Cumulative Dose Of Methotrexate Research Articles

Evaluation of liver elasticity with shear-wave elastography in juvenile idiopathic arthritis patients receiving methotrexate.

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.

Immune responses to mRNA vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory rheumatic diseases

BackgroundPatients with immune-mediated rheumatic diseases (IMRDs) are commonly treated with immunosuppressors and prone to infections. Recently introduced mRNA SARS-CoV-2 vaccines have demonstrated extraordinary efficacy across all ages. Immunosuppressed patients were...

Usefulness of noninvasive diagnostic procedures for assessment of methotrexate hepatotoxicity in patients with rheumatoid arthritis

Methotrexate (MTX) is recommended as a first-line treatment for rheumatoid arthritis (RA). There are no strict guidelines regarding monitoring for liver damage in RA patients. This study aimed to evaluate noninvasive diagnostic procedures in assessing liver fibrosis in RA patients. Ninety-six RA patients were recruited for this study. The procollagen III N-terminal peptide (PIIINP) serum level was measured in all patients. The Enhanced Liver Fibrosis score (ELF-1) was calculated for 82 patients. Transient elastography (TE) was performed in 91 patients, those examined were divided into two groups: a study and control group, comprising patients with and without risk factors for liver fibrosis, respectively. The TE result correlated only with the body mass index—BMI (p < 0.05); there was no correlation with the cumulative MTX dose (p = 0.33). The TE result was significantly higher in those with risk factors for liver fibrosis than in those without risk factors (TE result > = 7.1 kPa 28/42 vs 13/41, HR = 2.103, Mann–Whitney U test, approximately 0.02). There was a positive correlation between the PIIINP level and body weight (p = 0.028), cumulative MTX dose (p = 0.007), RA activity (p = 0.028) and diabetes mellitus (DM) (p = 0.001). There was a positive correlation between the ELF-1 score and age (p < 0.001), cumulative MTX dose (p = 0.007) and RA activity (p < 0.001). The PIIINP level and ELF-1 score are not organ specific, and readings may vary depending on RA activity. TE is organ specific and can be performed by a skilled ultrasonographer might be useful to assess actual liver condition.

Comparison of noninvasive screening tools for hepatic fibrosis, association with methotrexate cumulative dose, and risk factors in psoriasis patients.

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.

What is the impact of methotrexate on liver in patients with juvenile idiopathic arthritis? Results of liver SWE performed in a single centre.

Long-term therapy with low-dose methotrexate (MTX) is widely used in treatment of rheumatic diseases, in children. The purpose of this study was to evaluate liver elasticity in patients with juvenile idiopathic arthritis (JIA) who received MTX and compare the results with control group. Liver elasticity was evaluated with shear wave elastography (SWE) technique in 25 patients aged 3-17 years who were followed up with JIA and received MTX and compared with 25 healthy controls of the same age and weight. Factors that had an effect on liver elasticity were examined. The mean SWE value of patients was 2.64 ± 2.13 m/s and 24.10 ± 18.50kPa, whereas 1.83 ± 0.16 m/s and 10.09 ± 1.83kPa in control group. There was a significant difference in liver elasticity in the patient and control groups. When the patients were evaluated as Group 1 (< 1000 mg) and Group 2 (≥ 1000 mg) according to the cumulative MTX dose, no significant difference was obtained. There was positive correlation between liver elasticity and weekly MTX dose and age. Our study revealed that liver elasticity significantly decreased in patients who received MTX when compared with the control group. The elastography technique will be understood better over time and used safely in many areas.

P-88 EVALUATION OF STEATOSIS AND LIVER FIBROSIS IN PATIENTS WITH PSORIASIS: THE IMPACT OF METHOTREXATE AND METABOLIC FACTORS ON THE SEVERITY OF THE DISEASE

