Long-term Methotrexate Therapy Research Articles

Prevalence of Methotrexate-Induced Lung Involvement in Psoriasis Patients

Background: Seventy five psoriasis patients who visited the Pakistani Institute of Medical Sciences in Islamabad from January 2021 to January 2022 were examined to assess the incidence of methotrexate-induced lung involvement. Long-term methotrexate therapy often results in lung involvement, which may present as pleuritis, pneumonia, fibrosis, and obliterative bronchiolitis. Clinical evaluations and case data were retrospectively reviewed. Out of the Seventy five individuals tested, the results indicate that 15 (15%) had mild to moderate lung involvement, while 4 (4%) had severe lung involvement. In 67% of the patients, there was no discernible lung involvement. The frequency of methotrexate-induced lung involvement at the Pakistani Institute of Medical Sciences is quite low, despite the fact that it is a possible side effect of long- term methotrexate usage for psoriasis patients. If long-term methotrexate usage raises the likelihood of lung involvement in psoriasis patients, further investigation is required. Objectives: Identifying the frequency of methotrexate-induced lung involvement in psoriasis patients seen at the Pakistani Institute of Medical Sciences in Islamabad from January 2021 to January 2022 is the goal of this research. Methods: Seventy five psoriasis patients who were seen between January 2021 and January 2022 at the Pakistani Institute of Medical Sciences (PIMS) in Islamabad were the subject of the research. Lung involvement was evaluated by a retrospective examination of the case files and clinical evaluation, which may have required pulmonary function tests, chest X-rays, or even chest CT scans. There was no discernible lung involvement, mild to moderate lung involvement, severe lung involvement, or no lung involvement at all. Results: Seventy-five individuals were examined; fifteen (15%) had mild to moderate lung involvement, four (4%) had severe lung involvement, and sixty-seven (67%) had no discernible lung involvement. Conclusion: According to the study's findings, although methotrexate-induced lung involvement is a possible side effect of long-term methotrexate usage for people with psoriasis, it is not very common at the Pakistani Institute of Medical Sciences. 67% of the individuals in the study had no observable lung involvement. If long-term methotrexate usage raises the likelihood of lung involvement in psoriasis patients, further investigation is required. Keyword: Methotrexate, Psoriasis, Lung Involvement, Prevalence, PIMS

Risk of liver fibrosis associated with long-term methotrexate therapy may be overestimated

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 ≥7.9kPa. 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 ≥7.9kPa (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.

Noninvasive Assessment of Liver Fibrosis by Magnetic Resonance Elastography in Patients with Rheumatic Disease on Long-Term Methotrexate Treatment

Background: Long-term methotrexate (MTX) use is associated with hepatic fibrosis in patients with rheumatic diseases. Liver biopsy (invasive conventional diagnostic procedure for hepatic fibrosis) is associated with sampling errors and procedural risks. Magnetic resonance elastography (MRE) is a novel, reliable, and noninvasive imaging technique with excellent diagnostic accuracy for staging hepatic fibrosis and cirrhosis. Till date, studies are scarce on its use in staging MTX-induced liver fibrosis and cirrhosis. The aim of this study is to assess the usefulness of MRE in detecting and quantifying liver fibrosis and to compare these with biochemical parameters in patients with rheumatic diseases on long-term MTX therapy. Methods: Patients with different rheumatic diseases, aged ≥18 years and on MTX treatment for >5 years were included in the study. Their medical records were reviewed, and data regarding demographics, diagnosis, disease duration, MTX dosage and duration were collected. On the day of MRE examination, series of biochemical parameters were conducted in patients. Predefined cutoff MRE values were used for staging liver fibrosis. Results: A total of 48 subjects diagnosed with different rheumatic diseases on long-term MTX were recruited in the study, and majority of them were female (n = 41). The mean age and body mass index of the patients were 53.56 ± 8.36 years and 28.08 ± 4.43, respectively. Around 37.5% (n = 18) of the patients had abnormal aspartate transaminase (AST)-to-platelet count ratio index (APRI) score. The mean MRE value of the study group was 2.83 ± 0.90 kPa. Around 45.83% (n = 22) of the patients had normal liver stiffness values (<2.5) whereas stages F0 (2.5–2.9 kPa), F1 (2.9–3.5 kPa), F2 (3.5–4.0 kPa), F3 (4.0–5.0 kPa), and F4 (>5.0 kPa) were observed in 12.5% (n = 6), 18.75% (n = 9), 10.42% (n = 5), 10.42% (n = 5), and 2.08% (n = 1) of the patients, respectively. MRE values did not correlate with disease duration and cumulative dose of MTX. However, a positive correlation was observed between MRE and liver biochemical parameters (AST: Alanine transaminase [ALT] ratio, ALT, platelet count, APRI, albumin, and mean liver size; P > 0.05). Conclusion: Considering the risk for complications with liver biopsy, MRE provides a reliable, highly accurate, noninvasive assessment of hepatic fibrosis in patients with rheumatic diseases receiving long-term MTX therapy.

