Methotrexate Treatment Research Articles

Reasons for discontinuation of methotrexate in the treatment of rheumatoid arthritis and challenges of methotrexate resumption: a single-center, retrospective study

Abstract Background Methotrexate (MTX) is an anchor drug used for the treatment of rheumatoid arthritis (RA); hence, understanding the reasons for MTX discontinuation in RA can help improve its treatment. Therefore, this study aimed to investigate the reasons for MTX discontinuation and to identify future challenges in RA treatment regarding the discontinuation and resumption of MTX treatment. Results MTX administration was discontinued in 771 patients with RA. The reasons for MTX discontinuation were as follows: (1) infectious diseases (20.0%), (2) malignancy (14.1%), and (3) respiratory problems (10.2%). Some patients did not resume MTX therapy even after the infections were cured. Liver dysfunction (8.0%) did not improve with MTX discontinuation and was often associated with fatty liver disease. In addition to adverse events, MTX discontinuation was due to patient preference (4.3%), planning for pregnancy (5.1%), invalidity (5.7%), remission (5.6%), remission with biologics (4.7%), old age (2.6%), and poor compliance (1.6%). Conclusions This study revealed diverse reasons for the discontinuation of MTX; there are cases in which MTX is discontinued but should be considered for resumption. Furthermore, issues such as the indications for MTX discontinuation should still be debated, and multicenter evidence must be collected and examined in future studies.

Annexin A6 Polymorphism Is Associated with Pro-atherogenic Lipid Profiles and with the Downregulation of Methotrexate on Anti-Atherogenic Lipid Profiles in Psoriasis.

Annexin A6 (AnxA6) is a lipid-binding protein that regulates cholesterol homeostasis and secretory pathways. However, the correlation of AnxA6 polymorphism with lipometabolism has never been studied in psoriasis. To investigate the impact of AnxA6 polymorphism on lipid profiles and the expression of AnxA6 protein in both peripheral blood mononuclear cells (PBMCs) and lipometabolism in psoriasis. A total of 265 psoriatic patients received methotrexate (MTX) treatment for 12 weeks, after which their lipid profiles were determined by measuring total cholesterol (TC), triglycerides (TGs), lipoprotein (a) [LP(a)], high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein (LDL), apolipoprotein (a)1 (ApoA1), and apolipoprotein B (ApoB). In addition, AnxA6 (rs11960458) was genotyped in 262 patients and the expression of AnxA6 in PBMCs was measured by Western blotting at baseline and week 8 post-MTX treatment. The CC genotype carriers of rs11960458 had a lower expression of AnxA6 and lower levels of the pro-atherogenic lipids TC, LDL, and ApoB compared to TC genotype carriers. MTX significantly downregulated the levels of the anti-atherogenic lipids HDL-C and ApoA1 and the level of AnxA6 in TC genotype carriers, as well as the level of TGs in CC genotype carriers. The polymorphism of AnxA6, rs11960458, was statistically associated with the levels of pro-atherogenic lipids and with the downregulation of MTX on the levels of anti-atherogenic lipids and TGs in psoriasis.

Clinical Presentation as a Predictor of the Response to Methotrexate Therapy in Patients with Ectopic Pregnancy.

Ectopic pregnancy can be fatal if not diagnosed and timely treated. There is an increase in ectopic pregnancy rate which attributes in part to fertility medications and procedures and early diagnosis. Methotrexate, a folic acid antagonist, is widely used in the medical treatment of ectopic pregnancy. Many studies examined the safety and success rate of methotrexate looking into factors affecting the success rate, if the patient may present with symptoms such as abdominal pain, and some consider this as impeding rupture and it might affect the success of medical treatment. This study evaluates the success rate of methotrexate treatment outcomes in regard to presentation and looks into other factors that can help choosing a single or multiple dose modality. This is a retrospective review of 154 cases of ectopic pregnancy treated with methotrexate from January 2011 to December 2020 at King Khalid University Hospital (KKUH). Demographic data, clinical presentation, treatment progress, and outcome and failure rate were collected and analyzed. Student's t-test was used for statistical analysis of associations in SPSS. 154 patients were treated with MTX; of those patients, 25 received more than one dose. The difference between the responses to MTX treatment in symptomatic and asymptomatic individuals was not significant (p = 0.267). 131 (85%) had successful treatment. There were no associations between patient BMI, ectopic mass size, or ectopic mass site, the presence or absence of pelvic fluid on ultrasound at diagnosis, and the treatment success rate. There was a significant decline in the treatment success rate with increasing β-hCG levels on the presentation day (p = 0.035) and on day 4 (p value <0.001) of treatment. MTX treatment can be used to manage symptomatic patients with ectopic pregnancy. The success rate in symptomatic patients is not different from that in asymptomatic patients. β - hCG levels > 5000 IU/L. Pretreatment and on day 4 posttreatment is associated with higher failure rate.

