Combination Of Methotrexate Research Articles

Parent-Reported Medication Side Effects and Their Impact on Health-Related Quality of Life in Children With Juvenile Idiopathic Arthritis.

To describe the frequency and severity of parent-reported medication side effects (SEs) in children with juvenile idiopathic arthritis (JIA) relative to physician-reported actionable adverse events (AEs), and to assess their impact on health-related quality of life (HRQoL). Newly diagnosed JIA patients recruited between 2017 and 2019 to the Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) Registry were included. Parents reported presence and severity (0=no problem, 10=very severe) of medication SEs at every clinic visit. Physicians were asked to report any actionable AE. HRQoL was assessed using the Quality of My Life (QoML) questionnaire (0=the worst, 10=the best) and parent's global assessment (0=very well, 10=very poor). Analyses included proportion of visits with SEs or actionable AEs, cumulative incidence by Kaplan-Meier methods, and HRQoL impact measured with longitudinal mixed-effects models. SEs were reported at 371 of 884 (42%) visits (95% confidence interval [95% CI] 39, 45%) in 249 patients, with a median of 2 SEs per visit (interquartile range [IQR] 1-3), and median severity of 3 (IQR 1.5-5). Most SEs were gastrointestinal (32.5% of visits) or behavioral/psychiatric (22.4%). SE frequency was lowest with nonsteroidal antiinflammatory drugs alone (34.7%) and highest with prednisone and methotrexate combinations (66%). SE cumulative incidence was 67% (95% CI 59, 75) within 1 year of diagnosis, and 36% (95% CI 28, 44) for actionable AEs. Parent global and QoML scores were worse with SEs present; the impact persisted after adjusting for pain and number of active joints. Parents report that two-thirds of children with JIA experience SEs impacting their HRQoL within 1 year of diagnosis. SE mitigation strategies are needed in managing JIA.

Enhanced antitumor activity of combined methotrexate and histone deacetylase inhibitor valproic acid on mammary cancer in vitro and in vivo.

Histone deacetylase inhibitors (HDACIs) act as antiproliferative agents by promoting differentiation and inducing apoptosis. Valproic acid (VPA) is a HDACI that shows promising chemotherapeutic effect in a number of tumor cells. The present study aimed to investigate the inhibitory effect of VPA on the viability of mammary cancer cells and its enhancing effect with methotrexate (MTX) in vitro and in vivo. Treatment with VPA or MTX alone induced concentration-dependent cytotoxic effects in two breast cancer cell lines. Valproic acid increased significantly the cytotoxicity of MTX three times against MCF7. Valproic acid addition to MTX, however, did not produce any significant changes on MTX cytotoxicity against MDA-MB231. VPA (150 and 200mg/kg) significantly inhibited the growth of Ehrlich ascites carcinoma (EAC) and solid Ehrlich carcinoma (SEC) tumor mouse models and improved results were achieved for tumor inhibition when VPA was combined with MTX (1 and 2mg/kg) in vivo. The antitumor activity was not associated with a significant increase in toxicity or mice mortality rate. All these findings suggest that the combination of MTX and VPA may have clinical and (or) adjuvant therapeutic application in the treatment of mammary cancer.

The management of caesarian scar pregnancy with or without a combination of methods prior to hysteroscopy: Ovarian reserve trends and patient outcomes

Study ObjectiveThis study compared the efficacy and safety of a combination of uterine artery embolization or methotrexate before hysteroscopy in the treatment of cesarean scar pregnancy. MethodsWe divided 276 cesarean scar pregnancy patients into three groups. Group A underwent direct hysteroscopy; Group B received uterine artery embolization plus hysteroscopy; Group C received the systemic administration of methotrexate prior to hysteroscopy. ResultsThe patients in Group A lost significantly more blood than those in Groups B (P < 0.05). There were no significant differences between the three groups with regards to massive hemorrhage and transfusion (P > 0.05). None of the patients required hysterectomy. Group A was also associated with a significantly shorter period of hospitalization, reduced medical costs, and fewer adverse events than either Group B or C (P < 0.05). Moreover, among women of advanced age (≥35y), the levels of serum anti-Mullerian hormone in Group B were significantly lower than those of the baseline group (P<0.05), which were significantly lower than those in Group A after surgery (4.22 ± 2.35 vs 2.78± 1.89 ng/ml, P < 0.05). ConclusionDirect hysteroscopy is a reliable treatment option for most early type I cesarean scar pregnancy patients with a gestational sac. A combination of methotrexate and uterine artery embolization before hysteroscopy in these patients has limited remedial effects. uterine artery embolization may reduce ovarian reserve in patients aged ≥35y.