Methotrexate (MTX) is a crucial treatment drug in Psoriasis. Its impact on the development of liver fibrosis has been questioned since a high prevalence of non-alcoholic fatty liver disease has been described in this disease. To assess, in Psoriasis patients, the associated factors for liver steatosis and advanced fibrosis diagnosed by transient hepatic elastography (THE). This was a cross-sectional study in Psoriasis patients. Chronic liver diseases, use of steatogenic drugs (except MTX), and alcohol intake >20–30 g/day (women/men) were excluded. Demographic, anthropometric, clinical, and laboratory data were registered as well as time since psoriasis onset and cumulative MTX doses. THE cutoff points ≥7.9KPa (probe M) and ≥7.2KPa (probe XL) were considered for the diagnosis of advanced liver fibrosis and CAP values ≥248 dB/m for the diagnosis of steatosis. Logistic regression analysis was performed, and the significance level was 0.05. 141 patients were included (42.6% male, 53.7±12.4 years old, body mass index [BMI] 29.3±5.9 kg/m2). The prevalence of Diabetes Mellitus (DM), Metabolic Syndrome, Systemic Arterial Hypertension (SAH), and dyslipidemia was 28.4%, 55.3%, 57.4% and 73.7%, respectively. Overall, 67.4% had steatosis by CAP and 16.3% had advanced fibrosis by THE. Median time since psoriasis onset was 121.1 months (69.5-234.1). MTX cumulative dose ≥1000mg was found in 47.8% (median 2212.5mg [1360-3213.70]). In the regression analysis, BMI (OR 1.25 95% CI 1.12-1.38; p<0.001) and triglyceride levels (OR 1.01 95% CI 1.01-1.02; p=0.002) were the only variables independently associated with steatosis. DM (OR 4.8 95% CI 1.6-14.3; p=0.005) and SAH (OR 11.6 95% CI 2.2-61.1; p=0.004) were associated with advanced fibrosis. On a cohort of patients with Psoriasis, metabolic variables were the main factors related to liver steatosis and fibrosis. There was no association between cumulative MTX dose or disease duration and liver steatosis or fibrosis in this population.

Pediatric-Inspired Protocol Improved Overall Survival in Young Adult Aged 18-30 Years Old with Philadelphia-Negative Acute Lymphoblastic Leukemia Compared to the Standard Adult Hypercvad Protocol

Background:Pediatric acute lymphoblastic leukemia (ALL) have excellent overall survival (OS) compared to adult ALL even in the young adult group. The difference in OS was thought to be due to the difference in treatment protocol with the pediatric-inspired protocol being more intensive and with minimal residual disease (MRD) driven. Strong data has emerged over the past decade from different ALL study groups from Europe and North America to support the use of pediatric-inspired protocol for young adult up to age 30-40 years.HyperCVAD protocol, designed by MD Anderson group in early 90s, has been our standard treatment for adult ALL including young adult since year 2000. Over the past decade, a locally designed pediatric-inspired and MRD driven protocol - known as MASPORE Protocol was used with increasing frequency for those age 30 years and below. MASPORE protocol has higher cumulative dose of vincristine and methotrexate, and use of L-Asparaginase compared to HyperCVAD.In this retrospective study, we aimed to evaluate the safety, tolerability and efficacy of MASPORE protocol in relation to the standard adult ALL protocol - HyperCVAD in young adult aged 18-30 years who were diagnosed with Philadelphia-negative (Ph-) ALL.Method:Patients aged 18 to 30 years old with Ph- ALL who had received HyperCVAD or MASPORE regimen were retrospectively identified via our institution database. Clinical data, toxicity profile, and treatment outcome were collected, compared and analyzed.High risk disease was defined as high white blood cell (WBC) (>30x109/L for B-ALL, and >100x109/L for T-ALL), failure to achieve complete remission (CR) after induction, failure to achieve MRD target at 4 weeks and 8 weeks (in MASPORE group), hypodiploidy, t(9;22), t(4;11) and other MLL-gene rearrangement. An intensified chemotherapy regimen would be given to those high-risk disease in MASPORE regimen, while HyperCVAD regimen has a fixed intensity irrespective of risk.Results:A total of 30 consecutive Ph- ALL patients aged between 18 to 30 years old who were treated with HyperCVAD or MASPORE protocol were included in the analysis. 16 were treated with MASPORE protocol while 14 were treated with HyperCVAD protocol. The median age was 22 years old (Range: 18 - 29 years old). Median follow-up for MASPORE was 37.0 months and HyperCVAD was 85.0 months. HyperCVAD-treated patients were mainly from year 2004 to 2011, while more than 80% of MASPORE patients were treated after year 2013.18 patients had B-ALL, 11 with T-ALL and 1 with mixed phenotypes. 2 patients (1 in each group) had high cytogenetic risk. Median WBC was 14.1 (range: 1.9-287) and 10.1 (range: 1.2-242) for HyperCVAD and MASPORE respectively.All patients achieved CR at the end of induction with no early death (within 60 days of induction). Overall relapse rate was 33.3% with lower relapse rate observed in in MASPORE (18.8%) compared to 50.0% in HyperCVAD. (p-value: 0.07). 4 in HyperCVAD and 3 in MASPORE received allo-SCT subsequently.Median OS in MASPORE was not reached. Median OS for HyperCVAD was 26.3 months (95% CI: 3.6-49.1 months). Overall survival at 3 years were 84.0% and 46.2% in the MASPORE and HyperCVAD, respectively, p=0.038 (Figure 1).Median Leukemia Free Survival (LFS) in MASPORE was not reached. Median LFS in HyperCVAD was 12.5 months (95% CI: 4.2-20.8 months). LFS at 3 years were 75.8% and 38.5% in the MASPORE and HyperCVAD respectively, p=0.089 (Figure 2).6 patients in MASPORE had thrombotic events (3 with cerebral venous thrombosis and 3 with deep vein thrombosis (DVT)) while only 1 patient had DVT in HyperCVAD group. 11 patients in MASPORE group had at least 1 episode of grade 3 or more transaminitis, compared to 3 patients in HyperCVAD. 7 patients in HyperCVAD group had at least one episode of bacteremia during the course of treatment compared to 4 patients in the MASPORE group. Two treatment-related death were observed, both from HyperCVAD group.ConclusionsMASPORE protocol was well tolerated albeit higher rate of thrombotic events and transaminitis which most likely related to L-asparaginase, but with lower incidence of bacteremia and treatment related death. It showed a superior overall survival compared to HyperCVAD protocol and a trend towards improved leukemia free survival. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