Development of leukocytoclastic vasculitis during long-term methotrexate therapy in patients with rheumatoid arthritis: description of two clinical cases

Leukocytoclastic vasculitis (LCV) is a small vessel vasculitis characterized by immune complex depositions involving dermal post-capillary venules. Cutaneous small vessel vasculitis is most often idiopathic but may be aggravated by secondary causes, such as inflammatory conditions, infections, neoplasms, and drugs exposure.Herein, we describe two patients with a long history of rheumatoid arthritis (RA) treated with methotrexate (MTX) for more than ten years, who later developed generalized LCV with pancytopenia after a viral infection, one with herpes simplex virus, and the other with SARS-CoV-2 virus. Because of the worldwide use of MTX in treatment of RA, strict follow-up and preventive measures are needed nowadays, especially during COVID-19 pandemic, in order to avoid any infection which may provoke LCV with or without systemic manifestations. So, using MTX for treating RA or other similar disorders may be considered a double-edged sword, especially during COVID-19 pandemic.

P285 The utility of FibroScan in the monitoring of methotrexate therapy in inflammatory arthritis patients

Abstract Background/Aims Methotrexate (MTX) is a drug used to treat inflammatory arthropathies. A significant side effect of MTX is liver fibrosis. There are numerous ways to screen for liver fibrosis, liver biopsy being the gold-standard, but its invasive nature and accompanying adverse effects limits its utility as a screening tool. Guidelines advise the use of liver function tests, yet liver enzymes and synthetic liver function may be normal even in advanced disease. This leaves the question of the best screening tool for liver fibrosis unanswered. This data collection seeks to explore the utility of FibroScan in the screening of liver fibrosis in rheumatoid arthritis and psoriatic arthritis patients taking long-term methotrexate. Methods A hospital-based survey was conducted where electronic records of rheumatoid and psoriatic arthritis patients, who were referred for FibroScan due to being on long-term methotrexate therapy, were reviewed. Long-term MTX therapy was defined as MTX use of greater than ten years. The following data were collected: demographics, BMI, MTX duration, results of FibroScan, and impact on management. The primary outcome was to determine whether FibroScan altered the patients’ management as this has not been tested in the literature previously. ‘Change of management' was defined as reduction of MTX dose or cessation of MTX therapy. Three secondary outcomes were assessed. Firstly, relationship of BMI (body mass index) with FibroScan result. FibroScan result consisted of median elastography and controlled attenuation parameter (CAP). Secondly, relationship of BMI with impact on management. Finally, relationship of MTX therapy duration with impact on management. Results A total of 16 patients were identified. With regards to primary outcome, 29.4% of patients had their management changed secondary to FibroScan. In terms of secondary outcomes, positive correlations were found between BMI and median elastography and CAP. Mean BMI was greater in patients who had their management changed. Patients whose MTX was stopped had a greater mean MTX therapy duration. Conclusion These data show the utility of FibroScan to screen for liver fibrosis in patients on long-term MTX therapy. It recommends that practitioners consider FibroScan in patients who have been taking MTX for longer than 10 years, especially if they have associated risk factors such as high BMI. Disclosure M.H. Amin: None. E. Justice: None.

Prevalence of Vitamin D Deficiency in Patients Treated for Juvenile Idiopathic Arthritis and Potential Role of Methotrexate: A Preliminary Study.

