Combination Of Methotrexate Research Articles

Rituximab plus methotrexate combination as a salvage therapy in persistently active granulomatosis with polyangiitis.

The aim of this study was to describe the efficacy and safety of rituximab and MTX (RTX/MTX) combination therapy in ANCA-associated vasculitides (AAV). A retrospective French nationwide study was conducted in patients with AAV who received RTX/MTX combination therapy for persistently active disease. Seventeen patients were included. All patients had granulomatosis with polyangiitis (GPA), with positive ANCA in 76% of them, mainly with PR3-ANCA specificity. Sixteen patients (94%) had priorly failed to achieve remission with RTX and 11 (65%) with CYC. Patients had experienced a median of 3 (2-4) flares. Manifestations requiring RTX/MTX combination therapy were subglottic or bronchial stenosis in 6 patients (35%), orbital mass in 6 (35%), disabling ENT involvement in 2 (12%), and epiduritis and pachymeningitis in 1 case (6%) each. The median follow-up duration for the RTX/MTX combination therapy was 11 months (11-26 months). At 6 months, global response had been achieved in 15 patients (88%), including partial response in 11 (65%) and complete response in 4 (24%). At last evaluation, global response had been achieved in 16 patients (94%). Seven patients (41%) experienced severe adverse events (grade 3 or 4), including infections in 4 (24%) and hepatitis in 2 (12%). Combination therapy was withdrawn in 4 patients (24%), but never for safety concerns. In contrast, the MTX dose was decreased in 2 patients (12%) because of adverse events. One patient died of an unknown cause. RTX/MTX combination therapy could be an effective salvage therapy to treat persistently active GPA with granulomatous manifestations, with an acceptable safety profile.

Local and generalized bone loss in rheumatoid arthritis

The article presents a review of cross-sectional studies and long-term prospective observations dedicated to changes in bone mineral density (BMD) in patients with rheumatoid arthritis (RA) and factors influencing it. The relationship between local bone loss (erosion count) and generalized BMD loss was noted. It is indicated that existing RA treatment strategies are aimed at suppressing inflammation rather than preventing bone resorption. There is evidence that anti-inflammatory therapy using glucocorticoids, methotrexate, and biologic DMARDs in combination with antiresorptive drugs (bisphosphonates and denosumab) helps prevent BMD loss and the progression of erosions. It is emphasized that osteoporosis in RA, which belongs to the immune-mediated secondary osteopathies, is one of the most frequent and serious complications of RA, which determine the unfavorable course and prognosis of the underlying disease.

British Association of Dermatologists guidelines for the management of people with cutaneous lupus erythematosus 2021.

The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of cutaneous lupus erythematosus (CLE) in the presence or absence of systemic lupus erythematosus (SLE) in adults, young people and children. The document aims to: offer an appraisal of all relevant literature up to December 2020, focusing on any key developments address important, practical clinical questions relating to the primary guideline objective. provide guideline recommendations and if appropriate research recommendations.

P25 Early onset congenital sarcoidosis: Challenges in the management of recurrent severe bilateral uveitis and inflammatory arthritis