ABCB1/P-glycoprotein (Pgp) expression as stratification factor for treatment of patients with non-metastaticextremity high-grade osteosarcoma: A merged analysis of an Italian (ISG) and a Spanish (GEIS) sarcoma groups' multicentric prospective trials.

11527 Background: Overexpression of ABCB1/P-glycoprotein (Pgp) predicts poor outcome in retrospective osteosarcoma series.Two prospective trials with Pgp expression and post-induction histologic response as stratification factors were activated in Italy (ISG/OS-2) and Spain (GEIS-33). Methods: Patients ≤ 40 years with extremity non-metastatic high-grade osteosarcoma were eligible. Analysisi of Pgp expression from diagnostic biopsy was centralized. Preoperatively, all patients received methotrexate, adriamycin, cisplatinum (MAP). Surgery was performed at week 8. All patients received a dose of adriamycin following surgery. In case of Pgp overexpression (Pgp+), mifamurtide (2 mg/m2 twice/week for 3 months then weekly for 6 months) was added after surgery, with 4 consecutive cycles of ifosfamide 3 gr/m2/day, day 1-5 (HDIFO) in case of poor histologic response (necrosis &lt; 90%) to MAP. Patients without overexpression of Pgp (Pgp-) received MAP postoperatively, regardless the pathological response. From March 2013, an amendment increased high dose methotrexate cumulative dose from 60 g/m2 (5 cycles) to 120 mg/m2 (10 cycles). The post-amendment regimen was adopted in the observational prospective study by GEIS. Here we present the merged analysis of ISG/OS-2 patients treated post-amendment and GEIS-33. Results: From March 2013 to April 2018, 274 patients were included. Median age was 14 years (range 4-38), male/female: 163/111; 90 were Pgp-, 164 were Pgp+, 20 not evaluable. With a median follow-up of 48 months (1.3-78.5 months), the 3-year EFS and OS were 71.9% (95%CI 66-76.9) and 88% (95%CI: 83.2-91.5) respectively, with no inferior survival for Pgp positive patients and improved survival for good responders (Table). Conclusions: In this prospective uncontrolled study with a risk-adapted strategy for non-metastatic osteosarcoma, survival is superior to that of all ISG/GEIS previous series. The 3-year EFS of 71.9% compares favorably with other reports. Pgp+ patients performed well in this study, in which mifamurtide and HDIFO were added after a poor response to MAP. Clinical trial information: NCT01459484; NCT04383288. [Table: see text]

Risk of liver fibrosis induced by methotrexate and other rheumatoid arthritis medications according to the Fibrosis-4 Index.