LTBK-05. Outcomes of Infants and Young Children with Newly Diagnosed Localized (M0) SHH Medulloblastoma Treated on The NEXT Consortium “Head Start” 4 Protocol

Advances in RNA and DNA profiling have identified four core molecular subgroups of medulloblastoma of prognostic significance: Sonic Hedgehog (SHH) subtype, WNT subtype, Group 3, and Group 4. Infants and young children with SHH medulloblastoma have demonstrated a favorable outcome in clinical trials utilizing either high-dose chemotherapy (“Head Start”) or a combination of intravenous and intraventricular methotrexate (HIT-SKK). Two recently conducted clinical trials (COG ACNS1221 and St. Jude – SJYC07) failed to demonstrate similar survival advantage with conventional dose chemotherapy and without intraventricular methotrexate. “Head Start” 4 (HS 4) is a prospective randomized clinical trial that tailors treatment based on medulloblastoma molecular subgroups and response to induction chemotherapy to compare the efficacy of one versus versus three (tandem) cycles of myeloablative therapy. Eligibility includes newly diagnosed children less than six years of age with localized medulloblastoma. Eligible patients with SHH medulloblastoma were considered “low-risk” and non-randomly assigned to receive three cycles of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, etoposide, and high-dose methotrexate) followed by consolidation with single cycle of myeloablative chemotherapy (thiotepa, carboplatin, etoposide) and autologous hematopoietic progenitor cell rescue. Patients with less than a complete response after three induction cycles received two additional cycles prior to consolidation therapy. Only children between 6 -10 years old, or those with confirmed residual tumor post-consolidation, were meant to receive irradiation after consolidation. Twenty-eight children with localized SHH medulloblastoma were enrolled on the trial with a median age of 2.1 years (range: 0.3-5.9 years). Median follow-up for this cohort is 29.6 months (range: 7.0-58.6 months). The estimated 3-year event-free (EFS) and overall survival (OS) is 96% (CI: 89-100%) and 100%, respectively. The estimated 3-year EFS for SHH subtype 1 and 2 patients is 100% and 95%, respectively (p=0.65). None of the M0 SHH medulloblastoma patients received irradiation.

Takayasu arteritis with congestive heart failure in 26-year-old male: a case report

BackgroundTakayasu arteritis (TA) is included in large vessel vasculitis with unknown aetiopathogenesis. TA is one of the rare diseases with a predilection for young women. The diagnosis of TA is difficult due to variation in clinical presentations and non-specific initial symptoms. This case demonstrates rare TA in a young male with congestive heart failure as the predominant manifestation.Case presentationWe report a 26-year-old male presented with severe dyspnea, palpitation, orthopnea, paroxysmal nocturnal dyspnea, and claudication in the left arm. Four limbs blood pressure discrepancy was present. Chest X-ray showed cardiomegaly with calcification aortic arch and pulmonary edema. Echocardiography revealed that left ventricular ejection fraction decreased with severe aortic and mitral valve regurgitation. Computed tomography angiography showed stenosis of the left common carotid artery and total occlusion of the left subclavian artery with collateral artery. There was vascular thickness and calcification from the peri-aortic valve, ascending aorta, aortic arch, and thoracic descending aorta until abdominal aorta with high-grade stenosis on the inferior side of the renal artery branching accompanied by a post-stenotic dilatation.ConclusionsThis patient’s heart failure was precipitated by secondary hypertension and aortic regurgitation caused by vasculitis of TA. In general, there is no difference in the management of congestive heart failure in patients with TA. Optimized pharmacology therapy with combination steroid and methotrexate successfully inducing remission of TA after 3-months follow-up.

Comparative study of the effectiveness of combination therapy of vitiligo with methotrexate in combination with medium-wave narrow-band therapy UVB-311 nm and monotherapy UVB-311 nm