Abstract Case report - Introduction We report a rare case of 20-year-old male diagnosed with congenital sarcoidosis (Blau Syndrome) presenting with a triad of skin rash, arthritis and bilateral uveitis. He has had recurrent flares of sight-threatening bilateral uveitis, as well as persistent arthritis, which has continued despite treatment with multiple immunosuppressive agents and corticosteroids. The best control has been achieved with combination of methotrexate and infliximab which he has returned to; however, complications of frequent infections has necessitated breaks in treatment. Case report - Case description A 4-year-old male presented with inflammatory skin rash which was biopsied and diagnosed as sarcoid lesion. He developed bilateral blurring of vision and diagnosed with uveitis, which was treated with topical and oral steroids. He then experienced multiple joint pains with synovitis. His father had been diagnosed from a young age with sarcoidosis. Other possible causes were ruled out. From early childhood, our patient was treated with methotrexate, then methotrexate and azathioprine for recurrent uveitis, but required long-term oral prednisolone. He started infliximab with methotrexate in adolescence with good response and weaned his steroids. However, uveitis flared when infliximab was stopped for appendicectomy, requiring rescue with oral and intraocular steroids. Further flares with cystoid macular oedema secondary to sarcoid uveitis and arthritis flares required high-dose steroids, contributing to iatrogenic cushingoid syndrome. Beta-haemolytic streptococcal infection led to guttate psoriasis, after which he had more persistent polyarticular inflammation and tenosynovitis. Antibodies were detected against infliximab although clinically uveitis continued to respond. Adalimumab caused site injection reactions. MDT discussions recommenced higher dose infliximab. Long-standing nausea after methotrexate, oral or subcutaneous, despite folic acid and anti-emetics, became intolerable. Transfer of care to another rheumatology centre focused on trying to control his arthritis. Leflunomide and then mycophenolate-mofetil replaced methotrexate. Infliximab was then switched to tofacitinib (developed severe headache) and then baricitinib. Joint symptoms improved on baricitinib, and nausea reduced with mycophenolate; however, his uveitis flared severely again requiring further high-dose oral and intraocular steroid rescue. Further MDT and patient discussion resulted in restarting methotrexate 20mg weekly (enduring nausea) and infliximab 5mg/kg monthly. Uveitis settled and arthritis control remained stable over the last 12 months with reduction in prednisolone to 5mg daily. Recurrent infections with recent pilonidal sinus continue to cause treatment interruptions. Case report - Discussion Sarcoidosis is a chronic, idiopathic multisystem, granulomatous disorder rarely occurring in children. Early onset sarcoidosis/Blau syndrome (familial) is distinct, presenting in children around age 4 years and characterised by the triad of skin, joint and eye manifestations without the pulmonary involvement seen in adults. Children with Blau syndrome can develop severe complications such as blindness, growth retardation, heart involvement, renal failure and death. Our patient was diagnosed with Blau syndrome based on the symptom triad and NOD2 gene mutation positive. He had recurrent flares of severe uveitis and difficult to manage joint disease involving his wrists/hands, shoulders, knees, ankles with tenosynovitis. He required shoulder decompression, knee-meniscal surgery and plastic-surgery to finger tendons. With early treatment he has grown well and preserved visual acuity (6/9 in both eyes), with no other organ involvement. He works full-time. He has suffered from depression and struggled with body image issues, particularly from cushingoid changes. Difficult patient choices balanced medication side effects and control of eye/joint inflammation. He endures nausea after weekly methotrexate and some ongoing joint symptoms to enable his uveitis-responsive treatment to be prioritised. Recurrent infections interrupted use of the most efficacious immunosuppressive therapy (infliximab and methotrexate). Jak Inhibitors provided some benefit for joint symptoms but did not control his uveitis. Different mechanisms seem to be important in the perpetuation of his uveitis and arthritis given the differential responses to treatment. Other treatment options such as anti-IL1 therapy were considered; however, limited data for eye inflammation results in patient continuing on his current therapy. Multi-disciplinary care/co-ordination is essential in managing this complex, rare condition to balance optimisation of his medications to treat his most organ threatening and debilitating symptoms. Genetic studies have enabled confirmation of the familial basis of his condition and autosomal dominant inheritance risk. Case report - Key learning points

Molecular Changes in the Adipose Tissue Induced by Rheumatoid Arthritis: Effects of Disease-Modifying Anti-Rheumatic Drugs

Disease severity, progression and response to therapy might be worse in obese rheumatoid arthritis (RA) patients, but paradoxically, obesity also might protect from radiographic joint damage. Thus, the intricate relationship between obesity and RA needs urgent clarification. The aim of this study was to assess the influence of obesity on the onset and development of RA and to determine whether arthritis could modify the adipose tissue biology and whether conventional Disease Modifying Anti-Rheumatic Drugs (cDMARDs) can modulate these alterations. Two strategies were followed: (1) clinical profiling of two cohorts of RA: non-obese and obese patients; and (2) mechanistic studies carried out in both a collagen-induced arthritis (CIA) in an obese mouse model and 3T3-L1 adipocytes treated with cDMARDs (leflunomide, methotrexate, and hydroxychloroquine). In our cohort of RA patients with low-moderate disease activity, the presence of obesity was not related to a higher activity of the disease; actually, disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) was reduced in the obese RA patients. However, the induction of arthritis promoted transcriptomic changes in the adipose tissue under obesity condition in the obese CIA model. Treatment with hydroxychloroquine reduced weight and insulin resistance, accompanied by beneficial metabolic effects in the adipose tissue. These molecular changes in adipose tissue were also observed after methotrexate administration. In sum, arthritis might affect directly the inflammatory burden and metabolic alterations associated with obesity in adipose tissue. Clinicians should be cautious measuring the activity of the disease in obesity and managing the best therapeutic options for the metabolic comorbidities of these patients, where the combination of hydroxychloroquine and methotrexate should be considered to improve adipose tissue dysfunction in obese RA.

