BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and joint destruction. Iguratimod (IGU) is a novel conventional synthetic disease-modifying antirheumatic drugs (csDMARD) with good efficacy and safety for the treatment of active RA in China and Japan. However, the long-term effects of IGU on the progression of bone destruction or radiographic progression in patients with active RA remain unknown. We aimed to investigate the efficacy and safety of iguratimod (IGU), a combination of methotrexate (MTX) and IGU, and IGU in patients with active rheumatoid arthritis (RA) who were naïve to MTX. METHODS: This multicenter, double-blind, randomized, non-inferiority clinical trial was conducted at 28 centers for over 52 weeks in China. In total, 911 patients were randomized (1:1:1) to receive MTX monotherapy (10-15 mg weekly, n = 293), IGU monotherapy (25 mg twice daily, n = 297), or IGU + MTX (10-15 mg weekly for MTX and 25 mg twice daily for IGU, n = 305) for 52 weeks. The patients' clinical characteristics, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), disease activity score in 28 joints-C-reactive protein (DAS28-CRP) level, and disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) were assessed at baseline. The primary endpoints were the proportion of patients with ≥20% improvement according to the American College of Rheumatology (ACR20) response and changes in the van der Heijde-modified total Sharp score (vdH-mTSS) at week 52. RESULTS: The proportions of patients achieving an ACR20 response at week 52 were 77.44%, 77.05 %, and 65.87% for IGU monotherapy, IGU + MTX, and MTX monotherapy, respectively. The non-inferiority of IGU monotherapy to MTX monotherapy was established with the ACR20 (11.57%; 95% confidence interval [CI], 4.35-18.79%; P <0.001) and vdH-mTSS (-0.37; 95% CI, -1.22-0.47; P = 0.022). IGU monotherapy was also superior to MTX monotherapy in terms of ACR20 ( P = 0.002) but not the vdH-mTSS. The superiority of IGU + MTX over MTX monotherapy was confirmed in terms of the ACR20 (11.18%; 95% CI, 3.99-18.37%; P = 0.003), but not in the vdH-mTSS (-0.68; 95% CI, -1.46-0.11; P = 0.091). However, the difference in the incidence rates of adverse events was not statistically significant. CONCLUSIONS: IGU monotherapy/IGU + MTX showed a more favorable clinical response than did MTX monotherapy. IGU may have some clinical benefits over MTX in terms of radiographic progression, implying that IGU may be considered as an initial therapeutic option for patients with active RA. TRIAL REGISTRATION https://classic.clinicaltrials.gov/ , NCT01548001.
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Antirheumatic Agents/therapeutic use* ; Arthritis, Rheumatoid/drug therapy* ; Chromones/adverse effects* ; Double-Blind Method ; Drug Therapy, Combination ; Methotrexate/adverse effects* ; Treatment Outcome ; Sulfonamides

OBJECTIVE: To explore the risk factors for delayed excretion in adult acute lymphoblastic leukemia (ALL) patients treated with high-dose methotrexate (HD-MTX), and construct a risk prediction model to improve the safety of clinical medication. METHODS: From March 2010 to March 2023, 39 adult ALL patients who received 74 courses of HD-MTX chemotherapy in our hospital were analyzed retrospectively. The blood concentration of MTX was monitored by high-performance liquid chromatography (HPLC) at 0, 20 and 44 h after the end of MTX infusion. According to the MTX concentration of 44 h, the patients were divided into excretion delay group (≥0.3 μmol/L) and non-excretion delay group ( < 0.3 μmol/L), and the incidences of side effects were compared between the two groups. Clinical data and the results of laboratory test were collected. The risk factors associated with delayed MTX excretion were screened, and the independent risk factors for delayed excretion were identified by logistic regression analysis. A nomogram prediction model was established by R software based on the risk factors, and the predictive value of the model was also evaluated. RESULTS: A total of 27 courses of delayed excretion occurred in 74 courses of chemotherapy. As compared with the non-excretion delay group, the incidences of mucosal injury and nephrotoxicity increased significantly in the excretion delay group (both P <0.05). The dosage of MTX, blood uric acid level, and MTX peak concentration (i.e., blood drug concentration at 0 h after the end of MTX infusion) were independent factors influencing delayed MTX excretion. Based on these three independent factors, a nomogram prediction model was established for delayed MTX excretion. Calibration curve, concordance index (C-index), area under curve (AUC), and decision curve analysis showed that the model performed well. The model had showed good consistency and discrimination. CONCLUSION The incidence of delayed MTX excretion during HD-MTX chemotherapy in adult ALL patients is relatively high. The nomogram model based on the screened independent risk factors can be used to evaluate the risk of delayed excretion, timely identify individuals with high-risk of delayed excretion and adjust rescue measures combined with detection of MTX concentration to reduce the occurrence of side effects and ensure the safety of chemotherapy.
Humans ; Methotrexate/administration & dosage* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Retrospective Studies ; Risk Factors ; Adult ; Male ; Antimetabolites, Antineoplastic/therapeutic use* ; Female ; Nomograms ; Middle Aged