Background: Vitamin D deficiency is reported in rheumatological diseases in adults. The aim was to evaluate the prevalence of vitamin D deficiency in children with juvenile idiopathic arthritis (JIA) and to investigate potential correlations between vitamin D status and clinical factors, laboratory traits, and medical treatment, including methotrexate (MTX) and glucocorticoids (GCs). Methods: In 189 patients aged 3–17.7 years, with JIA in the stable stage of the disease, anthropometry, clinical status, serum 25-hydroxyvitamin D [25(OH)D], calcium (Ca), phosphate (PO4), total alkaline phosphatase (ALP), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were assessed. Results: Median 25(OH)D level was 15.00 ng/mL, interquartile range (IQR) 12.00 ng/mL. Vitamin D deficiency was found in 67.2% and was independent of sex, disease manifestation, and CRP, ESR, ALP, or PO4 levels. Higher doses of MTX corresponded with lower 25(OH)D levels using both univariate and multivariate models (p < 0.05). No such trend was found for GCs treatment. Serum Ca was lower in patients treated with GCs (p = 0.004), MTX (p = 0.03), and combined GCs/MTX (p = 0.034). Conclusions: JIA patients are vitamin D depleted independently of disease activity or inflammatory markers. MTX therapy may be an iatrogenic factor leading to inadequate 25(OH)D levels. Vitamin D supplementation should be considered in all children with JIA, particularly those receiving long-term MTX therapy.

Incidence and Risk Factors of Hepatic Fibrosis in Psoriatic Patients Receiving Methotrexate with Concomitant Acitretin Therapy and Methotrexate Monotherapy.

BackgroundThe use of methotrexate-acitretin (MTX-ACI) combination therapy in treating psoriasis has been limited due to concerns related to hepatic fibrosis. However, in vitro evidence revealed a protective effect of acitretin in methotrexate (MTX)-induced liver fibrosis.ObjectiveThis study aimed to compare the real-life incidence of hepatic fibrosis in patients with psoriasis receiving MTX-ACI and MTX monotherapy and to investigate factors associated with hepatic fibrosis in MTX-exposed patients.MethodsA retrospective cohort study was conducted based on a real-life registry containing data on patients with psoriasis who were administered MTX-ACI or MTX between 2008 and 2019 and underwent transient elastography according to cumulative MTX dose of 1.0–1.5 g and/or 3.5–4.0 g. Time-to-event analysis was performed to determine the cumulative incidence, incidence rate, and factors potentially affecting the occurrence of hepatic fibrosis.ResultsOf the 160 patients, 32 (20%) were treated with MTX-ACI, and 128 (80%) with MTX alone. Four patients (12.5%) in MTX-ACI group and 21 (16.4%) in MTX group developed hepatic fibrosis (p = 0.59). There was no statistically significant difference in cumulative incidence (16% in MTX-ACI vs 17% in MTX, p = 0.89) and incidence rate (37 cases per 1000 person-year in MTX-ACI vs 23 cases per 1000 person-year in MTX; hazard ratio [HR] = 1.07; p = 0.90) of hepatic fibrosis between the two groups. Diabetes and obesity were identified as significant factors associated with hepatic fibrosis (adjusted HR = 2.40, 95% confidence interval [CI]: 1.05–5.51; p = 0.04 and adjusted HR = 3.28, 95% CI: 1.18–9.16; p = 0.02, respectively) regardless of the cumulative MTX dose.ConclusionThe incidence of hepatic fibrosis in a real-life clinical situation, determined by transient elastography in patients with psoriasis receiving MTX-ACI, was not increased compared to those receiving MTX monotherapy. Type 2 diabetes mellitus and obesity were identified as risk factors of hepatic fibrosis; hence, patients with these factors receiving long-term MTX therapy should be regularly monitored for this particular event.

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.

P33 Spontaneous regression of confirmed diffuse large B-cell lymphoma after withdrawal of long-term methotrexate and infliximab therapy for rheumatoid arthritis, with concurrent discovery of rare high-grade urothelial carcinoma