BACKGROUND: Vitiligo, a multifactorial chronic acquired disease with a genetic predisposition, occurs due to the destruction of melanocytes of the skin and is characterized by the appearance of foci of depigmentation. Despite the fact that new therapies are emerging, there are no actual treatment regimens that would guarantee a positive result, including stopping the progression of the process, repigmentation. In this regard, it is advisable to search for drugs that have an immunosuppressive effect.&#x0D; AIMS: Clinical evaluation of the effectiveness of methotrexate in combination with UVB-311 nm and UVB-311 nm monotherapy in vitiligo.&#x0D; MATERIALS AND METHODS: 77 patients suffering from progressive vitiligo were included in this study. All patients were divided into 2 groups. A course of methotrexate therapy in combination with UV therapy was prescribed to 39 patients, UVB-311 nm monotherapy was performed in 38 patients. The lesion area relative to the body surface area was estimated using the VES index (Vitiligo extent score) on the vitiligo calculator. The effect of the disease on the quality of life was assessed using the Dermatology Life Quality Index (DLQI). The duration of the study was 6 months.&#x0D; RESULTS: The patients included in the study were divided into two groups randomly. There were 39 patients in group I, 38 in group II. 76 out of 77 patients completed it: 1 patient was excluded due to increased hepatic transaminases during methotrexate therapy. Among patients receiving combination therapy with methotrexate in combination with medium-wave narrow-band therapy UVB-311 nm, there was a more pronounced decrease in the percentage of depigmentation relative to the body surface area. And also patients of this group demonstrated the most active positive dynamics of the Dermatology Life Quality Index than patients who received only phototherapy.&#x0D; CONCLUSIONS: The study demonstrated good clinical efficacy of the drug. Small doses of methotrexate have a positive effect on the tolerability of the drug and prevent the development of side effects, which makes it possible to influence pathogenetic mechanisms for a long time, stabilizing the skin process.

Effect of methotrexate on response to Covid-19 mRNA vaccines in patients with Autoimmune Inflammatory Rheumatic Diseases: a longitudinal study

Abstract Humoral response to Covid-19 mRNA vaccines was assessed in 30 patients with autoimmune inflammatory rheumatic diseases (AIRD) taking methotrexate (MTX) and 22 volunteers at 8 and 24 weeks after the first vaccine. Ten patients were also followed at 2–4 weeks after the booster dose. Concentrations of neutralizing Anti-Spike and anti-RBD Ab (U/ml) were assessed using the V-PLEX Covid-19 ACE2 Neutralization kit. At 8 weeks after vaccine, median titers of anti-Spike and anti-receptor binding domain (RBD) Ab were significantly lower in patients receiving MTX (6.2, IQR [3.1–19.87] and 5.4 [2.5–15], respectively) vs. controls (25.4, [10–89] and 22.2 [10–88]). At 24 weeks post vaccine, neutralizing antibody titers declined in both groups. Although median anti-Spike and anti-RBD Ab levels remained significantly lower in patients (1.7 [0.0–3.6] and 1.9 [0.6–2.7], respectively) vs. controls (3.8 [1.2–6.6] and 3.5 [1.5–6.3]), the magnitude of the difference decreased from 4 fold at 8 weeks to 2 fold at 24 weeks. Lower titers of anti-Spike and anti-RBD Ab were found in patients taking MTX in combination with biologics (anti-TNFs or anti-Blyss) vs. those on MTX monotherapy, although only the anti-RBD Ab levels were statistically significant (2.7 [1.6–5.8] vs. 7.6 [3.8–17.4], p=0.04). Levels of neutralizing Ab did not differ in patients that held methotrexate around vaccination compared to those who did not. One control but no patients had breakthrough Covid-19 infections. After booster dose, Ab titers increased by a highly variable amount in all patients, ranging between 1.9 – 649 fold for anti-Spike Ab and 2.1 – 29 fold for anti-RBD Ab. Further studies are needed to assess the duration of the booster vaccine protection in this population. Supported by an ICTR grant from Univ of Maryland Sch of Medicine

The Impact of Traditional Chinese Medicine QingreHuoxue Treatment and the Combination of Methotrexate and Hydroxychloroquine on the Radiological Progression of Active Rheumatoid Arthritis: A 52-Week Follow-Up of a Randomized Controlled Clinical Study.

Traditional Chinese medicine (TCM) has been used successfully to treat rheumatoid arthritis (RA). QingreHuoxue treatment (QingreHuoxue decoction [QRHXD]/QingreHuoxue external preparation [QRHXEP]) is a Chinese medicine treatment for RA. To date, very few studies have compared the long-term effects of QRHXD with those of conventional disease-modifying antirheumatic drugs on RA disease activity and radiological progression. QRHXD delayed the radiological progression and showed long-term clinical efficacy of RA. In clinical experiments, the clinical evidence of delaying the radiological progression of RA patients was obtained. A portion of the patients who participated in the “Traditional Chinese Medicine QingreHuoxue Treatment vs. the Combination of Methotrexate and Hydroxychloroquine for Active Rheumatoid Arthritis” study were followed up for 52 weeks, and intention-to-treat (ITT) and compliance protocol (PP) analyses were used to collect and compare the clinical indicators and imaging data between baseline and week 52. Two radiologists who were blind to treatment scored the images independently. Of the 468 subjects, 141 completed the 52-week follow-up. There were no significant differences among the three groups: the traditional Chinese medicine comprehensive treatment group, the Western medicine treatment group, and the integrated traditional Chinese and Western medicine treatment group. There were no differences in the total Sharp score, joint space stenosis score, and joint erosion score at baseline or 52 weeks. In the comparison of the estimated annual radiographic progression (EARP) and the actual annual Sharp total score changes among the three groups, the actual changes were much lower than the EARP at baseline. The radiological progress in all three groups was well controlled. Results of the ITT and PP data sets showed that the disease activity score 28 level of the three groups at 52 weeks was significantly lower than that at baseline. During the 52-week treatment period, the clearance of heat and promotion of blood circulation controlled disease activity and delayed the radiological progress of active RA.