OBJECTIVE: To investigate the current status of methotrexate (MTX) application in rheumatoid arthritis (RA) patients. METHODS: The clinical and laboratory data of RA patients who attended in the Department of Rheumatology and Immunology of Peking University Third Hospital from January 1, 2022 to November 31, 2023 were collected retrospectively. In order to figure out the relationship between MTX use and RA disease control, we recorded information including the starting dose, maximum dose, current dose, reasons of discontinuation of MTX, etc. The t test, Mann-Whitney U test, Chi-square test, Fisher' s exact probability and multivariable Logistic regression were used for analysis. RESULTS: A total of 239 RA patients were enrolled, including 201 females and 38 males with a mean age of (54.5±14.3) years. Among them, 101 patients reached the therapeutic target [clinical remission or low disease activity assessed by 28-joint disease activity score (DAS28)-erythrocyte sedimentation rate (ESR)], accounting for 42.2% of the RA patients. Twenty-six patients met the European League Against Rheumatism (EULAR) definition of difficult-to-treat (D2T) RA, accounting for 10.9% of RA patients. The proportion of the RA patients who had ever used MTX was 84. 1%, and those who were currently on it accounted for only 39.7%. The MTX dose was generally low, with a starting dose of (9.5±3.0) mg/week, the maximum dose of 15.0 (10.0, 15.0) mg/week, and the current dose being (12.4±2.7) mg/week. The most common reasons for MTX dose reduction or discontinuation were adverse reactions, mainly including abnormalities of hepatic function, gastrointestinal discomfort, leucopenia, etc. Those who were currently on MTX had a higher rate of treatment to target (52.6% vs. 35.4%, P>0.05), lower disease activity score (DAS28-ESR, 3.6±1.8 vs. 4.2±1.8, P < 0.05), and fewer tender joint counts (4.8±8.3 vs. 8.6±10.4, P < 0.05) as compared with those who were not taking the drug, while swollen joint count, pain visual analog score and patient' s global score, C-reactive protein (CRP) level and ESR level were not significantly different between the two groups. Compared with those who did not reach the target of treatment, those who did had a higher rate of current MTX application (48.5% vs. 33.3%, P < 0.05), but the history of MTX did not differ between the two groups (84.2% vs. 84.1%, P>0.05). The maximum dose of MTX (median 15.0 mg/week vs. 13.7 mg/week, P>0.05) and the current dose [(12.9±2.5) mg/week vs. (11.8±2.8) mg/week, P>0.05] was higher in those who achieved the target, while the starting dose [(9.6±2.8) mg/week vs. (9.5±3.1) mg/week, P>0.05] and the rate of prior MTX (84.2% vs. 83.3%, P>0.05) was comparable between the two groups. The D2T RA patients had a higher rate of previous MTX use (96.2% vs. 82.6%, P < 0.05) and a higher starting dose [(11.6±4.3) mg/week vs. (9.8±2.7) mg/week, P>0.05], while the maximum dose (median 12.5 mg/week vs. 15.0 mg/week, P>0.05) and the current dose were both lower [(11.6±3.2) mg/week vs. (12.5±2.6) mg/week, P>0.05] than the non-D2T RA patients. CONCLUSION The proportion of regular use of MTX among RA patients was low and the dose was generally small. The RA patients with regular use of MTX had a higher rate of achieving treatment target and lower disease activity. Those who achieved the target had a higher rate of current MTX use, higher maximum and current doses than those who did not. The D2T RA patients had lower maximum and current doses of MTX than the non-D2T RA patients. Therefore, increasing the usage and dosage of MTX in RA patients may help to improve the rate of achieving treatment targets.
Humans ; Arthritis, Rheumatoid/drug therapy* ; Methotrexate/therapeutic use* ; Male ; Female ; Middle Aged ; Retrospective Studies ; Antirheumatic Agents/therapeutic use* ; Aged ; Adult ; Blood Sedimentation ; Severity of Illness Index ; Remission Induction