Abstract Background A 73 year old man was diagnosed with diffuse large B-cell lymphoma germinal centre phenotype, after presenting with a 86x70x45mm right anterior chest wall lesion. CT CAP showed no further lymphadenopathy but identified an additional solid mass in the right ureter. The patient had been on methotrexate for 15 years and infliximab for 13 years for well controlled rheumatoid arthritis, and these were both discontinued on diagnosis of lymphoma. Within three weeks of discontinuation, the lymphomatous mass had clinically noticeably shrunk, confirmed radiologically, and on PET evaluation showed just low-grade avidity. However, the ureteric tumour was avid on PET, suggestive of second pathology. Biopsy proved high grade urothelial carcinoma with neuroendocrine differentiation. Chemotherapy to treat the urothelial carcinoma was identified as a priority, and carboplatin and etoposide chemotherapy was commenced which also has activity in lymphoma. Radiotherapy will be considered in the future, if indicated following further imaging. Methods A literature search was conducted on occurrence of lymphoma and urothelial carcinoma with anti-TNFα biologics. Results The link between methotrexate and increased risk of lymphoma is well covered in literature. Anti-TNFα biologic drugs have also been linked to lymphoma, but definitive causality is difficult to establish due to low numbers of cases and confounding factors. No cases were found in literature to associate anti-TNFα drugs with urothelial, transitional cell or neuroendocrine carcinomas. Eight case studies were found which show a temporal link between discontinuation of anti-TNFα and regression of lymphoma. Of these, six cases reported regression following withdrawal of infliximab. One case involved infliximab monotherapy, three had combination therapy with methotrexate, and two with azathioprine. One case reported discontinuation of adalimumab, with continuation of methotrexate. Histology showed two cases of low grade lymphoma, two case of Hodgkin’s lymphoma, and four cases of diffuse large B Cell non-Hodgkin’s lymphoma, similar to our patient case. Conclusion This patient presented with two synchronous tumours: diffuse large B cell NHL and high grade neuroendocrine carcinoma of urothelial tract. Whereas lymphoma regressed on withdrawal of methotrexate and infliximab, there was no change in the urothelial malignancy. Lymphoma regression allowed the urothelial malignancy to take priority for oncological therapy. It can be concluded that withdrawal of anti-TNF agents can allow spontaneous regression of lymphoma, and this can modify patient treatment plans. Disclosures B.A. Jones None. A. O'Callaghan None. E.V. Ross None. A. Razack None. E. Wong None.

Ultrasound liver elastography for the detection of liver fibrosis in patients with psoriasis and reactive arthritis on long-term methotrexate therapy: A cross-sectional study.

Long-term low-dose methotrexate therapy is associated with liver fibrosis. Although liver biopsy is the gold standard for detecting fibrosis, it is an invasive procedure associated with morbidity and mortality risks. Hence noninvasive imaging techniques such as transient elastography (TE) and shear wave elastography (SWE) have been studied to measure liver stiffness. To assess the utility of TE and SWE in detecting fibrosis in patients with psoriasis and reactive arthritis on long-term methotrexate therapy. A cross-sectional prospective study was undertaken on 54 patients with psoriasis and reactive arthritis who had received ≥1.5 g of methotrexate. Various clinical and biochemical [fibrosis 4 index (FIB4), aspartate-transaminase-to-platelet ratio index (APRI)] parameters were calculated and liver stiffness measurement (LSM) was done with TE and SWE. The degree of steatosis was measured using controlled attenuation parameter (CAP). Liver biopsy was done when indicated and was interpreted by a pathologist blinded to clinical and imaging results. Fifty four patients with a mean age of 40.3 years and a male-to-female ratio of 5:1 were included. The mean cumulative methotrexate dose was 3.04 g. The median FIB4, APRI, and gamma-glutamyl transpeptidase-to-platelet ratio values were 0.75, 0.23, and 0.15, respectively. The median LSM for TE and SWE was 5.3 and 7.32 kPa, respectively. SWE and TE showed a weak positive correlation (r = 0.26, P = 0.053). The mean CAP was 217 dB/m (area under the receiver operating characteristic = 0.70). In the 19 of 26 cases whose liver biopsies could be assessed, only 4 (21%) showed F1 fibrosis (Ishak staging). The median LSM on SWE was significantly higher in patients with a cumulative methotrexate dose ≥ 4 g when compared with those with a dose <4 g (9.85 vs 7.1, P = 0.02). Other parameters did not correlate with TE and SWE. The small sample size and the low number of cases with significant fibrosis on histopathology were the major limitations of this study. Histologically detectable LF is uncommon in patients with psoriasis and reactive arthritis on long-term methotrexate therapy. Both TE and SWE are good at detecting the absence of fibrosis in these patients. In our study, SWE and TE values did not correlate with clinical, biochemical, or histopathological parameters.

Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats.

Hepatic injury is a major side effect associated with methotrexate (MTX) therapy resulting from inflammatory reactions and oxidative stress induction. Therefore, liver fibrosis incidence is augmented with long-term MTX therapy. Alpha lipoic acid (ALA) is a naturally occurring compound with potent antioxidant activity. This study explored the hepatoprotective mechanisms of ALA against MTX-induced hepatic injury in rats. Hepatic injury was induced in MTX group by 20 mg/kg body weight ip. injection of MTX. ALA group was pretreated with ALA 60 mmol/kg body weight ip. for five days followed by a single dose of MTX in the sixth day. Blood samples and liver tissues were then obtained to assess several biochemical parameters as serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), reduced glutathione (GSH), total antioxidant capacity (TAC) and lipid peroxidation. Nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway was studied by determining the extent of mRNA Nrf2 expression and the level of HO-1. Hepatic stellate cells (HSCs) activation was evaluated by estimating the expression of α-smooth muscle actin (α-SMA) and hydroxyproline content. Also, tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and caspase-3 were assessed by ELISA in addition to histopathological examination of liver samples. Results showed that ALA pretreatment improved liver function since serum ALT, AST and ALP levels were reduced. Additionally, ALA restored GSH and TAC levels when compared to MTX group and decreased lipid peroxidation. ALA exerted its antioxidant effect via Nrf2/HO-1 pathway as well as it showed anti-inflammatory and antiapoptotic effects by reducing TNF-α, iNOS, COX-2 and caspase-3 levels in liver tissue homogenate. Finally, ALA suppressed HSCs activation by decreasing α-SMA expression and hydroxyproline content in liver. It was concluded that ALA has hepatoprotective effects against MTX-induced hepatic injury mediated by Nrf2/HO-1 pathway as well as anti-inflammatory and antiapoptotic properties.

Assessment of hepatic fibrosis in patients with rheumatoid arthritis on long-term methotrexate therapy using transient elastography

Background: Methotrexate (MTX) is has been associated with hepatotoxicity including hepatic fibrosis; however, the incidence of severe hepatic fibrosis or cirrhosis with MTX use has remained a controversial issue. The gold standard test for detecting liver fibrosis has been a liver biopsy, which is an invasive procedure with potentially serious complications. The transient elastography (TE) is a noninvasive method of assessing hepatic fibrosis. The primary objective of this study was to assess the prevalence of hepatic fibrosis associated with long-term MTX therapy in patients with RA and the secondary objective was to assess the correlation of cumulative MTX dose with hepatic fibrosis as assessed by TE using Fibroscan. Methods: In this cross-sectional study patients with RA who had been on MTX treatment for >5 years were included. Hepatic fibrosis was determined by measuring the hepatic stiffness by TE method (by FibroScan) in kilopascal (kPa) in study patients. The hepatic stiffness of the patient group was compared with that of healthy controls. Results: A total of 160 patients and 63 healthy controls were included in the study. The mean age of the patients was 51±10.9 years and there were 139 female and 21 male patients.The median duration of MTX use was 317.5 weeks (range 260, 1302 years). Median MTX cumulative dose was 4225 mg (range 2340, 18,200 mg). Mean hepatic stiffness was 4.8 kPa (SD 1.35) in the patient group and 4.7 kPa (SD 1.07) in the control group (P = 0.550). Cumulative dose or duration of MTX treatment did not correlate with hepatic fibrosis. Conclusions: Severe hepatic fibrosis or cirrhosis as detected by the TE using Fibroscan was uncommon with high cumulative dose of MTX when administered in the low-dose weekly schedule. The cumulative dose of MTX did not correlate with hepatic fibrosis as assessed by FibroScan.

Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures

ObjectiveTo describe changes in immune parameters observed during long-term methotrexate (MTX) therapy in patients with active rheumatoid arthritis (RA) and explore correlations with simultaneously measured MTX pharmacokinetic (PKC) parameters.DesignProspective, open-label,...

Hepatic and hematological adverse effects of long-term low-dose methotrexate therapy in rheumatoid arthritis: An observational study.