Phenotypic Spectrum of CASPR2 and LGI1 Antibodies Associated Neurological Disorders in Children.

ObjectivesThe clinical data of patients with double-positive for leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies is limited, particularly for children. This study aimed to investigate and summarize the clinical features and long-term prognosis of children’s LGI1 and CASPR2 antibodies related to neurological disorders.MethodsWe collected the clinical data and prognosis of patients with dual positive antibodies of CASPR2 and LGI1, hospitalized in the Department of Neurology, Children’s Hospital of Chongqing Medical University. Furthermore, we summarized the clinical phenotypes of this disorder in children by reviewing the published literature.ResultsTwo patients presenting with variable neurological symptoms including pain, hypertension, profuse sweating, irritability, and dyssomnia from Children’s Hospital of Chongqing Medical University were enrolled in this study. Together with the two patients, we identified 17 children with dual CASPR2 and LGI1 antibodies, including 12 males and 5 females. At the onset, the median age was 4.1 years (range 1–16, interquartile range 2.5–13.5), with 9 children younger than 5 years and 6 adolescents. Of the 17 patients, 11 were diagnosed with Morvan syndrome, 4 with acquired neuromyotonia, 1 with Guillain-Barré syndrome, and 1 with Guillain-Barré syndrome combined with Morvan syndrome. Dysautonomia (14/17, 82.3%), pain (13/17, 76.4%), sleep disorders (13/17, 76.4%), encephalopathy (12/17, 70.5%), and weight loss (10/17, 58.8%) were the most frequently described symptoms overall. No tumors were identified. Of the 17 patients, 13 received immunotherapy comprising IVIG combination of IVMP during the acute symptomatic phase followed by oral prednisolone to maintain remission (n = 7), the combination of IVIG, IVMP, oral prednisolone and methotrexate (n = 1), the combination of IVIG, IVMP, and mycophenolate mofetil (n = 1), the combination of IVIG, IVMP, oral prednisolone, and rituximab (n = 1), IVIG only (n = 2), IVMP only (n = 1). Median modified Rankin Scale (mRS) scores in the acute phase were 3 (range 1–4) and improved gradually. Over the follow-up (median 8.6 months, range 1–36 months), 52.9% (9/17) of the patients recovered completely; one patient relapsed and showed immunotherapy-dependent.ConclusionLGI1 and CASPR2 double-positive antibodies associated with the neurological diseases can occur in children of all ages and involve multiple nervous systems. Morvan syndrome is the most common phenotype of this disorder. The long-term outcomes are mostly favorable upon immunotherapy.

Comparing methotrexate monotherapy with methotrexate plus leflunomide combination therapy in psoriatic arthritis (COMPLETE-PsA): a double-blind, placebo-controlled, randomised, trial.

Conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) are the preferred first-line treatment in patients with psoriatic arthritis, although there is a paucity of evidence for the efficacy of conventional synthetic DMARDs and especially their combination. We aimed to investigate whether a combination of methotrexate plus leflunomide is superior to methotrexate monotherapy at improving disease activity in patients with psoriatic arthritis. This single centre, investigator-initiated, double-blind, randomised, placebo-controlled trial was conducted at Sint Maartenskliniek in the Netherlands (locations included Boxmeer, Geldrop, Woerden, and Nijmegen). Patients aged 16 years or older with a clinical diagnosis of psoriatic arthritis and active disease (defined as two or more swollen joints; dactylitis counting as one swollen joint) were included. Patients were randomly allocated (1:1) and stratified by high disease activity (psoriatic arthritis disease activity score [PASDAS] ≥5·4) to either methotrexate plus leflunomide (combination therapy) or methotrexate plus placebo (monotherapy), using computer-generated stratified variable block randomisation. In both groups, patients received oral methotrexate 15 mg per week for the first 4 weeks and 25 mg per week thereafter combined with two leflunomide 10 mg tablets once per day or two placebo tablets. During the study period, the patients, nurses, researchers, and treating physicians were all masked to treatment allocation. The primary outcome was the difference in mean PASDAS at week 16, adjusted for baseline PASDAS, between the combination and monotherapy groups, assessed in the intention-to-treat population. This trial was registered with the Netherlands Trial Register (NL7404) on Dec 3, 2018. Between Feb 19, 2019, and March 11, 2021, 82 patients were screened for eligibility. Four patients were ineligible and 78 were enrolled and randomly assigned to either methotrexate plus leflunomide (n=39) or methotrexate plus placebo (n=39). 50 (64%) of 78 patients were male, 28 (36%) were female, and the median age of patients was 55·0 years (IQR 42·0-64·0). Methotrexate plus leflunomide combination therapy was superior to methotrexate monotherapy at week 16 (PASDAS 3·1 [SD 1·4] vs 3·7 [SD 1·3]; treatment difference -0·6, 90% CI -1·0 to -0·1; p=0·025). There were no study deaths. The most frequently occurring adverse events were nausea or vomiting (17 [44%] of 39 patients in the methotrexate plus leflunomide group vs 11 [28%] of 39 in the methotrexate plus placebo group), tiredness (9 [23%] vs 13 [33%]) and elevated alanine aminotransferase (12 [31%] vs 7 [18%]. Generally, the incidence of mostly mild adverse events was higher in the methotrexate plus leflunomide group than in the methotrexate plus placebo group. Methotrexate plus leflunomide combination therapy results in greater improvement in disease activity according to PASDAS in patients with psoriatic arthritis. However, methotrexate plus leflunomide combination therapy is less well tolerated than methotrexate monotherapy. Regional Junior Researcher Grant from the Sint Maartenskliniek.