Intermediate stage atherosclerosis regression using combined methotrexate- mediated ultrasound sonoporation therapy and gold nanoparticles- mediated X- rays- based Auger electron therapy

Abstract Background Atherosclerosis is a slow, progressive disease that may begin as early as childhood. Although the exact cause is unknown, atherosclerosis may start with damage or injury to the inner layer of an artery. Atherosclerosis is the main cause of stroke and myocardial infarction. In atherosclerosis, local inflammation and associated macrophage activity can lead to foam cell-rich lesion formation, making inflammation an important therapeutic target in cerebrovascular and cardiovascular diseases. Aims In this study, we developed an experimental pulsed low level focused ultrasound system, and investigated its effectiveness on intermediate stage atherosclerosis regression accompanied by intravenous lipid-based encapsulated methotrexate nanoparticles administration and lipid based encapsulated gold nanoparticles-mediated X-rays-based Auger electron therapy in the golden Syrian hamster common carotid artery, wherein diagnostic B-mode ultrasound is combined with ultrasound therapy system, with a goal of increased safety. Methods In this study, common carotid arteries of hamsters submitted to intermediate stage atherosclerosis using intravascular balloon injury and high-cholesterol diet injury. Then common carotid arteries of the treatment group (n=10) at the injured region, underwent pulsed low level focused ultrasound (F=1.3 MHz, P=24 W, PD=100 ms)-mediated sonoporation therapy accompanied by intravenous lipid-based encapsulated methotrexate nanoparticles (10ml/kg) administration and lipid based encapsulated gold nanoparticles-mediated X-rays (25 Gy)-based Auger electron therapy. Wall mean thickness and percentage of luminal cross-sectional area of stenosis were measured by ultrasonography and histopathology. Results Results from ultrasonography and histopathology showed a significant reduction in the mean value for wall mean thickness, percentage of luminal cross-sectional area of stenosis, lipid-laden cells and lipid droplets density at the stenotic region in the treatment group compared with the other groups (P<0.05) Conclusions Enhanced apoptotic and anti-proliferative effect of methotrexate, induced by enhanced inertial cavitation-based sonoporation effect of focused ultrasound, due to collapsed capsules accompanied by enhanced apoptotic effect of Auger electron therapy, can cause to regress of the intermediate stage atherosclerosis and significantly dilate the luminal cross-sectional area of stenosis. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mehrad Research Lab