Predictors of Successful Medical Management With Methotrexate in Unruptured Tubal Ectopic Pregnancy.

Introduction Medical treatment with methotrexate (MTX) is a safe and effective alternative to surgery in carefully selected cases of ectopic pregnancies diagnosed early prior to rupture. Aim To determine the optimal pre-treatment levels of beta human chorionic gonadotropin (𝛽-hCG) and its changing trends most likely to have a successful outcome with medical management. Material and methods A prospective observational study was conducted in a tertiary teaching hospital from December 2018 to May 2021. "Single-dose" MTX regime was used for medical management of ectopic pregnancy in patients fulfilling the selection criteria. The 𝛽-hCG levels were recorded at baseline and on day 4 and day 7 of MTX injection. Thereafter, at weekly intervals till complete resolution or surgical intervention due to failure of medical management. In addition, receiver operating characteristic (ROC) curve analysis for a pre-treatment 𝛽-hCG cut-off value and changing trends in post-treatment 𝛽- hCG levels most likely to have a successful outcome with MTX treatment were determined. Results Fifty patients fulfilling the inclusion criteria were included in the study, with successful medical management in 33 (66%). The mean pre-treatment 𝛽-hCGlevels in women with successful medical management were 3270.97 (+/- 901) compared to 5249.17 (+/-808.02) for those with treatment failure (p=0.00001). The mean 𝛽-hCG level in the failed treatment group was significantly higher on day 4 than the pre-treatment levels (6742.56 +/- 572 vs. 5249.17+/- 808.02; p<0.05). Inadequate reduction of 𝛽-hCG level on day 7 (<15% of day 4 levels) requiring repeat dosage of MTX was more likely to have an unsuccessful outcome (p=0.00001). The area under curve (AUC) value of 0.905 (95% CI: 0.814-0.996) depicted that pre-treatment 𝛽-hCG level of 4000 mIU/ml taken as the cut-off value was able to predict levels ≤4000 mIU/ml had a greater likelihood of successful outcome with MTX, having a sensitivity of 84.5%, specificity of 83.3%, positive predictive value (PPV) of 90.3%, and negative predictive value (NPV) of 75% (p< 0.05). Demographic variables or previous clinical history, considered risk factors for ectopic pregnancy, did not affect the outcome of medical management in this study. Conclusion Medical management of ectopic pregnancy is a viable first-line treatment option in carefully selected patients. In this study, the most important predictors for the successful outcome of medical management were the pre-treatment β-hCG levels and their fall on day 4 and day 7 after MTX therapy.

Spontaneous tendon rupture in a patient with systemic sclerosis: a case report

BackgroundSystemic sclerosis (SSc) is an incurable autoimmune disease characterized by progressive skin fibrosis and organ failure. Tenosynovitis is a common musculoskeletal manifestation, but tendon rupture has seldom reported in SSc.Case presentationWe present a rare case of a 49-year-old female with SSc who has suffered from bilateral tendon rupture of the fourth and fifth digits with positive antinuclear antibody (ANA) and anti-centromere B antibody, but negative rheumatoid factor in serum. In the extensor tendons of the patient’s hands, inflammation, edema, hypertrophy and tendon interruption were detected with ultrasound and magnetic resonance imaging(MRI). Tendon transfer repair surgery was performed and 10 mg/week methotrexate was then used in this patient. Her hand function was improved well with methotrexate and rehabilitation treatment postoperatively.ConclusionsEarly detection of tenosynovitis is necessary to prevent tendon rupture in SSc patients. Ultrasound and Magnetic Resonance Imaging appear to be useful examinations for evaluating tendon pathology for early detection.