Quercetin and Methotrexate in Combination have Anticancer Activity in Osteosarcoma Cells and Repress Oncogenic MicroRNA-223

Osteosarcoma (OS) is one of the most common bone neoplasms in adolescents. Notable short- and long-term toxic effects of OS chemotherapy regimens have been reported. Hence, new chemotherapeutic agents with the ability to potentiate OS chemotherapy drugs and protect non-tumorous tissues are required. Saos-2 cells were treated with Methotrexate (MTX) and Quercetin (Que) (a polyphenolic flavonoid with anti-tumor effects) alone and in combination. MTT assay was performed to investigate the cytotoxicity of the drugs. Moreover, apoptosis-involved genes, including miR-223, p53, BCL-2, CBX7, and CYLD expression were analyzed via qRT-PCR. Annexin V-FITC/PI kit was employed to assess the apoptosis rate. The MTT results showed that Que increases MTX cytotoxicity on OS cells. The measured IC50s are 142.3 µM for QUE and 13.7 ng/ml for MTX. A decline in MTX IC50 value was observed from 13.7 ng/ml to 8.45 ng/ml in the presence of Que. Moreover, the mRNA expression outcomes indicated that the combination therapy significantly up-regulates the tumor suppressor genes, such as p53, CBX7, and CYLD, and declines anti-apoptotic genes BCL-2 and miR-223, which can lead to proliferation inhibition and apoptosis inducement. Furthermore, the apoptosis rate increased significantly from 6.03% in the control group to 38.35% in Saos-2 cells that were treated with the combination of MTX and Que. Que, with the potential to boost the anticancer activity of MTX on Saos-2 cancer cells through proliferation inhibition and apoptosis induction, is a good candidate for combination therapy.

Thymoquinone Augments Methotrexate-Induced Apoptosis on Osteosarcoma Cells.

Osteosarcoma (OS) as the most frequent primary bone malignancy in children and adolescents has a short survival rate in advanced stages. Alternative herbal medicines with fewer side effects or the potency to protect common therapy's side effects can be helpful in combinational therapies. Herein, we aim to explore the effects of Thymoquinone (TQ) combined with Methotrexate (MTX) on Saos-2 cells apoptosis. The effects of TQ and MTX alone or in combination on Saos-2 cell viability were measured by MTT assay. Real-time PCR was applied for the measurement of Bax, BCL-2, and caspase-9 mRNA expression. Apoptosis evaluation was conducted by flow cytometry. TQ improves the cytotoxic effects of MTX on Saos-2 cells proliferation at lower doses. Indeed, the IC50 of MTX decreased from 26 μM to 15 μM when it combined with TQ. TQ and MTX can induce the expression level of pro-apoptotic factors, Bax and caspase-9 while inhibiting anti-apoptotic protein BCL-2. Moreover, the combination of TQ and MTX potentiates apoptosis to 73%, compared to either TQ (48%) or MTX (53%) treated cells. The co-treatment of TQ and MTX is associated with the up-regulation of apoptotic factors and down-regulation of anti-apoptotic factors, conducting apoptosis aggravation and OS cell death.

Effects of CMF and MET on glutamate and dopamine levels in the brain, and their impact on cognitive function.