We aimed to estimate the amount of scarring in the liver with the fibrosis-4 (FIB-4) index in patients with rheumatoid arthritis (RA) with special interest in methotrexate (MTX) influence. This was a cross-sectional monocentric study including successive RA patients recruited for a 12-month period. Data on liver function, disease activity, hepatotoxic and cardiovascular risk factors were systematically collected. The FIB-4 index was calculated according the following formula: (age(years)× AST(U/L)/platelet (PLT) (109/L)×√ALT(U/L)). We included 170 patients with established RA: 141 (83%) were women with a mean age of 59±12 years and mean disease duration of 15±11 years. The FIB-4 was low and not significantly different between patients receiving MTX (n=102), patients previously treated with MTX (n=39) and patients never treated with MTX (n=29). No correlation was observed between FIB-4 values and cumulative MTX dose (r=0.09, p=0.271). No relationship was observed between FIB-4 and MTX treatment duration. The FIB-4 index was found significantly increased in patients receiving leflunomide (n=24), (median (range) 1.58 (0.46-3.16) vs. 1.18 (0.54-3.40), p=0.019) and tocilizumab (n=14), (median (range) 1.82 (0.75-3.73) vs. 1.18 (0.54-3.40), p=0.005) compared to patients not receiving DMARDs (n=29). Multivariate logistic regression analyses revealed an independent association between increased FIB-4 (>1.45) and male gender, low disease activity, and treatment with leflunomide and tocilizumab. RA patients with long-term maintenance MTX therapy have low FIB-4 values suggesting that MTX is not associated with an increased risk of advanced liver fibrosis. Increased FIB-4 values have been detected in leflunomide- and tocilizumab-treated patients, which will deserve dedicated further investigations.

Is methotrexate hepatotoxicity associated with cumulative dose? A systematic review and meta-analysis.

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'sz-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.

Prevalence of liver fibrosis by Fibroscan in patients on long-term methotrexate therapy for rheumatoid arthritis.

Data on the long-term use of methotrexate (MTX) causing liver fibrosis in patients with rheumatoid arthritis (RA) is sparse. Liver biopsy is the gold standard to assess fibrosis but is an invasive procedure. Transient elastography (TE) by Fibroscan is a noninvasive validated tool to detect and quantify liver fibrosis. The present study aimed to assess the prevalence of liver fibrosis by Fibroscan in patients with RA on long-term MTX therapy and its correlation with cumulative dose of MTX. This cross-sectional study included adult patients (≥ 18 years age) of RA who had been on MTX for ≥ 3 years. The patients' records were reviewed, and the cumulative dose of MTX was calculated. Liver fibrosis was assessed by TE method, and the cutoff value of 7.1 kPa (kilopascal) was considered abnormal (liver fibrosis). Spearman's rank test was used to assess the correlation between the cumulative dose of MTX and Fibroscan score. Seventy-five patients were enrolled of which 69 were females (92%). The mean age was 47.2 ± 11.3 years. The mean body mass index and waist circumference were 24.8 ± 3.9 kg/m2 and 91.6 ± 9.9 cm, respectively. The median duration and cumulative dose of MTX were 336 weeks (interquartile range,144-912 weeks) and 6300 mg (interquartile range, 2400-22,000 mg), respectively. The mean liver stiffness was 5.22 ± 2.03 kPa. Twelve patients (16%) had Fibroscan score ≥ 7.1 kPa, of which 3 patients had severe liver stiffness (9.5 to 12.5 kPa) and one patient had liver stiffness in the range of cirrhosis (> 12.5 kPa). Fibroscan scores significantly correlated with cumulative dose of MTX (r= 0.30, p = 0.008). Long-term MTX therapy in RA was associated with increased liver stiffness on Fibroscan. Key Points • Fibroscan is a useful tool for monitoring MTX-induced liver fibrosis. • Liver fibrosis as evidenced by increased liver stiffness on Fibroscan is prevalent among patients on long-term MTX therapy for RA.