OBJECTIVE: To explore the short-term efficacy and adverse reactions of orelabrutinib combined with high-dose methotrexate (HD-MTX) in the first-line treatment of elderly high-risk primary central nervous system lymphoma (PCNSL), as well as the survival of patients. METHODS: Twenty-five elderly patients with high-risk primary central nervous system diffuse large B-cell lymphoma admitted to Fujian Provincial Hospital from June 2016 to June 2022 were enrolled in this study, and complete clinical data from all patients were collected retrospectively, and the cut-off for follow-up was December 2022. 15 patients had received temmozolomide combined with HD-MTX regimen for at least four cycles, sequential lenalidomide maintenance therapy, while 10 patients had received orelabrutinib combined with HD-MTX regimen for at least four cycles, sequential orelabrutinib maintenance therapy. The short-term efficacy and adverse reactions of the two groups of patients after treatment were observed. Kaplan-Meier was used to analyze the progression-free survival (PFS) and time to progression (TTP). RESULTS: The objective response rate (ORR) and 2-year median FPS of orelabrutinib combined with HD-MTX regimen group were similar to the temozolomide combined with HD-MTX regimen group (ORR: 100% vs 66.7%; 2-year median PFS: 16 months vs 15 months, P>0.05). The 2-year median TTP of the orelabrutinib+HD-MTX regimen group was better than that of the temozolomide+HD-MTX regimen group (not reached vs 12 months, P<0.05). There were no significant differences in adverse reactions such as gastrointestinal reactions, bone marrow suppression, liver and kidney damage, cardiotoxicity, pneumonia and bleeding between these two groups (P>0.05). CONCLUSION For elderly patients with high-risk PCNSL, orelabrutinib combined with HD-MTX has reliable short-term efficacy, good safety, and tolerable adverse reactions, which is worthy of clinical promotion.
Humans ; Aged ; Methotrexate/adverse effects* ; Retrospective Studies ; Temozolomide/therapeutic use* ; Central Nervous System Neoplasms/drug therapy* ; Antineoplastic Combined Chemotherapy Protocols ; Lymphoma, Large B-Cell, Diffuse/drug therapy* ; Central Nervous System

Objective: To explore the prognostic factors of extracellular NK/T cell lymphoma (ENKTL) treated with pegaspargase/L-asparaginase. Methods: The clinical data of 656 ENKTL patients diagnosed at 11 medical centers in the Huaihai Lymphoma Working Group from March 2014 to April 2021 were retrospectively analyzed. The patients were randomly divided into two groups: a training set (460 cases) and a validation set (196 cases) at 7∶3, and the prognostic factors of the patients were analyzed. A prognostic scoring system was established, and the predictive performance of different models was compared. Results: Patients' median age was 46 (34, 57) years, with 456 males (69.5% ) and 561 nasal involvement (85.5% ). 203 patients (30.9% ) received a chemotherapy regimen based on L-asparaginase combined with anthracyclines, and the 5-year overall survival rate of patients treated with P-GEMOX regimen (pegaspargase+gemcitabine+oxaliplatin) was better than those treated with SMILE regimen (methotrexate+dexamethasone+cyclophosphamide+L-asparaginase+etoposide) (85.9% vs 63.8% ; P=0.004). The results of multivariate analysis showed that gender, CA stage, the Eastern Cooperative Oncology Group performance status (ECOG PS) score, HGB, and EB virus DNA were independent influencing factors for the prognosis of ENKTL patients (P<0.05). In this study, the predictive performance of the prognostic factors is superior to the international prognostic index, Korean prognostic index, and prognostic index of natural killer lymphoma. Conclusion: Gender, CA stage, ECOG PS score, HGB, and EB virus DNA are prognostic factors for ENKTL patients treated with pegaspargase/L-asparaginase.
Male ; Humans ; Middle Aged ; Asparaginase/therapeutic use* ; Prognosis ; Retrospective Studies ; Lymphoma, Extranodal NK-T-Cell/drug therapy* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Etoposide ; Cyclophosphamide ; Methotrexate/therapeutic use* ; DNA/therapeutic use* ; Treatment Outcome