A meta-analysis of methotrexate polyglutamates in relation to efficacy and toxicity of methotrexate in inflammatory arthritis, colitis and dermatitis.

In immune-mediated inflammatory diseases (IMIDs), early symptom control is a key therapeutic goal. Methotrexate (MTX) is the first-line treatment across IMIDs. However, MTX is underutilized and suboptimally dosed, partly due to the inability of making individualized treatment decisions through therapeutic drug monitoring (TDM). To implement TDM in clinical practice, establishing a relationship between drug concentration and disease activity is paramount. In this meta-analysis, we investigated the relationship between concentrations of MTX polyglutamates (MTX-PG) in erythrocytes and efficacy as well as toxicity across IMIDs. Studies analysing MTX-PG in relation to disease activity and/or toxicity were included for inflammatory arthritis (rheumatoid [RA] and juvenile idiopathic arthritis [JIA]), inflammatory bowel disease (Crohn's and ulcerative colitis) and dermatitis (psoriasis and atopic dermatitis). Meta-analyses were performed resulting in several summary effect measures: regression coefficient (β), correlation coefficient and mean difference (of MTX-PG in responders vs. nonresponders) for IMIDs separately and collectively. Twenty-five studies were included. In RA and JIA, higher MTX-PG was significantly associated with lower disease activity at 3months (β: -0.002; 95% confidence interval [CI]: -0.004 to -0.001) and after 4months of MTX use (β: -0.003; 95% CI: -0.005 to -0.002). Similarly, higher MTX-PG correlated with lower disease activity in psoriasis (R: -0.82; 95% CI: -0.976 to -0.102). Higher MTX-PG was observed in RA, JIA and psoriasis responders (mean difference: 5.2nmol/L MTX-PGtotal ; P< .01). We showed that higher concentrations of erythrocyte MTX-PG were associated with lower disease activity in RA, JIA and psoriasis. These findings are an important step towards implementation of TDM for MTX treatment across IMIDs.

High-intensity focused ultrasound ablation combined with systemic methotrexate treatment of intramural ectopic pregnancy: A case report

Intramural ectopic pregnancy (IMP) is a rare ectopic pregnancy with an unclear etiology, and standard treatment guidelines currently remain unclear. The main treatment option is local excision of IMP via laparoscopy or laparotomy. A 32-year-old woman with adenomyosis presented with amenorrhea for 7 weeks and a serum β-human chorionic gonadotropin (HCG) level of 6882 IU/L. The patient had a history of laparotomy for adenomyosis 5 years previously. Three-dimensional ultrasonography showed a live gestational sac (GS) of 9 × 15 × 18 mm located in the left posterior wall of the uterus and a sinus tract connecting the sac and the endometrial cavity. MRI revealed the GS located in the adenomyosis and a 1.0-cm sinus tract connecting the GS and the endometrial cavity. IMP with adenomyosis. High-intensity focused ultrasound (HIFU) treatment combined with systemic methotrexate (MTX) was performed to treat IMP, which would avoid operation and massive bleeding. Serum β-HCG levels decreased to normal 4 weeks after HIFU treatment and the GS was not found on MRI after 4 months. The sinus tract was significantly shortened after the HIFU treatment. HIFU ablation combined with systemic MTX is effective for the treatment of IMP and is favorable for maintaining fertility.

Identification of SNPs associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis.

Methotrexate is one of the cornerstones of rheumatoid arthritis (RA) therapy. Genetic factors or single nucleotide polymorphisms (SNPs) are responsible for 15%-30% of the variation in drug response. Identification of clinically effective SNP biomarkers for predicting methotrexate (MTX) sensitivity has been a challenge. The aim of this study was to explore the association between the disease related outcome of MTX treatment and 23 SNPs in 8 genes of the MTX pathway, as well as one pro-inflammatory related gene in RA patients naïve to MTX. Categorical outcomes such as Disease Activity Score (DAS)-based European Alliance of Associations for Rheumatology (EULAR) non-response at 4 months, The American College of Rheumatology and EULAR (ACR/EULAR) non-remission at 6months, and failure to sustain MTX monotherapy from 12 to 24months were assessed, together with continuous outcomes of disease activity, joint pain and fatigue. We found that the SNPs rs1801394 in the MTRR gene, rs408626 in DHFR gene, and rs2259571 in AIF-1 gene were significantly associated with disease activity relevant continuous outcomes. Additionally, SNP rs1801133 in the MTHFR gene was identified to be associated with improved fatigue. Moreover, associations with p values at uncorrected significance level were found in SNPs and different categorical outcomes: 1) rs1476413 in the MTHFR gene and rs3784864 in ABCC1 gene are associated with ACR/EULAR non-remission; 2) rs1801133 in the MTHFR gene is associated with EULAR response; 3) rs246240 in the ABCC1 gene, rs2259571 in the AIF-1 gene, rs2274808 in the SLC19A1 gene and rs1476413 in the MTHFR gene are associated with failure to MTX monotherapy after 12-24months. The results suggest that SNPs in genes associated with MTX activity may be used to predict MTX relevant-clinical outcomes in patients with RA.

