ORIGINAL ARTICLE: Lack of association between elevated mean red cell volume and haematological toxicity in patients receiving long‐term methotrexate for rheumatoid arthritis

Aims: It has been suggested that elevated mean red cell volume (MCV) may be a predictor of haematological toxicity in rheumatoid arthritis (RA) patients receiving methotrexate (MTX). We wished to identify whether there was an association between MCV, red cell folate and haematological toxicity in patients on MTX monotherapy for the long‐term management of RA. Methods: Evidence of haematological toxicity was sought by note review of patients recruited in a cross‐sectional study of MTX monotherapy in RA. Retrospective data included MCVs from before MTX initiation and after 3 and 6 months of treatment. Data were collected prospectively every 6 months for up to 2 years after enrolment. Any record of cytopenia or the development of haematological malignancy was recorded from commencement of MTX until the present day. Red cell folate concentrations were tested on enrolment to the study. Results: A total of 165 patients was included, 74.5% female, median disease duration 7 years (range 3 months–57 years). The median duration of MTX treatment was 74.9 months (range 10–241 months) giving 1030.2 patient‐years of MTX exposure. Twenty‐four patients (14.5%) had a MCV > 98 fL on study entry. Evidence of haematological abnormality was found in six patients (3.6%); chronic lymphocytic leukaemia (1), persistent lymphocytosis (1), persistent monocytosis (1) and neutropenia (3). There was no association between red cell folate or MCV and haematological toxicity. Conclusion: Neutropenia and pancytopenia are rare side‐effects of MTX therapy in this cohort. Elevated MCV or low mean red cell folate does not appear to be associated with haematological malignancy or toxicity in this cohort of patients on long‐term MTX therapy.     

Non‐invasive diagnosis of non‐alcoholic steatohepatitis and advanced fibrosis in Japan: A targeted literature review

Despite the invasive nature of liver biopsy, it remains the current standard for diagnosing non‐alcoholic steatohepatitis (NASH) and fibrosis staging. Given the rising prevalence of non‐alcoholic fatty liver disease (NAFLD) in Japan, there is a need for reliable non‐invasive tests to accurately and efficiently identify NASH and advanced (F3/F4) fibrosis. A review of published works from English and Japanese sources was undertaken in PubMed, Embase, and Ichushi Web to identify studies reporting diagnostic characteristics of NITs in biopsy‐proven Japanese NAFLD/NASH patients including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve. The performance of non‐invasive tests for two diagnostic questions were assessed, namely: (i) identifying NASH cases among NAFLD; and (ii) distinguishing advanced fibrosis (F3–4) from milder fibrosis (F0–2). Twenty‐five studies reported outcomes for serum biomarkers, imaging, scoring systems, and novel complex techniques (based on multivariable regression models) for both diagnostic questions. Serum biomarkers were the most commonly assessed method for NASH identification, whereas scoring systems and imaging techniques were most commonly studied for fibrosis staging. In general, tests for NASH identification showed higher PPVs than NPVs, suggesting their usefulness in identifying probable NASH cases. The reverse was observed for fibrosis staging, with higher NPVs than PPVs, suggesting their use in excluding patients at low risk of F3/F4 disease rather than identifying definite F3/F4 fibrosis. In Japanese studies, simple scoring systems and imaging techniques showed particular usefulness in prediction of fibrosis staging, and combinations of serum biomarkers showed diagnostic potential for NASH screening.     

A case of emphysematous pyelonephritis in a patient with rheumatoid arthritis taking corticosteroid and low‐dose methotrexate

Rheumatoid arthritis (RA) is a systemic autoimmune disease that is characterized by chronic synovial inflammation. Patients with RA have increased risk of infection; this is related to RA itself or the adverse effects of medication. In this report, we describe a case of emphysematous pyelonephritis in a patient with RA associated with AA amyloidosis and steroid‐induced diabetes mellitus who was taking corticosteroid and low‐dose methotrexate.     

Risk factors for abnormal hepatic enzyme elevation by methotrexate treatment in patients with rheumatoid arthritis: A hospital based-cohort study

Objectives: Methotrexate (MTX) is used as first-line treatment of rheumatoid arthritis (RA) worldwide. Large interindividual differences in MTX effectiveness and safety occur, and the most frequent adverse reaction is hepatotoxicity, although the main cause remains unknown. We investigated factors associated with MTX-induced hepatic enzyme elevation in a hospital-based cohort study.