The lungs are one of the most common extra-articular organs involved in rheumatoid arthritis (RA), which is reported to occur in up to 60% to 80% of RA patients. Respiratory complications are the second leading cause of death due to RA. Although there is a wide spectrum of RA-associated respiratory diseases, interstitial lung disease is the most common manifestation and it impacts the prognosis of RA. There has been progress in understanding the management and progression of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and RA-associated respiratory diseases recently, for example, opportunistic pulmonary infectious diseases and toxicity from RA therapies. From a chest physicians' perspective, we will update the diagnosis and treatment of RA-associated ILD, methotrexate-associated lung disease, and the complication of Pneumocystis jiroveci pneumonia in RA in this review.
Humans ; Arthritis, Rheumatoid/complications* ; Methotrexate/therapeutic use* ; Lung Diseases, Interstitial/complications* ; Prognosis ; Lung

OBJECTIVE: To analyze recurrence and progression patterns of primary central nervous system lymphoma (PCNSL) in patients without whole brain radiotherapy (WBRT) and assess the value of WBRT in PCNSL treatment. METHODS: This retrospective single-center study included 27 patients with PCNSL, who experienced recurrence/progression after achieving complete remission (CR), partial remission, or stable disease following initial treatments with chemotherapy but without WBRT. The patients were followed up regularly after the treatment for treatment efficacy assessment. By comparing the anatomical location of the lesions on magnetic resonance images (MRI) at the initial diagnosis and at recurrence/progression, we analyzed the patterns of relapse/progression in patients with different treatment responses and different initial status of the lesions. RESULTS: MRI data showed that in 16 (59.26%) of the 27 patients, recurrence/progression occurred in out-field area (outside the simulated clinical target volume [CTV]) but within the simulated WBRT target area in 16 (59.26%) patients, and within the CTV (in-field) in 11 (40.74%) patients. None of the patients had extracranial recurrence of the tumor. Of the 11 patients who achieved CR after the initial treatments, 9 (81.82%) had PCNSL recurrences in the out-field area but within WBRT target area; of the 13 patients with a single lesion at the initial treatment, 11 (84.62%) experienced PCNSL recurrence in the out-field area but within WBRT target area. CONCLUSIONS Systemic therapy combined with WBRT still remains the standard treatment for PCNSL patients, especially those who achieve CR after treatment or have a single initial lesion. Future prospective studies with larger sample sizes are needed to further explore the role of low-dose WBRT in PCNSL treatment.
Humans ; Lymphoma/radiotherapy* ; Central Nervous System Neoplasms/pathology* ; Retrospective Studies ; Prospective Studies ; Neoplasm Recurrence, Local/drug therapy* ; Combined Modality Therapy ; Brain/pathology* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Methotrexate

Objective: To investigate the clinical characteristics of systemic juvenile idiopathic arthritis combined with coronary artery dilatation. Methods: A retrospective analysis was performed on the clinical data, including clinical manifestations, blood routine, inflammatory factors, echocardiography, vascular ultrasound and CT angiography, treatment and outcomes, etc, of 5 cases with systemic juvenile idiopathic arthritis combined with coronary artery dilation admitted to Department of Rheumatology in the affiliated Children's Hospital of Capital Institute of Pediatrics from May 2019 to June 2021. Results: There were 2 males and 3 females among 5 cases. The onset age ranged from 7 months to 4 years 7 months.The diagnostic time ranged from 1.5 months to 3.0 months.Four cases were diagnosed as atypical Kawasaki disease. Three cases showed unilateral coronary artery dilation.Two cases showed bilateral coronary artery dilation.Four cases developed multiple organ injuries.Three cases developed macrophage activation syndrome.Three cases developed lung injury.Two cases developed pericardial effusion.One case developed pulmonary hypertension.As for treatment, 3 cases treated with methylprednisolone pulse therapy and methotrexate combined with cyclosporine, improved after the final application of biological agents, and have stopped prednisone. The other 2 cases were treated with adequate oral prednisone and gradually reduced, and methotrexate was added at the same time, 1 case relapsed in the process of reduction. No other vascular involvement was found in 5 cases. Coronary artery dilation recovered completely after 1 to 3 months of treatment. Conclusions: Systemic juvenile idiopathic arthritis combined with coronary artery dilatation has the clinical characteristics of small onset age, long diagnostic time, prone to multiple organ injuries. Corticosteroids and conventional immunosuppressive agents are not sensitive, and biological agents should be used as soon as possible.The prognosis of coronary artery dilation is good after timely treatment.
Arthritis, Juvenile/drug therapy* ; Biological Factors/therapeutic use* ; Child ; Coronary Aneurysm/etiology* ; Coronary Artery Disease/therapy* ; Dilatation ; Dilatation, Pathologic ; Female ; Humans ; Infant ; Male ; Methotrexate ; Prednisone/therapeutic use* ; Retrospective Studies