Nano-Theranostic Modality for Visualization of the Placenta and Photo-Hyperthermia for Potential Management of Ectopic Pregnancy.

Ectopic pregnancy (EP) is the leading cause of maternity-related death in the first trimester of pregnancy. Approximately 98% of ectopic implantations occur in the fallopian tube, and expedient management is crucial for preventing hemorrhage and maternal death in the event of tubal rupture. Current ultrasound strategies misdiagnose EP in up to 40% of cases, and the failure rate of methotrexate treatment for confirmed EP exceeds 10%. Here the first theranostic strategy for potential management of EP is reported using a near-infrared naphthalocyanine dye encapsulated within polymeric nanoparticles. These nanoparticles preferentially accumulate in the developing murine placenta within 24 h following systemic administration, and enable visualization of implantation sites at various gestational stages via fluorescence and photoacoustic imaging. These nanoparticles do not traverse the placental barrier to the fetus or impact fetal development. However, excitation of nanoparticles localized in specific placentas with focused NIR light generates heat (>43°C) sufficient for disruption of placental function, resulting in the demise of targeted fetuses with no effect on adjacent fetuses. This novel approach would enable diagnostic confirmation of EP when current imaging strategies are unsuccessful, and elimination of EP could subsequently be achieved using the same nano-agent to generate localized hyperthermia resulting in targeted placental impairment.

Safety of Novel Inpatient High Dose Methotrexate Protocol with Reduced Length of Hospital Stay

Introduction: High dose methotrexate (HD-MTX) treatment needs close monitoring, forced diuresis using intravenous hydration to ensure rapid drug clearance, and leucovorin rescue. Delayed clearance can result in serious adverse events such as severe mucositis and pancytopenia. Most institutions keep patients hospitalized until complete drug clearance, which can take up to 4-5 days on average (Binder, A et al.). Patients who exhibit normal drug clearance kinetics exhibit no increase in toxicity. Method: We developed modified protocol at Regions Hospital where patients can be discharged if their initial post-infusion methotrexate drug levels demonstrate normal clearance kinetics [< 5 mM (micromoles/L) at 24 hours or < 1 mM at 48 hours], they are able to maintain adequate oral hydration and have no evidence of renal or hepatic dysfunction. Patients are prescribed oral leucovorin at discharge to complete 7 days of treatment. Many institutions use a protocol that involves serial methotrexate drug level monitoring each day until the level is below 0.1-0.05 mM. We conducted a retrospective chart review to determine if the modified protocol is comparable to the commonly used standard protocol in terms of safety. We summarized patient- and cycle-specific characteristics and assessed the incidence of renal, hepatic, gastrointestinal, and hematologic toxicities among patients treated with HD-MTX (defined as ≥ 1000 mg/m2). Results: We retrospectively reviewed medical records of 53 patients who received intravenous methotrexate in our institution between 2015-2019. Only 29 patients had received HD-MTX (defined as ≥ 1000 mg/m2). Median age was 65 years [33-86], 55.2% (n=16) were male. HD MTX was given for B-cell lymphoma with high risk for CNS recurrence in 15 patients (51.7%), primary CNS lymphoma in 12 patients (41.4%) and acute lymphocytic lymphoma in 2 patients (6.9%). Median MTX dosage was 9 g [4-18]. Median 24-hour MTX-level was 3.78 mM and 48- hour MTX-level was 0.39 mM. (Tables 1-2). Of the total number of 156 cycles, grade III or more of hematological, hepatic, and renal toxicities were reported in (9.6%, 1.3% and 0%) respectively. There was no increase from low grade (0, I, II) to high grade (III, IV) toxicities. Mucositis was not reported after any of these cycles; however, febrile neutropenia occurred after 4 cycles (2.4%). Overall, there was no increase in toxicity compared to toxicity of historical protocol (Stoller RG. et al.). Length of hospital stay (LOS) was 3 days [1-79] comparing with 4-5 days to what reported historically. (Table 2). Conclusion: Our date suggests that patients who received high dose methotrexate can be safely discharged early if they exhibit normal drug clearance kinetics with in the first 48 hours after infusion, maintain normal renal function and continue oral hydration and leucovorin as outpatient. Adopting this protocol may have an economic benefit by shortening the length of hospitalization by 1-2 days. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lyt-200, a Humanized Anti-Galectin-9 Antibody, Exhibits Preclinical Efficacy in Models of Hematological Malignancies