Methods: Study participants were 114 Japanese adult RA outpatients prescribed MTX. Sixteen types of single-nucleotide polymorphisms were investigated using real-time PCR. Patient characteristics were collected from the electronic medical records. The onset of MTX-induced abnormal hepatic enzyme elevation was defined according to deviation from normal liver enzyme reference values during treatment. The observation period was 1 year after beginning MTX. Associations between MTX-induced hepatic enzyme elevation and patient characteristics were evaluated using the multivariate logistic regression model.

Results: Thirty-two patients experienced MTX-induced abnormal hepatic enzyme elevation. In multivariate analysis, MTX dosage, estimated glomerular filtration rate (eGFR), and genetic polymorphisms of ABCB1 3435C>T and ATIC 347C>G were associated with abnormal hepatic enzyme elevation.

Conclusions: MTX-induced abnormal hepatic enzyme elevation in Japanese RA patients was associated with dosage and eGFR as nongenetic factors, and with ABCB1 3435C>T and ATIC 347C>G as genetic factors in this hospital-based cohort study.     

Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a preliminary study from China

Aim: To report the efficacy and safety of infliximab in the treatment of active rheumatoid arthritis (RA) in Chinese patients. Methods: This is a multicentre double‐blind placebo controlled study. Patients with active RA despite being on a stable dose of methotrexate were randomly assigned to receive either infliximab 3 mg/kg body weight or placebo infusion at weeks 0, 2, 6 and 14. All patients continued their stable dose of methotrexate throughout the study. Patients were assessed at weeks 0, 2, 6, 14 and 18 for the American College of Rheumatology (ACR) 20%, 50% and 70% response (ACR20, 50 and 70, respectively). Health assessment questionnaire (HAQ), erythrocyte sedimentation rate (ESR), c‐reactive protein (CRP), duration of morning stiffness and adverse effects were monitored. Results: Infliximab was effective in improving the disease activity of RA with significant ACR20 response observed at week 2 (infliximab vs. placebo 52.87%vs. 13.95%, P < 0.05). Significant differences in the ACR20 and ACR50 response rates between the two treatment groups were also observed at week 18 (75.86% and 43.68% of patients receiving infliximab vs. 48.84% and 25.58% and 13.95% of patients on placebo, P = 0.0003 and P = 0.011, respectively). Infliximab was generally well tolerated. The rate of adverse events and withdrawal due to adverse events were similar between the two groups. Most adverse reactions were transient. One patient in the infliximab group developed tuberculosis during the study. One patient in the placebo group developed antinuclear antibodies without obvious signs of systemic lupus erythematosus. Conclusion: In this preliminary study, infliximab infusions, at a dose of 3 mg/kg body weight given at various intervals over 14 weeks, were effective in controlling the signs and symptoms of active RA in Chinese. Infliximab also appeared to be well tolerated. Further studies involving a larger number of patients over a more prolonged period will further evaluate the long‐term efficacy and safety of infliximab in this group of patients.     

The combination of a blood test and Fibroscan improves the non‐invasive diagnosis of liver fibrosis

Background and aims: Blood tests and liver stiffness evaluation (LSE) by ultrasonographic elastometry are accurate tools for diagnosing liver fibrosis. We evaluated whether their synchronous combination in new scores could improve the diagnostic accuracy and reduce liver biopsy requirement in algorithm. Methods: Three hundred and ninety patients with chronic liver disease of miscellaneous causes were included. Five blood fibrosis tests were evaluated: APRI, FIB‐4, Hepascore, Fibrotest and FibroMeter. The reference was fibrosis Metavir staging. Results: Diagnosis of significant fibrosis (Metavir F≥2). The most accurate synchronous combination was FibroMeter+LSE, which provided a significantly higher area under the receiver operating characteristic curve (0.892) than LSE alone (0.867, P=0.011) or Fibrometer (0.834, P<10^?3). An algorithm using the FibroMeter+LSE combination and then a liver biopsy in indeterminate cases had 91.9% diagnostic accuracy and required significantly fewer biopsies (20.2%) than previously published Bordeaux algorithm (28.6%, P=0.02) or sequential algorithm for fibrosis evaluation (SAFE) (55.7%, P<10^?3). The Angers algorithm performance was not significantly different between viral hepatitis and other causes. Diagnosis of cirrhosis. The most accurate synchronous combination was LSE+FibroMeter, which provided ≥90% predictive values for cirrhosis in 90.6% of patients vs 87.4% for LSE (P=0.02) and 57.9% for FibroMeter (P<10^?3). An algorithm including the LSE+FibroMeter combination, and then a liver biopsy in indeterminate cases, had a significantly higher diagnostic accuracy than the SAFE algorithm (91.0 vs 79.8%, P<10^?3), and required significantly fewer biopsies than the Bordeaux algorithm (9.3 vs 25.3%, P<10^?3). Conclusion: The synchronous combination of a blood test plus LSE improves the accuracy of the non‐invasive diagnosis of liver fibrosis and, consequently, markedly decreases the biopsy requirement in the diagnostic algorithm, notably to <10% in cirrhosis diagnosis.     