Chemotherapy can cause cognitive impairment in cancer survivors. CMF, the combination of cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU), is employed for the treatment of several types of cancers, such as metastatic breast cancer. Metformin (MET) is an antidiabetic medication used to treat type 2 diabetes that can reportedly alleviate some toxic effects. In the current study, we investigated the ability of MET to alleviate the effects of CMF in neuronal toxicity. Rats were treated with two doses of CMF (intraperitoneal injection) and MET (in the daily drinking water). Rats were subjected to fear conditioning memory tests to evaluate memory function following treatment, and brain samples were collected and homogenized using neuronal lysis buffer for assessment of glutamate and dopamine levels by high-performance liquid chromatography (HPLC). Fear conditioning memory tests revealed a significant reduction in memory function in CMF and CMF+MET groups vs. controls, but no significant change in MET groups vs. controls was detected. Similarly, CMF and CMF+MET groups revealed a significant increase in glutamate and dopamine levels in the brain of MET, CMF, and MET+CMF groups vs. controls based on HPLC results. In addition, although glutamate and dopamine levels were increased, levels varied between groups, with highest levels in the CMF+MET group. Our results demonstrate that cognitive impairment in CMF and CMF+MET groups could result from increased glutamate and dopamine levels in the brain, leading to brain toxicity and failure of MET to alleviate the toxic effects of CMF.

Efficacy of Tocilizumab Monotherapy Versus Tocilizumab and Methotrexate Combination Therapy in the Prevention of Radiographic Progression in Rheumatoid Arthritis: An Analysis Using Individual Patient Data From Multiple Clinical Trials

ObjectiveTo compare the effects of preventing radiographic progression (in its 3 components) of tocilizumab (TCZ) monotherapy with those of TCZ and methotrexate (MTX) in combination therapy (TCZ + MTX), and to evaluate possible effect modifiers in this model.MethodsRandomized trials that compared TCZ monotherapy to TCZ + MTX combination therapy for differences in radiographic progression were analyzed on an individual patient data level using mixed‐effects models, and data were collected from 820 subjects with either early rheumatoid arthritis (RA) or established RA. Outcomes were classified as the absence of radiographic progression after 2 years (i.e., preventing radiographic progression) as measured by total Sharp/van der Heijde score (SHS), erosion score, and joint space narrowing (JSN) score. Effect modification by baseline joint damage, disease duration, and Disease Activity Score in 28 joints (DAS28) was studied.ResultsOverall, TCZ + MTX combination therapy was more effective in preventing radiographic progression compared to TCZ monotherapy, which was measured by total SHS score. However, in patients with early RA who had more joint damage compared to those with less joint damage at baseline (relative risk [RR] 1.02 versus RR 0.91, respectively) or in patients with a lower DAS28 score compared to those with a higher DAS28 score (RR 1.04 versus RR 0.92, respectively) at baseline, this advantage disappeared. In patients with established RA, the advantage of TCZ + MTX versus TCZ alone in the prevention of radiographic progression disappeared with a longer disease duration at baseline (RR 1.04 versus 0.83). Results of erosion scores as an outcome were in line with these findings, though findings for JSN scores were less clear.ConclusionCombination therapy with TCZ + MTX is more effective in preventing radiographic progression compared to TCZ monotherapy, but the effectiveness of TCZ monotherapy may approximate the effectiveness of TCZ + MTX in patients with early RA who have more joint damage and/or a lower DAS28 at baseline and in patients with established RA who have longer disease duration.

Combination effect of methotrexate with Narrowband Ultraviolet B (NB-UVB) phototherapy in psoriasis vulgaris patients in dermatology and venereology outpatient clinic Dr. Soetomo General Academic Hospital, Surabaya, Indonesia

Background: Psoriasis is a chronic, recurrent, inflammatory skin disease that alters the quality of life. Systemic therapy and biologic agents are prescribed for severe and widespread psoriasis, but these drugs may have systemic side effects and immune suppression. Narrowband Ultraviolet B (NB-UVB) phototherapy remains one of the most effective and safe treatments for psoriasis.Methods: This study was an observational retrospective cohort with one group pretest and post-test design. A retrospective analysis was done on 16 medical records of patients who met the inclusion criteria. The efficacy of the therapy was identified and analyzed using the SPSS version 17 for Windows.Results: This study found that 16 psoriasis patients received NB-UVB phototherapy, 11 (68.75%) in men and 5 (31.25%) in women. The mean age was 47.31 years. There was a statistically significant difference in the reduction in PASI score before and after receiving combination methotrexate with 24 sessions of NB-UVB phototherapy (p=0.000); the delta PASI score was 45,02%. A statistical analysis based on the number of phototherapy sessions per week showed enhanced results when patients attended 3 phototherapy sessions per week (p = 0.001).Conclusion: There was a statistically significant reduction in PASI score in psoriasis vulgaris patients before and after receiving combination methotrexate with 24 sessions of NB-UVB phototherapy.