Fibrosis indexes in adolescents with juvenile idiopathic arthritis treated with methotrexate

Juvenile idiopathic arthritis is the most common form of arthritis in children and adolescents. Methotrexate is the mainstay of juvenile idiopathic arthritis treatment. Methotrexate is well known to cause serum aminotransferase elevations, and longterm therapy has been linked to the development of fatty liver disease, fibrosis and even cirrhosis. The aim of the study was to assess non-invasive liver fibrosis indexes in adolescents with juvenile idiopathic arthritis treated with methotrexate. Materials and methods: A total of 68 children with juvenile idiopathic arthritis were enrolled in the study. A total of 68 children – 25 boys (36.8%) and 43 girls (63.2%) – were examined. The children were divided into four groups based on the methotrexate cumulative dose. The following data were analysed: total bilirubin and its fractions, cholesterol, β-lipoproteins, aspartate transaminase, alanine aminotransferase. Fibrosis indexes, i.e. APRI, FIB-4 score, AAR, AARPRI, were studied. Results: When studying the dynamics of non-invasive indices, their heterogeneous nature and cumulative dose dependence are determined. Statistically significant changes in fibrosis indexes and biochemical parameters were observed when the children reached cumulative methotrexate doses of 1 g and 3 g. Conclusions: It is possible to monitor carefully liver condition during the whole treatment and conduct a more in-depth examination only if it is necessary. Our data shows that the APRI index (AST to platelet ratio index) is most indicative.

Prevalence and risk factors of moderate to severe hepatic steatosis in patients with rheumatoid arthritis: an ultrasonography cross-sectional case-control study.

Background:The independent association between hepatic steatosis and rheumatoid arthritis is poorly defined.Methods:The presence of moderate to severe steatosis was assessed, using liver ultrasonography, in 364 consecutive non-diabetic subjects (223 patients with rheumatoid arthritis and 141 age- and sex-matched healthy controls). Adjusted multiple regression analysis was performed to explore the association between rheumatoid arthritis and moderate to severe steatosis in the overall sample and identify independent risk factors in the rheumatoid arthritis subgroup.Results:The prevalence of moderate to severe steatosis in the overall sample was 31.3%, with a significantly higher prevalence in patients with rheumatoid arthritis than healthy controls (38.7% versus 19.7%, p < 0.0001). After adjustment for sex, age, cholesterol, triglycerides, body mass index, waist, hypertension and smoke, rheumatoid arthritis remained significantly associated with moderate to severe steatosis [odds ratio (95% confidence interval) = 2.24 (1.31, 3.84); p = 0.003]. In the rheumatoid arthritis group, male sex, higher body mass index, higher triglycerides concentrations and higher cumulative dosage of methotrexate [odds ratio (95% confidence interval) = 1.11 (1.01, 1.23); p = 0.026] were significantly associated with moderate to severe steatosis, while systemic inflammation, disease activity, use of steroids and biologics were not.Conclusion:Rheumatoid arthritis is independently associated with moderate to severe steatosis, with male sex, higher body mass index and cumulative dose of methotrexate being predisposing factors. Further prospective studies are warranted to confirm our findings and to investigate the effect of steatosis on liver outcomes in the rheumatoid arthritis population.

Methotrexate use does not increase the prevalence of hepatic steatosis: a real-world retrospective nested case-control study.