LIPID PROFILES AND MATRIX METALLOPROTEINASE-3 IN PATIENTS WITH RHEUMATOID ARTHRITIS

TOPIC: Cardiovascular Disease TYPE: Original Investigations PURPOSE: Rheumatoid arthritis (RA) is associated with an unexplained increased cardiovascular risk. Matrix metalloproteinase-3 (MMP-3) is the most important protease involved in RA inflammation which may play a role in the development of cardiovascular events. Specific role of MMP-3 in cardiac pathology in RA patients (pts) is not well investigated.OBJECTIVE: To compare levels lipid profiles and MMP-3 in patients (pts) with active RA and healthy people. METHODS: Thirty nine RA pts (33 women and 6 men, median age 56,5 [49; 65] years), with active arthritis (mean disease duration 96 [48; 190] months; DAS28 5,8 [5,3;6,3]; HAQ 1,8 [1,3; 2,2]) were enrolled in the study. Twenty three pts (59%) received methotrexate, 5 (13%) – the combination of methotrexate with oral glucocorticoids, 10 (26%) - oral glucocorticoids monotherapy. The control group consisted of 29 volunteers (21 women and 8 men, median age 58,5 [53; 62] years). The concentration of total cholesterol (TC) and triglycerides (TG) in the blood determined colorimetrically, low density lipoprotein cholesterol (LDL-C) – homogeneous enzymatic colorimetric method, high density lipoprotein cholesterol (HDL-C) – quantitative photometric method. Atherogenic index (AI) calculated by the formula: IA = (HC – HDL-C)/HDL-C. Serum MMP-3 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Rates of dyslipidemia were similar in RA pts (23/39 (59%) and control group subjects (15/29 (52%). Concentrations of lipids were also similar in both groups and were as follows: total cholesterol was 5,2 [4,9; 6,2]mmol/l in RA pts and 6,3[5,1; 6,6]mmol/l in the control group; HDL cholesterol - 1,7 [1,4; 2,0]mmol/l and 1,7[1,5; 2,1]mmol/l,LDL cholesterol - 3,3 [2,8; 4,0]mmol/l and 3,6[3,0; 4,0]mmol/l, triglycerides - 1,3 [1,0; 1,6]mmol/l and 1,4[1,1; 1,8]mmol/l, the atherogenic index of plasma - 2,4 [1,8; 2,8] and 2,4 [1,9; 3,0], respectively. Elevated MMP-3 levels were detected more frequently in RA pts (31/39 (79%)) vs healthy controls (2/29 (7%), p<0,0001). MMP-3 concentrations were higher in RA pts (57,0 [36,6; 114,3ng/ml), than in the control group subjects (13,4 [9,9; 20,4]mg/ml, p <0,0001). In RA pts and in healthy controls, MMP-3 levels demonstrated significant correlation with erythrocyte sedimentation rate (ESR) (r =0,64, p < 0,05) and C-reactive protein (CRP) (r =0,52, p < 0,05) values. In the RA group, concentrations of HDL cholesterol were negatively correlated with MMP-3 (r = -0,5, p < 0,05), CRP (r = -0,53, p< 0,05), and DAS28 (r = -0,4, p< 0,05). Showed no correlation between the levels of lipids and MMP-3 in control group. CONCLUSIONS: RA pts exhibited higher serum MMP-3 levels than healthy individuals. Obtained results suggest that MMP-3 and CRP may produce a negative impact on HDL-Cl levels in pts with active RA. CLINICAL IMPLICATIONS: Control over RA activity probably avoids the development of dyslipidemia in RA pts. DISCLOSURES: No relevant relationships by Maria Cherkasova, source=Web Response No relevant relationships by Elena Gerasimova, source=Web Response No relevant relationships by Tatiana Popkova, source=Web Response

Metformin sensitises hepatocarcinoma cells to methotrexate by targeting dihydrofolate reductase

Metformin, the first-line drug for type II diabetes, has recently been considered an anticancer agent. However, the molecular target and underlying mechanism of metformin’s anti-cancer effects remain largely unclear. Herein, we report that metformin treatment increases the sensitivity of hepatocarcinoma cells to methotrexate (MTX) by suppressing the expression of the one-carbon metabolism enzyme DHFR. We show that the combination of metformin and MTX blocks nucleotide metabolism and thus effectively inhibits cell cycle progression and tumorigenesis. Mechanistically, metformin not only transcriptionally represses DHFR via E2F4 but also promotes lysosomal degradation of the DHFR protein. Notably, metformin dramatically increases the response of patient-derived hepatocarcinoma organoids to MTX without obvious toxicity to organoids derived from normal liver tissue. Taken together, our findings identify an important role for DHFR in the suppressive effects of metformin on therapeutic resistance, thus revealing a therapeutically targetable potential vulnerability in hepatocarcinoma.

The effects of iguratimod combined with methotrexate and hydroxychloroquine on bone mineral density in patients with rheumatoid arthritis.