Patients with relapse and refractory (R/R) hematological malignancies typically have 5-year overall survival rates of less than 50% when receiving chimeric antigen receptor (CAR) T-cell therapy and less than 30% after receiving hematopoietic stem cell transplantation (HSCT). Human leukemia cells utilize a variety of biochemical mechanisms, which allow them to escape host immune surveillance. These molecular pathways cause impairment of the anti-cancer activities of immune cells, which could attack and kill leukemia cells. These dismal outcomes for patients with R/R disease highlight the need for novel treatment regimens when current therapeutic options are exhausted. Galectins are s-type lectins that promote diverse biological processes including adhesion, signaling, and immunosuppression. In acute myeloid leukemia (AML), galectin-9 (GAL-9) maintains the leukemia initiating cell (LIC) population and plays an important role in treatment resistance. We recently tested LYT-200, a fully humanized IgG4 αGAL-9 monoclonal antibody, developed by PureTech Health, which has so far been well tolerated with no dose limiting toxicities in a Phase I clinical trial for solid tumors (NCT04666688). We tested LYT-200 in vitro and in vivo across multiple hematological malignancies. Flow cytometry was used to assess the surface expression of GAL-9 on human B-ALL, AML, T-cell acute lymphoblastic leukemia (T-ALL), and diffuse large B-cell lymphoma (DLBCL) cell lines relative to receptor T-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) and Programmed cell death protein-1 (PD-1) expression. Compared to healthy human peripheral blood mononuclear cells (PBMCs), where GAL-9 surface expression was low or absent depending on the immune cell, GAL-9 was highly expressed on the surface of all human blood cancer cell lines tested (>100-fold increase). Notably, GAL-9 expression was comparable to PD-1 surface expression and higher than that of TIM-3 on AML, B-ALL, T-ALL, and DLBCL cells. Treating all cell lines with LYT-200 relative to control immunoglobulin resulted in extensive cell death, which occurred after 48 and 72 hours of treatment. Furthermore, a side-by-side comparison with αTIM-3 antibody treatment at equivalent concentrations, revealed that LYT-200 treatment was significantly more effective at killing blood cancer cells at low doses of 10-100 ng/mL in vitro. The in vitro efficacy of LYT-200 against multiple blood cancer subtypes extended to in vivo protection and survival benefit in murine models of T-ALL and AML, both in immunocompromised and immunocompetent mice. When immunocompromised mice were transplanted with human T-ALL cell lines or patient-derived samples, single-agent treatment with LYT-200 (1.5 mg/kg/weekly) was comparable to survival results obtained with methotrexate (0.75 mg/kg/weekly) administration. Notably, the combination of LYT-200 and methotrexate treatments led to the best survival outcomes in both contexts. Similar results were obtained in xenograft studies of AML, where single-agent LYT-200 (1.5 mg/kg/weekly) treatment was more effective at protecting mice than cytarabine (100 mg/kg/weekly). However, combining both treatments resulted in the best survival outcomes with greater than 80% of mice surviving over 2 months after disease appearance. In all, our results demonstrate that GAL-9 is an important driver of multiple blood cancer subtypes and that targeting GAL-9 with LYT-200 represents a potential novel treatment strategy which warrants additional pre-clinical and clinical testing.

Effects of methotrexate and etanercept treatment in moderate and severe psoriasis.