We aimed to determine whether methotrexate (MTX) treatment in patients with rheumatoid arthritis (RA) leads to the development of non-alcoholic fatty liver (NAFL). Data were derived from records of all patients with RA who underwent abdominal ultrasonography at the Jeonbuk National University Hospital. Patients with ultrasound-proven NAFL were identified, and those without NAFL were matched by age and sex using the propensity score matching method at 1:3 ratio. We also analyzed the Health Insurance Review and Assessment Service-National Patient Samples, a nationwide cohort database, to determine the association between MTX use and NAFL in a large number of patients (n = 24,653). In the hospital cohort, 92 patients with NAFL did not show significant differences in the cumulative MTX dose when compared with the no-NAFL group (n = 276) (1908.5 ± 1757.5 vs. 1948.6 ± 2118.8mg, p = 0.911). The prevalence of NAFL was not significantly different across strata of cumulative MTX dose. Multiple logistic analyses identified hypertriglyceridemia (OR, 4.88 [95% CI, 1.13-20.93]) and higher body mass index (OR, 1.22 [95% CI, 1.05-1.41]) as being associated with an increased risk of NAFL. In the nationwide cohort, the MTX exposure rate between the NAFL and no-NAFL groups was not significantly different. Collectively, no significant association between NAFL development and administration of MTX was detected in this study. Our results suggest that it is more efficient to adjust for individualized risk factors for NAFL prevention rather than discontinuation of MTX in patients with RA. Key Points • NAFLD has been highlighted with increasing prevalence worldwide and possible progression to end-stage liver disease. • Cumulative dose or exposure history of MTX does not show a significant association with NAFLD prevalence. • Modifying well-established risk factors is more efficient in NAFLD prevention rather than discontinuation of MTX.

Urine NGAL and KIM-1: tubular injury markers in acute lymphoblastic leukemia survivors

IntroductionNephrotoxicity is a potential adverse effect of anticancer treatment in childhood. Cytostatics, abdominal radiotherapy, total body irradiation (TBI) and some agents used in supportive care may induce acute kidney injury (AKI) or lead to chronic kidney disease (CKD). The aim of this study was to test the hypothesis whether urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are increased in acute lymphoblastic leukemia (ALL) survivors.MethodThe study cohort consisted of 86 patients (42 females) previously treated for ALL. The median time after cessation of treatment was 6.55 (IQR: 1.96–9.93) years and median age at the time of study: 12 (IQR: 6.76–16.00). The control group included 53 healthy peers. Immunoenzymatic ELISA commercial kits were used to measure urine KIM-1 and NGAL levels.ResultsThe median levels of urine uNGAL (p < 0.05), uNGAL/creatinine (cr.) ratio (p < 0.0001) and uKIM-1/creatinine ratio (p < 0.0001) were significantly higher in ALL survivors in comparison with healthy controls. Female patients had significantly higher levels of NGAL and NGAL/cr. than males (mean 8.42 ± 7.1 vs. 4.59 ± 4.5 ng/mL and 86.57 ± 77 vs. 37.7 ± 37 ng/mg, respectively; p < 0.01). Of all the study participants, 11 (13%) presented eGFR below 90 mL/min/1.73 m2. The NGAL/cr. ratio seemed to be the best predictor of decreased eGFR (AUC = 0.65). The cumulative dose of methotrexate and cyclophosphamide did not predict the values of the urine NGAL, NGAL/cr., KIM-1/cr. and eGFR.Five years after the end of treatment, the patients had higher levels of uKIM-1 (1.02 ± 0.8 vs. 0.62 ± 0.6 ng/mL, p < 0.01), uNGAL (7.9 ± 6.7 vs. 4.6 ± 5 ng/mL, p < 0.01) and lower eGFR (114 ± 29 vs. 134 ± 35 mL/min/1.73 m2, p < 0.01) in comparison with ALL survivors with the observation period of less than 5 years.ConclusionWe demonstrated that ALL survivors have higher levels of urine NGAL, NGAL/cr. and uKIM-1/cr. ratio as compared to the control group. Further long-term follow-up studies are necessary to assess the significance of the NGAL and KIM-1 and their relationship to kidney damage after anticancer treatment in childhood.

Fibroblast growth factor and hepatocyte growth factor in adolescents with juvenile idiopathic arthritis treated with methotrexate