In this study, we aimed to explore the effects of iguratimod (IGU) combined with methotrexate (MTX) and hydroxychloroquine (HCQ) on bone mineral density (BMD) in patients with rheumatoid arthritis (RA). 76 patients who received IGU combined with MTX and HCQ were included in this retrospective study. After 48 weeks treatment of IGU combined with MTX and HCQ, the BMD at the L1-L4 (p <0.01), left femoral neck (p <0.01) and left total hip (p <0.01) were significantly increased. Especially, the BMD at left femoral neck was significantly increased from baseline to week 24 (p <0.05). With regard to inflammatory reaction, there were statistically significant reductions in the RF (p <0.05), CRP (p <0.05), ESR (p <0.01), anti-CCP (p <0.01) from baseline to week 48. The most common adverse events were gastrointestinal reaction and transaminase elevation. The combination of IGU, MTX and HCQ could significantly improve the BMD and restrain inflammatory reaction. No additional adverse events were noticed in our research. This study provides valuable information for treatment of osteopenia in patients with RA.

Comparative Study between the Efficacy of Platelet Rich Plasma with Methotrexate and Methotrexate Alone in Treatment of Chronic Plaque Psoriasis

Abstract Background Psoriasis affects up to 3% of the world's population or more than 125 million people. There is an urgent need for new treatment strategy, as up to 50% of patients are not satisfied with current therapies. We evaluated the efficiency of combined platelet rich plasma (PRP) and methotrexate (MTX) injection in management of psoriasis vulgaris and combared it with methotrexate injection only. Objectives The aim of this work is to compare between the clinical efficacy of platelet rich plasma with methotrexate and methotrexate alone in treatment of chronic plaque psoriasis. Patients and Methods Forty patients with chronic plaque psoriasis were divided into two groups. Twenty patients were assigned into combinational treatment group (PRP + MTX) and monotherapy group (MTX alone) consisted of another tweenty patients. All patients in combinational therapy group received autologous intralesional PRP at 0,4 and 8 weeks combined with methotrethate im injection once every week for 12 weeks, while patients in monotherapy group received only methotrexate im injection once every week for 12 weeks. Results There were statistically significant decreased DLQI score after 6 and 12 weeks of treatment in females compared to males only in group B, while no significant differences were found between males and females in group A patients, This could be attributed to the greater concern in females as psoriasis is considered as a cosmotic problem. Conclusion Combination treatment of PRP with MTX is more effective than MTX alone in treatment of psoriasis vulgaris.

Impact of Medications on COVID-19 Outcomes in Inflammatory Bowel Disease: Analysis of More Than 6000 Patients From an International Registry

Impact of Medications on COVID-19 Outcomes in Inflammatory Bowel Disease: Analysis of More Than 6000 Patients From an International Registry

Osteosarcoma in Children: Not Only Chemotherapy.

Osteosarcoma (OS) is the most severe bone malignant tumor, responsible for altered osteoid deposition and with a high rate of metastasis. It is characterized by heterogeneity, chemoresistance and its interaction with bone microenvironment. The 5-year survival rate is about 67% for patients with localized OS, while it remains at 20% in case of metastases. The standard therapy for OS patients is represented by neoadjuvant chemotherapy, surgical resection, and adjuvant chemotherapy. The most used chemotherapy regimen for children is the combination of high-dose methotrexate, doxorubicin, and cisplatin. Considered that the necessary administration of high-dose chemotherapy is responsible for a lot of acute and chronic side effects, the identification of novel therapeutic strategies to ameliorate OS outcome and the patients’ life expectancy is necessary. In this review we provide an overview on new possible innovative therapeutic strategies in OS.

Safety of long-term use of four common conventional disease modifying anti-rheumatic drugs in rheumatoid arthritis.

Conventional disease-modifying antirheumatic drugs (DMARDs) have been used in the management of rheumatoid arthritis for a long time. Whereas methotrexate (MTX) is the anchor drug, leflunomide, hydroxychloroquine and sulfasalazine are used along with MTX either in combination or sequentially. Together these four drugs are the most commonly used DMARDs. They are also used in combination with biological DMARDs (bDMARDs) to enhance their efficacy and MTX in particular to reduce antibodies against anti-tumour necrosis factor. Despite their widespread use, concerns regarding their safety especially when used long-term hinder their optimum use in clinical medicine. In this narrative review we have critically appraised the available literature regarding the safety of these four DMARDs when used long-term.

Juvenile dermatomyositis in Thai children: Retrospective review of 30 cases from a tertiary care center.