Objectives:Methotrexate (MTX) is the most commonly used cost-effective disease-modifying antirheumatoid drug (DMARD). Its main dose-limiting adverse effects are hepatic and hematopoietic. This cross-sectional, observational study evaluated the prevalence of hepatic and hematological adverse effects with long-term low-dose MTX therapy.Materials and Methods:Rheumatoid arthritis (RA) patients taking ≤15 mg/week MTX for at least 2 years were enrolled from the rheumatology outpatient department. Demographic, disease, drug treatment profiles, and hematological and hepatic enzyme levels were noted.Results:Of the 204 patients enrolled, the frequency of raised alanine transaminase level (≥3-fold rise above the upper limit of normal) was 6.37% (95% confidence interval of 3.76–10.59) including two biopsy-proven hepatic fibrosis cases. About 5.4% had severe anemia (<8 g/dl) and 4.4% had leukopenia.Conclusion:Long-term low-dose MTX is safe in RA patients in the Indian population. The patterns of adverse effects were similar to those documented in earlier studies. However, our study results suggest that disease duration, cumulative MTX dose, concomitant DMARD intake are not risk factors associated with hepatic or hematological adverse effects.

Drug-induced Liver Disease in Patients with Diabetes Mellitus.

The study presented here was accomplished to assess the course of drug-induced liver diseases in patient’s rheumatoid arthritis receiving long-term methotrexate therapy. Diabetes mellitus was revealed as the most significant risk factor. The combination of diabetes mellitus with other risk factors (female sex) resulted in increased hepatic fibrosis, degree of hepatic encephalopathy and reduction of hepatic functions. The effectiveness and safety of ursodeoxycholic acid and cytolytic type-with S-Adenosyl methionine was also evaluated.Abbreviations13C-MBT: 13C-methacetin breath test; ALT: alanine aminotransferase; AP: alkaline phosphatase; AST: aspartic transaminase; DILD: drug-induced liver disease; DM: diabetes mellitus; HE: hepatic encephalopathy; HFM: hepatic functional mass; SAMe: S-Adenosyl methionine; UDCA: ursodeoxycholic acid.How to cite this articleIryna K, Helen M, Elena S. Drug-induced Liver Disease in Patients with Diabetes Mellitus. Euroasian J Hepato-Gastroenterol 2015;5(2):83-86.

Autoimmune hepatitis as an adverse effect of long-term methotrexate therapy

Methotrexate (MTX) is one of the most commonly used medicines in the treatment of psoriatic arthritis. The drug can produce steatosis and cirrhosis. Autoimmune hepatitis is a rare and serious adverse effect. We describe the case of a 53-year-old woman who developed autoimmune hepatitis after a long-term use of MTX for psoriatic arthritis. Hepatitis was completely resolved 4 months after stopping this drug. The pathophysiologic mechanisms of a drug-induced autoimmunity are unclear and complex. This report confirms the need to monitor liver enzymes carefully in patients using long-term treatment with MTX for psoriasis or rheumatoid arthritis.

Assessment of methotrexate hepatotoxicity in psoriasis patients: a prospective evaluation of four serum fibrosis markers

Low-dose oral methotrexate (MTX) is an effective immunosuppressive therapy for chronic plaque psoriasis. However, its use is hampered by the risk of liver fibrosis. To compare the results of serial measurements of serum fibrosis markers during the remission-induction phase of treatment with MTX to those of patients on biological therapy and long-term MTX therapy (>2 years). Serum concentrations of hyaluronic acid, N-terminal propeptide of collagen type III (PIIINP) and the results of two multi-test algorithms Fibrotest and Hepascore were evaluated in patients with chronic plaque psoriasis (N = 24, age: 28-79 years, baseline Psoriasis Area Severity Index PASI 13.5, range 2.2-33) at baseline and weeks 16 and 26 after the start of pharmacokinetically guided therapy with MTX (Group A). Patients on established therapy with biologics (N = 15, Group B) and long-term MTX users (N = 10, Group C) with the mean baseline PASI scores of 0.9 and 1.2 were studied in parallel cohorts. At baseline, HA, Hepascore and PIIINP were correlated with PASI of Group A patients. At weeks 16 and 26, HA decreased by 48% and 40% (P < 0.001) and Hepascore by 31 (P < 0.01) and 20% (P < 0.05) respectively. PASI75 (≥ 75% improvement from baseline PASI) was observed in 76% of Group A patients by week 26 and the absolute decreases in PASI and both fibrosis markers were correlated (HA: r = 0.49, P = 0.018, Hepascore: r = 0.47, P = 0.022). In contrast, no significant within-group differences were found in HA and Hepascore results of patients in the groups B and C. PIIINP and Fibrotest were stable in all groups. The fibrosis markers hyaluronic acid and Hepascore (the multiple test algorithm which includes hyaluronic acid) are less liver specific and more prone to reflect psoriasis activity than PIIINP and Fibrotest.