Bioavailability, anti-inflammatory and anti-arthritic effect of Acetyl Keto Boswellic acid and its combination with methotrexate in an arthritic animal model

Ethnopharmacological relevanceRheumatoid arthritis is one of the most common disabling chronic progressive autoimmune diseases affecting the adult world population. Boswellia serrata has been a known anti-inflammatory agent since ancient times. Therefore, research on Boswellia extract based on Acetyl Keto Boswellic Acid (AKBA) content evaluating its efficacy and safety is necessary.The study aimed to find a suitable Boswellia extract rich in AKBA to evaluate its bioavailability, anti-inflammatory, and anti-arthritic effect. In addition, the synergistic action of AKBA extract with methotrexate (MTX) was also assessed on an animal model. Materials and methodsOral bioavailability of AKBA and the anti-inflammatory activity of 10% AKBA (5, 10, 20, 40 mg/kg b.w) was assessed and compared with 2% AKBA (40 mg/kg) and diclofenac (10 mg/kg). The effect of 10% AKBA at 20 mg/kg and 40 mg/kg was evaluated in the FCA induced arthritis animal model alone and combined with methotrexate (MTX) at 2 mg/kg b.w. Subplantar injection of FCA produced edema within a few hours with progressive arthritis by the 9th day after injection. All the treatments were initiated from the 10th day until the 45th day. Oral administration of 10% AKBA was done daily and MTX by intraperitoneal route once a week from day 10 to day 45. Paw volume, erythrocyte sedimentation rate (ESR), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP), total bilirubin, oxidative markers (superoxide dismutase (SOD) levels, malondialdehyde (MDA), total proteins and liver histopathology were examined. Results10% AKBA provided 8.48-fold, 24.22-fold, 47.36-fold, and 110.53-fold higher AUC (0-α) of AKBA at 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg, respectively compared to 2% AKBA at 40 mg/kg. Percentage paw edema inhibition of 10% AKBA at 20 mg/kg and 40 mg/kg were significantly higher than 2% regular AKBA (40 mg/kg) and diclofenac (10 mg/kg). 10% AKBA at a dose of 20 and 40 mg/kg significantly reduced ESR compared with FCA treated group. A combination of methotrexate with 10% AKBA showed the highest reduction in ESR. 10% AKBA at both dose levels significantly reduced hepatic marker enzymes and total bilirubin levels. Treatment with 10% AKBA showed a significant increase in total proteins, antioxidant enzymes and a decrease in malondialdehyde levels. Similarly, 10% AKBA protected the hepatocytes compared with the FCA and FCA + MTX treated group. 10% AKBA was capable of significantly minimizing FCA and FCA + MTX induced changes. ConclusionAnti-inflammatory activity of AKBA due to inhibition of lipoxygenase (LOX) enzymes supports the use of AKBA in inflammatory disorders. Combination therapy of 10% AKBA with MTX is effective in inhibiting arthritis and circumventing hepatotoxicity produced by MTX in arthritic animals.

Search of official nationwide database in Japan for adverse events associated with disease-modifying antirheumatic drug therapies: focus on therapies in combination with methotrexate

ABSTRACT Background Disease-modifying antirheumatic drugs (DMARDs) are essential for rheumatoid arthritis (RA) therapy. The adverse events (AEs) evaluation should focus on that methotrexate (MTX) is frequently prescribed in combination with others (combination MTX). Methods A search of the website of the official Japanese Agency for AEs, including lymphoproliferative disease (LPD), cytopenia, interstitial pneumonia, infectious pneumonia other than Pneumocystis jirovecii pneumonia (PCP) (i-Pn), and PCP, associated with MTX, tacrolimus, adalimumab, tocilizumab, and abatacept therapies reported from 2014 to 2016 was performed. Number of each AE cases and its ratio to total number of AEs cases were examined. Combination MTX was checked for RA cases. Results A total of 8874 cases were listed. In 3955 MTX cases, LPD was most frequent (36.4%). In any of the other four DMARDs cases, i-Pn was most frequent (4.2 ~ 15.3%); PCP cases showed most frequent combination MTX (94.4%). In total, including cases reported for MTX therapy, 98.2% of LPD and 97.6% of PCP cases had MTX, and less than 90% of the other AEs cases had MTX. Conclusion LPD was by far the most frequent AE associated with MTX therapy. PCP was strongly associated with combination MTX. For any of the other four DMARDs, i-Pn was most frequent.