Biochemical and biophysical assessment of MTX-induced liver fibrosis in psoriasis patients: Fibrotest predicts the presence and Fibroscan predicts the absence of significant liver fibrosis.

BACKGROUND: Methotrexate (MTX) use is associated with hepatic fibrosis in psoriasis patients. To monitor this serial liver biopsies were performed. The Fibroscan and the Fibrotest are two novel, non-invasive methods that might be able to assess MTX-induced hepatic fibrosis. AIM: Evaluating the accuracy and feasibility of the Fibroscan and Fibrotest to detect significant MTX-induced liver fibrosis in psoriasis patients. Methods: We assessed 24 psoriasis patients who had a recent liver biopsy during MTX use. The results from the Fibroscan and Fibrotest were compared with liver histology. RESULTS: Fibroscan values (n=20) ranged between 3.3 and 18.4 kPa (median value 6.4 kPa) and correctly identified 88% of the patients without significant liver fibrosis (Metavir score /=F2, Fibrotest >0.31). CONCLUSION: In this population, Fibrotest accurately predicted the presence of significant liver fibrosis while the Fibroscan accurately predicted the absence of significant liver fibrosis in MTX users. This suggests that a combination of Fibrotest and Fibroscan should prospectively be evaluated in monitoring and detecting significant MTX-induced liver fibrosis in psoriasis patients.     

来氟米特及甲氨蝶呤对早期严重类风湿关节炎的治疗作用

目的研究来氟米特及甲氨蝶呤联合运用对早期严重类风湿关节炎临床症状，特别是对关节损害的作用。方法108例早期严重类风湿关节炎患者随机分为来氟米特组、来氟米特＋甲氨蝶呤组及来氟米特＋羟氯喹组，治疗前作相应的临床、实验室及影像学检查，以来氟米特30mg／d，连续2天后改为20mg／d，甲氨蝶呤10mg／w，羟氯喹400mg／d治疗12个月后，再评价患者临床、实验室及影像学的改变。结果来氟米特组、来氟米特＋甲氨蝶呤组及来氟米特＋羟氯喹组治疗12个月后，关节疼痛数明显减少，关节肿胀亦得到明显改善，晨僵时间显著缩短，其中尤以来氟米特＋甲氨蝶呤效果明显。关节侵蚀及Larsen-Dale积分在来氟米特＋甲氨蝶呤组改善亦较其他两组显著。但血沉及C反应蛋白改变不显著。结论来氟米特及甲氨蝶呤联合运用对早期类风湿关节炎的临床症状及关节损害的改善具有明显的效果。     

Efficacy and safety of tofacitinib in Japanese patients with rheumatoid arthritis by background methotrexate dose: A post hoc analysis of clinical trial data

Abstract

Objectives: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We investigated concomitant methotrexate (MTX) dose on tofacitinib efficacy/safety in Japanese RA patients.

Methods: This post hoc analysis pooled data from a 3-month phase 2 study (NCT00603512) and a 24-month phase 3 study (NCT00847613). Patients (N= 254) received tofacitinib (low-dose (1 or 3?mg), 5?mg, 10?mg) twice daily (BID) or placebo, with low-dose (>0 to 8?mg/week) or high-dose (>8?mg/week) MTX. Efficacy (ACR20/50/70 and DAS28-4 (ESR)<2.6 response rates; changes from baseline (CFB) in DAS28-4 (ESR) and HAQ-DI) and safety (adverse events (AEs), discontinuations due to AEs, serious AEs, and deaths) were assessed through month 3.

Results: At month 3, ACR20/50/70 response rates, mean DAS28-4 (ESR) CFB and HAQ-DI CFB were similar across MTX doses and generally greater for all tofacitinib doses versus placebo. AE rates with low-dose/high-dose MTX were: placebo, 28.6%/52.9%; tofacitinib low-dose, 50.0%/66.7%; 5?mg BID, 56.5%/64.3%; 10?mg BID, 73.8%/67.7%.

Conclusion: Tofacitinib efficacy in Japanese RA patients may be unaffected by background MTX dose. AE rates with low-dose versus high-dose MTX were lower with placebo, tofacitinib low-dose or 5?mg BID, but not 10?mg BID, with no apparent differences across system organ class/laboratory parameters.