A long-term follow-up study of methotrexate in juvenile localized scleroderma (morphea)

Recent studies report that methotrexate (MTX) is beneficial in the treatment of juvenile localized scleroderma (JLS) but little is known about its long-term effectiveness. We assessed the therapeutic role of MTX in children with JLS who were followed up for a prolonged period. A cohort of patients with JLS, previously enrolled in a double-blind, randomized controlled trial and treated with oral MTX (15 mg/m(2)/wk) and prednisone (1 mg/kg/d, maximum 50 mg) for the first 3 months, were prospectively followed up. Lesions were evaluated clinically, with infrared thermography, and by a computerized skin score. Response to treatment was defined as: (1) no new lesions; (2) skin score rate less than 1; and (3) decrease in lesion temperature by at least 10% compared with baseline. Clinical remission (CR) on medication was defined when response was maintained, on treatment, for at least 6 months, and complete CR when response was maintained, without treatment, for at least 6 months. Of 65 patients treated with MTX, 48 (73.8%) were responders, 10 (15.4%) relapsed by 24 months since MTX start, and 7 (10.8%) were lost to follow-up. Among the responders, 35 (72.9%) maintained CR for a mean of 25 months and 13 (27.1%) were in CR on medication. Adverse effects seen in 28 patients (48.3%) were generally mild and never required treatment discontinuation. The use of objective measures not widely available, such as infrared thermography and computerized skin score, makes it difficult to compare data from previous studies. Long-term MTX therapy is beneficial and well tolerated for JLS.

Methotrexate-Induced Cutaneous Ulcers in a Nonpsoriatic Patient: Case Report and Review of the Literature

Methotrexate is a mainstay of treatment for autoimmune conditions such as rheumatoid arthritis and psoriasis. Methotrexate has numerous potential side effects and, in rare circumstances, can lead to cutaneous ulceration. Methotrexate can cause skin ulceration, and stopping this medication can lead to complete healing of the ulcerated lesion. A 67-year-old man with rheumatoid arthritis on long-term methotrexate therapy presented to hospital with ulcers on his hands, elbows, and lower extremities. He had no history of psoriasis. Shortly after admission, the patient was noted to have pancytopenia. A bone marrow biopsy showed a hypocellular marrow. Both the cutaneous ulcers and the hypocellular marrow were thought to be induced by methotrexate. The ulcerated areas were biopsied, and histopathology showed no evidence of vasculitis. After 1 month of rehabilitative skin care, the patient's ulcers healed almost completely and his bone marrow suppression recovered. We report the fifth case of methotrexate-induced cutaneous ulceration in a nonpsoriatic patient and review the literature on this unusual drug reaction. Methotrexate can induce cutaneous ulceration in nonpsoriatic patients and should be considered a potential cause of ulceration in patients treated with this antimitotic agent.

Eruptive molluscum contagiosums in a patient with rheumatoid arthritis and lung cancer

A 67-year-old woman with rheumatoid arthritis (RA) treated with systemic prednisolone and methotrexate over 20 years developed eruptive molluscum contagiosums on the trunk and extremities. Investigation revealed lung cancer 2 years later. Newly development of molluscum contagiosums ceased after the surgical operation of lung cancer. Immunologic dysfunctions have been shown in RA, and especially patients under long-term methotrexate therapy are susceptible to miscellaneous skin conditions. Eruptive molluscum contagiosums are induced in association with hematologic malignancies such as lymphoma, leukemia, and HIV infection; however, it is important to investigate internal malignancies, not only hematologic malignancies but also solid cancers, when patients with RA under immunosuppressive therapies presented eruptive or disseminated molluscum contagiosums.