, flare occurred in 43 (44.3%) patients; the median time to flare was 99 (28-168) days. According to univariate logistic regression analysis, C-reactive protein, erythrocyte sedimentation rate (ESR) at discontinuation, the average ESR in the 6 months before discontinuation of MTX, a weekly dose of MTX before discontinuation, and use of other conventional synthetic disease-modifying antirheumatic drugs were associated with a higher risk of disease flare. In multivariable analysis, a weekly dose of MTX before discontinuation (odds ratio 1.014; 95% CI 1.014-1.342; P = .031) was significantly associated with flare risk.

Among patients with RA who achieved low disease activity with long-term treatment with MTX, more than half remained flare free after MTX discontinuation. A higher MTX dose before discontinuation was associated with a high flare risk.

The aims were to determine the incidence rate, predictive factors and severity of liver injury that develops during MTX treatment for RA and to evaluate the role of pretreatment hepatic fat deposition.

We used an ongoing real-life registry containing RA patients who had started MTX between August 2007 and April 2018 at participating institutions. The liver-to-spleen attenuation ratio on CT scans at enrolment was used to evaluate pretreatment fat deposition quantitatively. Patients were followed until persistent transaminitis developed or until the end of the study. Liver biopsy was performed for patients who presented with persistent transaminitis.

We followed 289 new MTX users without pretreatment elevations of transaminases (mean follow-up time, 58.3 months). Hepatic fat deposition was detected in half of the patients at enrolment. During follow-up, persistent transaminitis occurred at a crude incidence rate of 3.13 per 100 person-years, and the cumulative incidence at 5 years was estimated to be 13%. A multivariate Fine-Gray regression analysis showed that the most important predictive factors were pre-existing moderate to severe fat deposition (adjusted hazard ratio, 7.69; 95% CI: 3.10, 19.10) and obesity (adjusted hazard ratio, 2.68; 95% CI: 1.37, 5.25). Non-alcoholic steatohepatitis (NASH) was the most predominant pattern in liver biopsy samples. Hepatic fibrosis was found in 90% of samples, but most cases were not advanced.

Aggravation of underlying fatty liver to NASH with fibrosis seems to be an important mechanism of liver injury that occurs in MTX-treated RA patients.

Psoriasis is a chronic inflammatory disease involving multiple organ systems and affecting approximately 2% of the world's population. In this guideline, we focus the discussion on systemic, nonbiologic medications for the treatment of this disease. We provide detailed discussion of efficacy and safety for the most commonly used medications, including methotrexate, cyclosporine, and acitretin, and provide recommendations to assist prescribers in initiating and managing patients on these treatments. Additionally, we discuss newer therapies, including tofacitinib and apremilast, and briefly touch on a number of other medications, including fumaric acid esters (used outside the United States) and therapies that are no longer widely used for the treatment of psoriasis (ie, hydroxyurea, leflunomide, mycophenolate mofetil, thioguanine, and tacrolimus).

The reported hepatotoxicity of methotrexate underlines the need for a repeated non-invasive and reliable evaluation of liver fibrosis. We estimated, using a non-invasive strategy, the prevalence of significant liver fibrosis in patients treated by methotrexate and the predictors of significant fibrosis (fibrosis≥F2).

Fibrosis was prospectively evaluated using 9 non-invasive tests in consecutive patients with psoriasis, rheumatoid arthritis, or Crohn's disease. Significant fibrosis was assessed without liver biopsy by defining a "specific method" (result given by the majority of the tests) and a "sensitive method" (at least one test indicating a stage≥F2).

One hundred and thirty-one patients (66 Psoriasis, 40 rheumatoid arthritis, and 25 Crohn's disease) were enrolled, including 83 receiving methotrexate. Seven tests were performed on average per patient, with a complete concordance in 75% of cases. Fibroscan® was interpretable in only 61% of patients. The best performances (AUROC>0.9) for predicting significant fibrosis were obtained by tests dedicated to steatohepatitis (FibroMeter NAFLD, NFS and FPI). The prevalence of fibrosis≥F2 according to the "specific" or the "sensitive" assessment of fibrosis was 10% and 28%, respectively. Methotrexate exposure did not influence the fibrosis stage. Factors independently associated with significant fibrosis according our "sensitive method" were age, male gender, and metabolic syndrome.

We provided a non-invasive approach for identifying liver fibrosis≥F2 by using 8 biochemical tests and Fibroscan®. In this population, the risk of significant fibrosis was related to age, male gender, and presence of metabolic syndrome, but was not influenced by methotrexate.

Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.

Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.