Juvenile dermatomyositis is a rare condition, but it is the most common idiopathic inflammatory myopathy in pediatric patients. To study the clinical manifestations, investigations, treatment, clinical course, and outcomes of juvenile dermatomyositis in Thai children. This retrospective study included juvenile dermatomyositis patients treated at Siriraj Hospital, a 2,300-bed national tertiary referral center in Bangkok, Thailand, from 1994 to 2019. Thirty patients (22 females and 8 males) were included with a female to male ratio of 2.7:1. Median age at diagnosis was 5.1 years (range, 2.6-14.8 years). Median duration of illness before diagnosis was 6.5 months (range, 0.3-84.0 months). Acute and subacute onset occurred in the majority of patients. Presenting symptoms included muscle weakness in 27/30 (90%), skin rash in 26/30 (86.7%), muscle pain in 17/26 (65.4%), and arthralgia in 4/18 (22.2%) of patients. Dermatologic examination revealed Gottron's rash, heliotrope rash, and periungual telangiectasia in 25/30 (83.3%), 21/30 (70.0%), and 15/24 (62.5%) of patients, respectively. Interestingly, scalp dermatitis was found in 8/21 (38.1%) of patients. The most commonly used treatment regimen in this series was a combination of prednisolone and methotrexate. During the median follow-up of 3.1 years (range, 0.0-18.5 years), only one-third of patients were seen to have monocyclic disease. Extraskeletal osteosarcoma at a previous lesion of calcinosis cutis was observed in one patient at 12 years after juvenile dermatomyositis onset. This was a retrospective single-center study, and our results may not be generalizable to other healthcare settings. Prospective multicenter studies are needed to confirm the findings of this study. juvenile dermatomyositis usually poses a diagnostic and therapeutic challenge, which can be compounded by the ethnic variations in the clinical presentation, as observed in this study. Asian patients tend to present with acute or subacute onset of disease, and arthralgia and/or arthritis are less common than in Caucasian patients. Scalp dermatitis is not uncommon in pediatric juvenile dermatomyositis patients. An association between juvenile dermatomyositis and malignancy, though rare, can occur.

A Bibliometric Analysis of Cyclophosphamide, Methotrexate, and Fluorouracil Breast Cancer Treatments: Implication for the Role of Inflammation in Cognitive Dysfunction.

Inflammation is considered one of the possible mechanisms behind long-term cognitive dysfunction persistent after chemotherapy treatment. The chemotherapy combination of cyclophosphamide, methotrexate, and fluorouracil (CMF) was one of the older methods of treating breast cancer patients. Decades later, these patients still report experiencing cognitive side effects. In this present bibliometric review, we applied the VOSviewer tool to describe the existing landscape on literature concerning inflammation as it relates to CMF and cognitive dysfunctions. As time progressed, we saw an increase in interest in the topic. By the mid-2010s there were approximately 1,000 publications per year. Terms related to the brain and CNS did not appear until the later years, and terms related to inflammation and breast cancer were very prevalent throughout the three decades. Also, in more recent years, inflammatory markers and plant-derived compounds used to alleviate side effects of the inflammatory response appeared in the search results. The USA remained the most prolific producer of CMF-, inflammation-, and cognitive dysfunction-related papers throughout the three decades followed by Asia and Europe. As research of cognitive dysfunction caused by inflammation due to chemotherapy treatment progresses, more opportunities emerge for therapeutic methods to improve the quality of life for long-term survivors.

Outcomes of Osteosarcoma in Children Without High-Dose Methotrexate: Could It Be Less Toxic Without Effecting Survival Rates?

Background: Osteosarcoma (OS) is the most common primary bone sarcoma in childhood. High-dose methotrexate, doxorubicine, cisplatin, and/or ifosfamide combinations are used as standard treatment in chemotherapy and could cause serious toxicity. Another alternative chemotherapy protocol is consisting of epirubicin, ifosfamide, and cisplatin (ECI), which we use in our center. The aim of this study was to evaluate the patients with OS who were treated with ECI protocol, retrospectively. Methods: Forty-three patients with OS diagnosed at our center between December 1995 and September 2017 were evaluated retrospectively. Results: The mean follow-up period was 31 months (5-145 months). Recurrence was detected in 15 of 43 patients. When the factors affecting relapse are examined, recurrence was higher in patients who were older than 10 years at the time of diagnosis, upper extremity involvement, osteoblastic, and chondroblastic subgroups, but there was no statistically significant difference. Five-year and 10-year overall survival rates were 67.4% and 58.9%, and event-free survival rates were 54% and 47.3%, respectively. While 5-year overall survival rate was 86.7% in nonrecurrent cases, this rate was 40.9% in recurrent cases and this difference was statistically significant (p = 0.023). Just two patients died because of the toxicity. Conclusion: The prognosis of OS is still poor in relapse cases, so the choice of chemotherapy for neoadjuvant and adjuvant therapy is vital. When the risk of toxicity is also considered, the first step of ECI protocol is seen as a preferable treatment option because the survival rates are similar to the literature.