Psoriasis is a disease of immunological origin that damages the skin and mucous membranes. Biological therapies with systemic medications are effective in treating moderate and severe psoriasis. Our objective was to evaluate the effects of methotrexate and etanercept treatment in this disease and to verify their response to the Psoriasis area and severity index (PASI) index in the initial and control phase. The number of patients treated at the Military Hospital in Guayaquil was 2.620 corresponding from July 2020 to July 2021; the selected sample according to the inclusion criteria was 94 patients with moderate and severe psoriasis. The method was retrospective, observational, descriptive, cross-sectional, correlational differential analytical, and approved by the Human Subjects Ethics Committee of the Specialties Hospital "Dr Teodoro Maldonado Carbo" of Guayaquil, Ecuador. In this study, the prevalence was 3.58%, and the body mass index was 28.13 corresponding to overweight and obesity. The PASI index in the initial stage before treatment was 10.8% and in the control phase, it decreased to 2.99%, showing a decrease in lesions and good improvement in the treatment of moderate and severe psoriasis. Student´s T, the combination of etanercept with methotrexate was compared with the response with the PASI index in the initial and control phases, presenting a value lower than 0.001, P = .05, which was very significant. In our study, treatment with etanercept and methotrexate in moderate and severe psoriasis had is a favorable response in reducing this disease. It is expected that, in Ecuador, the health authorities would implement the biologics for the treatment of moderate and several psoriasis and including them in the basic list of medicines of the Public Health Ministry.

Effects of fish oil on methotrexate-induced reproductive damage in rats.

Methotrexate (MTX) is a folic acid antagonist that is commonly used in paediatric and adult oncology to treat a variety of malignancies. Internal organs, including the testis, are severely cytotoxic and genotoxic to MTX. Omega-3, as an antioxidant, has been shown to protect rat testis tissue from injury. The effect of fish oil (FO) on MTX-induced reproductive damage in rats was investigated in this work. The 28 animals were divided into four groups for this purpose (control, FO, MTX, and MTX-FO). On the third day, the MTX group received a single intraperitoneal injection of 20 mg/kg MTX. Furthermore, in the FO and MTX-FO groups, FO was delivered through gavage once daily for 14 days. All animals euthanized under general anaesthesia on the 15th day. TBARS, catalase, glutathione peroxidase, glutathione (GSH), superoxide dismutase levels were measured biochemically. The Cosentino grading system was utilized for histology. Germ cell thickness and caspase-3 activity were also evaluated. In addition, sperm motility rate, epididymal sperm count, aberrant sperm rate, and sperm vitality were measured to assess sperm quality. Some TBARS levels have increased, but GSH levels decreased significantly in the MTX group. FO reduced TBARS levels while considerably increasing GSH levels. All sperm quality measures were significantly lowered in the MTX group, while FO had a recovery effect. There were no notable variations in histopathology across groups except for germ cell thickness, which reduced considerably in the MTX group and recovered with FO treatment. As a result, FO has been shown to reduce testicular toxicity following MTX treatment in rats.

Kliniğimizde Tedavi Edilen Tubal Ektopik Gebelik Olgularında Hemoperitonyumun Önemi ve Retrospektif Analizi

Aim: The purpose of this study is to present the importance of hemoperitoneum and retrospective analysis of tubal ectopic pregnancy cases treated in our clinic.&#x0D; Material and Methods: This study respectively included 86 women who were diagnosed and treated for tubal ectopic pregnancy (EP) in our single-centre clinic between January 2012 and August 2013. Age, date of last menstrual period, human chorionic gonadotropin (β-hCG) level, the size and the presence of tubal EP masses, fetal cardiac activity and treatment procedures were evaluated and compared. The presence of hemoperitoneum for predictive treatment methods and factors that affecting the success of treatment methods were investigated.&#x0D; Results: The mean age of the patients was 29.1±5.7 (16-41) years. Mean β-hCG level was 4448,5±8351,9 IU/L. Laparatomy was performed to 14 patients (16.3%), laparoscopy to 5 patients (5.8%), expectant management to 15 patients (17.4%). Methotrexate (MTX) treatment was given to 46 patients (53.5%) and laparoscopy was performed to 1 patient (1.2%) and laparatomy to 5 patients (5.8%) due to MTX treatment failure in 6 patients. Compared with the MTX treatment of tubal EP, the possible factors that affecting surgical management, such as the initial β-hCG level (p=0.004), whether there is hemorrhage in the abdominal cavity (p=0.03), the size of ectopic pregnancy mass (p=.005) and the presence of fetal heart activity (p

Autoimmune Hemolytic Anemia in Inflammatory Bowel Disease-Report of a Case and Review of the Literature.