Methotrexate (MTX) is a cornerstone of therapy worldwide for juvenile idiopathic arthritis (JIA). Despite the fact that fibrosis molecular mechanisms as well as MTX elimination and fibrosis indexes were studied a lot there is still not enough information for adolescence.The aim was to study dynamics of molecular-cellular mechanisms activation of fibrotic processes development in the liver in adolescents with juvenile idiopathic arthritis treated with methotrexate by determining the content of fibroblast growth factor and hepatocyte growth factor.Materials and methods: A total of 68 children with juvenile idiopathic arthritis, were enrolled in the study. 25 boys (36.8 %) and 43 girls (63.2 %) were examined. Children were divided into four groups in accordance with cumulative dose (CD) of methotrexate. The following data were analyzed: liver function tests (aspartate aminotransferase (AST) (U/L), alanylaminotransferase (ALT) (U/L)), lactate dehydrogenase (LDH) (U/L), adiponectin (μg / ml), BFGF (pg / ml), HGF (pg / ml), liver fibrosis indexes APRI and FIB-4 Score.Results. Positive effect of JIA treatment with MTX on the liver is noted. When CD MTX reaches 1 and3 grams, liver state studying is needed. When the CD MTX of1 gram is reached, regulatory mechanisms are involved that provoke liver regeneration. When the CD MTX reaches3 grams, the liver condition may deteriorate, which in the future can lead to irreversible processes of liver fibrosis.Conclusions: Thus, it is important to control possible liver disorders in adolescence treated with MTX. Monitoring the processes of liver fibrosis is appropriate at all stages of JIA treatment, but it is most advisable when the MTX cumulative dose is reaching 1 and3 grams

Echocardiographic study of juvenile dermatomyositis patients: new insights from speckle-tracking-derived strain.

This study aimed to investigate subclinical left ventricle (LV) systolic dysfunction in juvenile dermatomyositis (JDM) using two-dimensional speckle-tracking echocardiography (2DST). Possible associations between LV deformation impairment and disease activity/cumulative damage were also evaluated. Thirty-five consecutive JDM patients without cardiac symptoms and 35 healthy volunteers were enrolled. Clinical data were collected from medical records, and echocardiograms were performed by a pediatric cardiologist, unaware of patients' conditions. Patients and controls had similar age (12.6 ± 0.7 vs.12.5 ± 0.6; p = 0.97) and gender (11F:24M vs.11F:24M; p = 1.0). Median of JDM duration was 4.6 (0.04-17.6) years, and only 6/35 (17%) had active disease (disease activity score (DAS > 3)). Conventional echocardiogram revealed preserved LV ejection fraction (EF) (≥ 55%) in all individuals. In JDM, 2DST identified reduction of LV longitudinal [-22(-17.2 to -27.9) % vs. -23(-20.8 to -27.4) %; p = 0.028)] and circumferential -23.9 ± 2.8% vs. -26.7 ± 2.9%; p = 0.0002) strain. Lower longitudinal strain was associated with DAS >3 -19.9(-17.2 to -26.5)% vs. -22.1-18.9 to -27.9)%; p = 0.046], MDI extent > 0 [-19(-17.2 to -22.5)% vs. -22.1-19.2 to -27.9)%; p = 0.0008], MDI severity > 0 [-19(-17.2 to -22.1)% vs. -22.3(-20.3 to -27.9)%; p = 0.0001] and calcinosis[-20.6(-17.2 to -23)% vs. -22.3(-20.3 to -27.9)%; p = 0.03]. Lower circumferential strain was associated with MDI extent > 0 (-22.1 ± 3.87% vs. -24.4 ± 2.3%; p = 0.039), MDI severity > 0 (-21.7 ± 3% vs. 24.7 ± 2.3%; p = 0.004) and calcinosis (-22.5 ± 3.3% vs. -24.8 ± 2.1%; p = 0.02). There was a negative correlation between longitudinal strain and cumulative dose of prednisone (r = -0.44; p = 0.009) and methotrexate (r = -0.33; p = 0.0008). LV 2DST detected early systolic myocardial compromise in asymptomatic pediatric JDM patients, with preserved EF. Longitudinal strain impairment was associated with disease activity and cumulative damage, whereas circumferential strain impairment was associated exclusively with cumulative damage. • Serious cardiac involvement is rare but has been associated with death in juvenile dermatomyositis. • Two-dimensional speckle tracking stands out for the identification of subclinical myocardial compromise in juvenile dermatomyositis. • Longitudinal strain impairment is associated with disease activity and cumulative damage, whereas circumferential strain impairment is associated exclusively with cumulative damage.

Sex-Specific Associations Between Chemotherapy, Chronic Conditions, and Neurocognitive Impairment in Acute Lymphoblastic Leukemia Survivors: A Report From the Childhood Cancer Survivor Study.