Effectiveness of Combination of Leflunomide and Methotrexate Compared to Etanercept in the Treatment of Rheumatoid Arthritis: A Systematic Review and Meta-Analysis

Context: Rheumatoid arthritis (RA) is a chronic progressive systemic inflammatory condition, which affects mainly the joint synovial and does not have a definitive treatment. Data was collected using the American College of Rheumatology (ACR) score, and different levels of improvement were shown as ACR20, ACR50, and ACR70. The aim of this study was to compare the effectiveness of combination of leflunomide and methotrexate (LEF + MTX) to etanercept (ETN).&#x0D; Methods: This systematic review was performed to evaluate the effectiveness of LEF + MTX in comparison with ETN. Electronic databases, including cochrane, PubMed, Scopus, and CRD, were searched up to December 2015. Quality assessment was conducted by the Jadad scale and the Cochrane Collaboration’s tools. Meta-analysis was conducted for effective outcomes of the included studies. Effectiveness was measured by ACR. This review was updated up to January 2019.&#x0D; Results: Overall, 2780 eligible articles were retrieved, five of which were eligible for inclusion. Effectiveness outcomes showed an improvement in ACR criteria. Differences in the improvement of ACR70, ACR50, and ACR20 criteria in LEF + MTX groups compared to placebo groups were reported 0.78%, 20%, and 27%, respectively, and these differences compared to ETN groups were respectively 0.003%, 21.93%, and 32%.&#x0D; Conclusions: Combination of leflunomide and methotrexate is effective, and it can be used as before biomedical medications such as etanercept, as it is more cost-effective.

Ganciclovir and Its Hemocompatible More Lipophilic Derivative Can Enhance the Apoptotic Effects of Methotrexate by Inhibiting Breast Cancer Resistance Protein (BCRP)

Efflux transporters, namely ATP-binding cassette (ABC), are one of the primary reasons for cancer chemoresistance and the clinical failure of chemotherapy. Ganciclovir (GCV) is an antiviral agent used in herpes simplex virus thymidine kinase (HSV-TK) gene therapy. In this therapy, HSV-TK gene is delivered together with GCV into cancer cells to activate the phosphorylation process of GCV to active GCV-triphosphate, a DNA polymerase inhibitor. However, GCV interacts with efflux transporters that are responsible for the resistance of HSV-TK/GCV therapy. In the present study, it was explored whether GCV and its more lipophilic derivative (1) could inhibit effluxing of another chemotherapeutic, methotrexate (MTX), out of the human breast cancer cells. Firstly, it was found that the combination of GCV and MTX was more hemocompatible than the corresponding combination with compound 1. Secondly, both GCV and compound 1 enhanced the cellular accumulation of MTX in MCF-7 cells, the MTX exposure being 13–21 times greater compared to the MTX uptake alone. Subsequently, this also reduced the number of viable cells (41–56%) and increased the number of late apoptotic cells (46–55%). Moreover, both GCV and compound 1 were found to interact with breast cancer resistant protein (BCRP) more effectively than multidrug-resistant proteins (MRPs) in these cells. Since the expression of BCRP was higher in MCF-7 cells than in MDA-MB-231 cells, and the cellular uptake of GCV and compound 1 was smaller but increased in the presence of BCRP-selective inhibitor (Fumitremorgin C) in MCF-7 cells, we concluded that the improved apoptotic effects of higher MTX exposure were raised mainly from the inhibition of BCRP-mediated efflux of MTX. However, the effects of GCV and its derivatives on MTX metabolism and the quantitative expression of MTX metabolizing enzymes in various cancer cells need to be studied more thoroughly in the future.