Burden of hospitalizations and outpatient visits associated with moderate and severe acute graft-versus-host disease in Finland and Sweden: a real-world data study

PurposeThe aim of this study was to describe patient characteristics and quantify hospital stays and outpatient visits (H&OV) following diagnosis with moderate-to-severe acute graft-versus-host disease (aGVHD) in Finland and Sweden.MethodsA retrospective chart audit collected data from patient medical records of 3 specialized centers performing allogeneic hematopoietic stem cell transplantation (HSCT; Finland, n = 2; Sweden, n = 1). Eligible patients received allogeneic HSCT (January 1, 2016–June 30, 2017) from any donor source, were diagnosed with grade II–IV aGVHD (MAGIC or modified Glucksberg criteria) at any time from transplantation to 12 months before data collection, and were ≥ 18 years old at diagnosis. Criteria for comparing patients graded with modified Glucksberg and MAGIC severity scales were defined.ResultsFifty-five patients (Finland, n = 45; Sweden, n = 10) were included. Myeloablative conditioning was the most common conditioning regimen (81.8%); immunosuppression regimens were based on combinations of methotrexate (96.4%), in vivo T-cell depletion (80.0%), cyclosporine (63.6%), mycophenolate (40.0%), and tacrolimus (34.5%). Sixteen patients (29.1%) developed grade III/IV aGVHD; skin was the most common organ involved (80.0%). Most patients required ≥ 1 hospital stay (89.1%; median of 2 hospitalizations per patient); 7 patients (14.3%) required admission to an intensive care unit. Median hospitalization duration from HSCT to discharge was 26 days. Most patients also required outpatient or emergency department visits (90.9%). Subgroup analyses showed longer hospital stays for patients receiving multiple treatment lines; no clear differences in H&OV were observed between prophylactic regimens.ConclusionBased on this retrospective study, moderate-to-severe aGVHD is associated with considerable healthcare resource utilization in Finland and Sweden, particularly in patients who received multiple lines of therapy.

Cervical ectopic pregnancySuccessful management by combined systemic methotrexate, bilateral uterine embolization and suction evacuation

: A 31-year female, G4P2L2A1 with two previous cesarean deliveries and one dilatation and curettage, was diagnosed with cervical ectopic pregnancy of 8 weeks and two days without any cardiac activity. She had a complaint of slight pain in the abdomen without any bleeding per vagina. She was initially managed with multi-dose systemic methotrexate therapy. The value of beta-HCG decreased by about 70%. She then underwent bilateral uterine artery embolization followed by ultrasound-guided suction evacuation with descending cervical artery ligation with cervical balloon tamponade. The patient was asymptomatic throughout her hospital stay. Her beta-HCG value dropped to 10 IU/ml and usg showed empty endocervical canal on weekly follow-up.: Conservation methods like systemic methotrexate or potassium chloride, along with minimally invasive techniques like bilateral uterine artery embolization, are among the most effective and safe fertility-sparing modalities in managing cervical ectopic pregnancy. Proper case selection and availability of required infrastructure at tertiary care centers are mandatory.

Co-treatment of Nimbolide augmented the anti-arthritic effects of methotrexate while protecting against organ toxicities

Prolonged exposure to the pharmacological doses of disease-modifying anti-rheumatic drugs (DMARDs) often results in major organ toxicities resulting in poor patient compliance. Methotrexate (MTX) is one of the commonly prescribed DMARDs for the treatment of arthritis, which results in vital organ dysfunction. To retain the anti-arthritic activity of MTX with the reduction in toxicities, combination therapies are warranted. Nimbolide (NMB) is a potent anticancer, anti-inflammatory and anti-fibrotic agent whose potential has been demonstrated in various pre-clinical models. Monoarthritis was developed with Complete Freund's Adjuvant in the knees of Wistar rats and treatment was given with either NMB (3 mg/kg/day) or MTX (2 mg/kg/week) alone or combination therapy (NMB + MTX). The anti-arthritic effects were evaluated by arthritic scoring, radiological imaging, synovial tissue proteins analysis, and histopathological staining. While hepato-renal toxicity was assessed in serum by evaluating the kidney and liver functional parameters, in tissues by oxidative-nitrosative stress markers, and pro-inflammatory cytokines levels. Histopathological analysis was performed to study the extent of tissue damage. Molecular studies like immunoblotting and immunohistochemistry were performed to understand the effect of combination therapy. We thereby report that monotherapy with either NMB or MTX exhibited significant anti-arthritic effects, while combination therapy resulted in augmented anti-arthritic effects with significant reduction in hepato-renal toxicity produced by MTX probably through anti-inflammatory and anti-oxidant effects. Therefore, our proposed combination of NMB and MTX may serve as a potential strategy for the effective management of arthritis.