The purpose was to examine associations between treatment and chronic health conditions with neurocognitive impairment survivors of acute lymphoblastic leukemia (ALL) treated with chemotherapy only. This cross-sectional study included 1207 ALL survivors (54.0% female; mean age 30.6 years) and 2273 siblings (56.9% female; mean age 47.6 years), who completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire. Multivariable logistic regression compared prevalence of neurocognitive impairment between survivors and siblings by sex. Associations between neurocognitive impairment with treatment exposures and chronic conditions (graded according to Common Terminology Criteria for Adverse Events) were also examined. Statistical tests were 2-sided. Relative to same-sex siblings, male and female ALL survivors reported increased prevalence of impaired task efficiency (males: 11.7% vs 16.9%; adjusted odds ratio [OR] = 1.89, 95% confidence interval [CI] = 1.31 to 2.74; females: 12.5% vs 17.6%; OR = 1.50, 95% CI = 1.07 to 2.14), as well as impaired memory (males: 11.6% vs 19.9%, OR = 1.89, CI = 1.31 to 2.74; females: 14.78% vs 25.4%, OR = 1.96, 95% CI = 1.43 to 2.70, respectively). Among male survivors, impaired task efficiency was associated with 2-4 neurologic conditions (OR = 4.33, 95% CI = 1.76 to 10.68) and with pulmonary conditions (OR = 4.99, 95% CI = 1.51 to 16.50), and impaired memory was associated with increased cumulative dose of intrathecal methotrexate (OR = 1.68, 95% CI = 1.16 to 2.46) and with exposure to dexamethasone (OR = 2.44, 95% CI = 1.19 to 5.01). In female survivors, grade 2-4 endocrine conditions were associated with higher risk of impaired task efficiency (OR = 2.19, 95% CI = 1.20 to 3.97) and memory (OR = 2.26, 95% CI = 1.31 to 3.92). Neurocognitive impairment is associated with methotrexate, dexamethasone, and chronic health conditions in a sex-specific manner, highlighting the need to investigate physiological mechanisms and monitor impact through survivorship.

Prevalence of and factors associated to chronic kidney disease and hypertension in a cohort of children with juvenile idiopathic arthritis.

We evaluated chronic kidney disease (CKD) (proteinuria or estimated glomerular filtration rate < 60 mL/min/1.73 m2) or hypertension prevalence in 110 children with juvenile idiopathic arthritis (JIA). CKD and hypertension were clustered under the umbrella term of "renal injury". Median age at the last visit was 14 years. Nine out of 110 (8.1%) patients showed renal injury (8 hypertension, 1 proteinuria). Patients with renal injury presented higher age at last visit, longer duration of active JIA, shorter intervals free from JIA relapses, longer duration of non-steroidal anti-inflammatory drugs (NSAIDs) treatment but with similar cumulative NSAIDs dose and higher rate of methotrexate (MTX) prescription, longer time of MTX administration, and higher cumulative MTX dose compared to patients without renal injury. At the last visit, patients with and without renal injury presented similar prevalence of active disease. The cumulative proportion of patients free from renal injury at 240 months since JIA onset was 40.72% for all population; while the cumulative proportion was 23.7% for patients undergoing NSAIDs+MTX treatment and 100% for those undergoing NSAIDs (p = 0.039) treatment.Conclusion:About 8% of the children with JIA develop hypertension or CKD. The main risk factor was longer exposure to both NSAIDs and MTX due to a more severe form of the disease. What is Known •Anecdotal reports showed that rarely juvenile idiopathic arthritis (JIA) could present renal involvement due to prolonged and uncontrolled inflammation (renal amyloidosis) or to long exposure to anti-rheumatic drugs. •No cohort studies investigated renal health in children with JIA. What is new •About 8% of the children with JIA developed hypertension or chronic kidney disease. •The main risk factor was long exposure to non-steroidal anti-inflammatory drugs and methotrexate for patients suffering from a more severe form of the disease. •In JIA patients, periodic evaluation of renal function, blood pressure and proteinuria should be warranted.

Six-month flare risk after discontinuing long-term methotrexate treatment in patients having rheumatoid arthritis with low disease activity.

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 >10years. Disease flare was defined as an increase in Disease Activity Score of 28 joints (DAS28) of >1.2 within 6months 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 11.7g; the median duration of exposure to MTX was 19years. 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 6months 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.