A wide spectrum of extraintestinal manifestations (EIMs) can burden patients with inflammatory bowel disease (IBD). EIMs contribute fairly to morbidity and mortality rates in IBD patients. Moreover, EIMs in IBD patients are so frequent that some suggest that IBD should be approached as a systemic disorder. Anemia is very common in IBD patients. The two most common types of anemia in IBD, iron deficiency anemia and anemia of chronic disease, are extraintestinal complications. Autoimmune hemolytic anemia (AIHA) is a rare extraintestinal manifestation of IBD, more frequent in ulcerative colitis (UC) than in Crohn's disease (CD). In this case-based review of the literature, we present a 36-year-old female patient diagnosed with Crohn's disease (CD) and Coombs positive AIHA, complicated by pulmonary thromboembolism and successfully treated with anti-tumor necrosis factor (anti-TNF) therapy. The underlying pathophysiological mechanism of AIHA in IBD is unclear. Treatment options for AIHA in IBD patients before biologic therapy included corticosteroids alone or in combination with azathioprine (AZA), methotrexate, and surgical treatment (colectomy and/or splenectomy). Currently, biologic therapy is a promising therapeutic option, especially in corticosteroid refractory or corticosteroid-dependent IBD patients with AIHA.

Analysis of clinical and imaging features of 6 cases of linear scleroderma en coup de sabre with central nervous system involvement in children

Objective: To summarize the clinical and imaging features of linear scleroderma en coup de saber (LSCS) with central nervous system involvement in children. Methods: The clinical data(clinical manifestations and imaging features) of 6 children diagnosed with LSCS with central nervous system involvement who were admitted to Beijing Children's Hospital Affiliated to Capital Medical University from May 2019 to November 2021 were retrospectively analyzed. Results: The 6 patients were all female, aged 6.8 (3.3, 11.0) years at the time of diagnosis, and aged 3.0 (1.7, 4.1) years at the time of discovery of facial skin lesions. Facial skin lesions appeared before neurological symptoms in 5 cases, and neurological symptoms appeared 2 months before skin lesions in 1 case. All the patients had "sword wound" skin lesions on the forehead with alopecia. Neurological manifestations included epileptic seizures in 6 cases, focal neurological defects in 5 cases, and headaches in 2 cases. The intracranial lesions were all ipsilateral to the skin lesions. The magnetic resonance imaging (MRI) of 6 cases showed abnormal signals mainly involving white matter in 1 hemisphere, and 3 cases showed local encephalomalacia. The scattered low signal was observed in 5 cases on susceptibility weighted imaging. Localized brain parenchyma or leptomeninges enhancement was seen on Gadolinium-enhanced sequences in 5 cases. Scattered foci of calcification on the affected side were seen on cranial CT in 4 cases. Skin biopsy was performed in 2 cases. Part of the lesion of the brain was removed in 1 case, and the pathological findings suggested small vasculitis, which was consistent with skin pathological changes. All patients received symptomatic treatment with antiepileptic drugs. Oral prednisone combined with methotrexate was given in 4 cases, and 1 case was given oral prednisone only. One case was presumed to be in the resting stage of the disease due to significant cerebral atrophy in half of the brain, and only antiepileptic drugs were added. The patients were followed up for 6-36 months. The skin lesions of scleroderma and alopecia did not progress in 5 cases, and hemifacial atrophy was developed in 1 case, which was considered to be combined with Parry-Romberg syndrome. The seizures were controlled in 4 cases. One case had reduced seizure frequency but left hemiplegia. One patient still had intractable epilepsy and paroxysmal headache. Conclusions: LSCS with central nervous system involvement is more common in girls, with seizures and neurological defects as the main manifestations. Intracranial lesions are mostly ipsilateral to the skin lesions. Cerebral microbleeds, calcification, and encephalomalacia foci are common, and the pathological changes in skin and intracranial lesions are consistent with small-vessel vasculitis. Prednisone combined with methotrexate treatment has shown some efficacy, but some children remain with refractory epilepsy and neurological deficit symptoms.