We aimed to evaluate the effectiveness and safety of single-course initial regimens in patients with low-risk gestational trophoblastic neoplasia (GTN). In this trial (NCT01823315), 276 patients were analyzed. Patients were allocated to three initiated regimens: single-course methotrexate (MTX), single-course MTX + dactinomycin (ACTD), and multi-course MTX (control arm). The primary endpoint was the complete remission (CR) rate by initial drug(s). The primary CR rate was 64.4% with multi-course MTX in the control arm. For the single-course MTX arm, the CR rate was 35.8% by one course; it increased to 59.3% after subsequent multi-course MTX, with non-inferiority to the control (difference -5.1%,95% confidence interval (CI) -19.4% to 9.2%, P = 0.014). After further treatment with multi-course ACTD, the CR rate (93.3%) was similar to that of the control (95.2%, P = 0.577). For the single-course MTX + ACTD arm, the CR rate was 46.7% by one course, which increased to 89.1% after subsequent multi-course, with non-inferiority (difference 24.7%, 95% CI 12.8%-36.6%, P < 0.001) to the control. It was similar to the CR rate by MTX and further ACTD in the control arm (89.1% vs. 95.2%, P =0.135). Four patients experienced recurrence, with no death, during the 2-year follow-up. We demonstrated that chemotherapy initiation with single-course MTX may be an alternative regimen for patients with low-risk GTN.
Antineoplastic Combined Chemotherapy Protocols/adverse effects* ; Dactinomycin/adverse effects* ; Female ; Gestational Trophoblastic Disease/drug therapy* ; Humans ; Methotrexate/therapeutic use* ; Pregnancy ; Retrospective Studies

BACKGROUND: Biological agents, such as tumor necrosis factor inhibitors (TNFi), have been widely used in rheumatoid arthritis (RA) patients and greatly improved goal achievement. The aim of this study was to investigate whether conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) combination was better in reducing relapse than methotrexate (MTX) monotherapy, and more cost-effective than continuing TNFi plus MTX in RA patients who achieved low disease activity (LDA) with TNFi and MTX therapy. METHODS: RA patients who failed to csDMARDs received an induction therapy of MTX plus TNFi for maximally 12 weeks. Those achieving LDA in 12 weeks were randomly assigned at a 1:1:1 ratio into three groups: (A) adding hydroxychloroquine and sulfasalazine for the first 12 weeks and then discontinuing TNFi for the following 48 weeks; (B) maintaining TNFi and MTX for 60 weeks; and (C) maintaining TNFi and MTX for the first 12 weeks and then discontinuing TNFi for the following 48 weeks. The primary outcome was relapse. RESULTS: A total of 117 patients were enrolled for induction therapy and 67 patients who achieved LDA within 12 weeks were randomized, with 24, 21, and 22 patients in groups A, B, and C, respectively. The relapse rates of groups A and B during the entire 60 weeks were comparable [10/22 (45.5%) vs. 7/20 (35.0%), χ2 = 0.475, P = 0.491], however, significantly lower than that of group C [10/22 (45.5%) vs. 17/20 (85.0%), χ2 = 5.517, P = 0.019; 7/20 (35.0%) vs. 17/20 (85.0%), χ2 = 11.035, P = 0.004, respectively]. Taking RMB 100,000 Yuan as the threshold of willingness to pay, compared to MTX monotherapy (group C), both TNFi maintenance and triple csDMARDs therapies were cost-effective, but triple csDMARDs therapy was better. CONCLUSION: For RA patients who have achieved LDA with TNFi and MTX, csDMARDs triple therapy was a cost-effective option in favor of reducing relapse. TRIAL REGISTRATION ClinicalTrials.gov, NCT02320630.
Humans ; Cost-Benefit Analysis ; Drug Therapy, Combination ; Treatment Outcome ; Arthritis, Rheumatoid/drug therapy* ; Antirheumatic Agents/therapeutic use* ; Methotrexate/therapeutic use* ; Recurrence