Sustained Remission in Rheumatoid Arthritis: Time to Withdraw Treatment?

With increasing numbers of patients with rheumatoid arthritis achieving sustained remission, medication withdrawal is an important consideration to reduce polypharmacy and associated adverse events. An article from the journal Arthritis & Rheumatology (1) explores the treatment withdrawal options for patients on etanercept and methotrexate combination therapies and suggests methotrexate withdrawal has the least impact on disease worsening. There are limitations in the study, including the use of only one disease activity score and no assessment of radiographic progression, but, overall, the article provides a good framework for future studies on treatment withdrawal options and the possibility of medication reduction for patients.

NON-TUBAL ECTOPIC (NTE) PREGNANCIES IN ASSISTED REPRODUCTIVE TECHNOLOGY (ART): 10-YEARS OF EXPERIENCE AT A LARGE URBAN UNIVERSITY BASED FERTILITY CENTER

BackgroundNon-tubal ectopic (NTE) pregnancies account for 7-10% of ectopic pregnancies, but disproportionately high mortalities.1,2 Infertility and assisted reproductive technology (ART) are risk factors, but limited data exists on NTE from fertility centers.1ObjectiveThe purpose of this case series was to review all confirmed NTEs at a high-volume fertility center to gain insights into diagnosis and outcomes.Materials and MethodsNTE from all pregnancy cycles (spontaneous (SPON), ovulation induction (OI), frozen embryo transfer (FET), Fresh ET, donor egg (DE)) were included over a 10 year period (2009-2019). Ultrasounds were performed in our center, and confirmed by outside radiologist. Cases were reviewed for medical, surgical and fertility history, NTE diagnosis and management, and subsequent pregnancy outcomes. Rates are reported as % or median (range).Results15 NTEs were identified; 9 cornual (7 ART, 2 SPON), 5 cesarean scar (C-scar, all ART) and 1 cervical (SPON). No abdominal or ovarian NTE were identified. No NTE resulted from OI. Age at diagnosis was 40 years (31-51). Infertility diagnoses and type of ART cycles were mixed (53% FET, 13% fresh ET, 20% DE, 60% euploid embryo). The majority of NTEs presented without symptoms (47%) or with vaginal bleeding (40%). Median cycle day (CD) of diagnosis was CD 42 (37-52) by outside ultrasound for cornual and c-scar NTEs. The cervical NTE was initially diagnosed as pregnancy failure on CD 45, with final diagnosis on CD 77. 83% of NTE from ART had a human chorionic gonadotropin (hCG) CD 28 level <70mIU/mL and 67% had a hCG CD 35 level <1000mIU/mL. All C-scar NTEs and 44% of cornual NTEs had fetal cardiac activity. 1st line treatment included medical and surgical approaches: expectant management (3), single dose methotrexate (MTX) (4), combination MTX (1), misoprostol (1), D&C (3), laparoscopy (2). 47% failed, including 100% of single dose MTX. 2nd line treatment included single dose MTX (2), multidose MTX (2), double uterine balloon (1) or D&C (3). 1 C-scar NTE hemorrhaged requiring transfusion and uterine artery embolization. Median CD of resolution was 96 (67-159). 60% of patients tried for pregnancy at our center after resolution of NTE; 27% had a successful live birth or ongoing pregnancy. Interestingly, 2 patients with cornual NTE had histories of bilateral salpingectomy, presenting with high hCGs (21,361 and 31,819), failed initial management (MTX requiring 2nd dose, then wedge resection, and laparoscopic resection and subsequent MTX), and took the longest time to resolution (CD 157 and CD 159). Of these 2 cornual NTEs: 1 became pregnant on a subsequent ART cycle; the other has not attempted further treatment.ConclusionsNTEs are rare, even in high volume fertility clinics. Early sonographic diagnosis and close monitoring can prevent morbidities, but first line treatments often fail. Day 28 and 35 hcg levels can be useful in risk assessment, diagnosis and patient counseling. Patients with history of bilateral salpingectomies may require closer evaluation and longer time to resolution of cornual NTEs.SupportNo financial support to disclose