Seropositivity-Dependent Association between LINE-1 Methylation and Response to Methotrexate Therapy in Early Rheumatoid Arthritis Patients.

Methotrexate (MTX) is considered the first choice among disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) treatment. However, response to it varies as approximately 40% of the patients do not respond and would lose the most effective period of treatment time. Therefore, having a predictive biomarker before starting MTX treatment is of utmost importance. Methylation of long interspersed nucleotide element-1 (LINE-1) is generally considered a surrogate marker for global genomic methylation, which has been reported to associate with disease activity after MTX therapy. We performed a prospective study on 273 naïve early RA (ERA) patients who were treated with MTX, followed up to 12 months, and classified according to their therapy response. The baseline LINE-1 methylation levels in peripheral blood mononuclear cells (PBMC) of cases were assessed by bisulfite pyrosequencing. Baseline LINE-1 methylation level per se turned out not to predict the response to the therapy, nor did age, sex, body mass index, or smoking status. However, if cases were stratified according to positivity to rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) or seronegativity, we observed an opposite association between baseline LINE-1 methylation levels and optimal response to MTX therapy among responders. The best response to MTX therapy was associated with hypermethylated LINE-1 among double-positive ERA cases (p-value: 0.002) and with hypomethylated LINE-1 in seronegative ERA patients (p-value: 0.01). The LINE-1 methylation level in PBMCs of naïve ERA cases associates with the degree of response to MTX therapy in an opposite way depending on the presence of RF and ACPA antibodies. Our results suggest LINE-1 methylation level as a new epigenetic biomarker for predicting the degree of response to MTX in both double-positive and seronegative ERA patients.

Red Cell Distribution Width and Absolute Lymphocyte Count Associate With Biomarkers of Inflammation and Subsequent Mortality in Rheumatoid Arthritis.

Morbidity and mortality in rheumatoid arthritis (RA) is partly mitigated by maintaining immune and hematologic homeostasis. Identification of those at risk is challenging. Red cell distribution width (RDW) and absolute lymphocyte count (ALC) associate with cardiovascular disease (CVD) and mortality in the general population, and with disease activity in RA. How these variables relate to inflammation and mortality in RA was investigated. In a retrospective single Veterans Affairs (VA) Rheumatology Clinic cohort of 327 patients with RA treated with methotrexate (MTX)+/- a tumor necrosis factor (TNF) inhibitor (TNFi), we evaluated RDW and ALC before and during therapy and in relation to subsequent mortality. Findings were validated in a national VA cohort (n = 13,914). In a subset of patients and controls, we evaluated inflammatory markers. In the local cohort, high RDW and low ALC prior to MTX treatment was associated with subsequent mortality over 10 years (both P < 0.001). The highest mortality was observed in those with both high RDW and low ALC. This remained after adjusting for age and comorbidities and was validated in the national RA cohort. In the immunology cohort, soluble and cellular inflammatory markers were higher in patients with RA than in controls. ALC correlated with age, plasma TNF receptor II, natural killer HLA-DR mean fluorescence intensity, and CD4CM/CD8CM HLA-DR/CD38%, whereas RDW associated with age and ALC. MTX initiation was followed by an increase in RDW and a decrease in ALC. TNFi therapy added to MTX resulted in an increase in ALC. RDW and ALC before disease-modifying antirheumatic drug therapy are associated with biomarkers of monocyte/macrophage inflammation and subsequent mortality. The mechanistic linkage between TNF signaling and lymphopenia found here warrants further investigation.

Longitudinal MicroSPECT Imaging of Systemic Sclerosis Model Mice with [99mTc]Tc-HYNFA via Folate Receptor Targeting.

Noninvasive single-photon emission computed tomography (SPECT) imaging with [99mTc]Tc-HYNFA via folate receptor (FR) targeting was proposed to assess the inflammation and therapeutic effect of systemic sclerosis (SSc) in model mice. The radiochemical yield and purity of [99mTc]Tc-HYNFA were over 95%, with a specific activity of about 9.36 ± 0.17 MBq/nmol. At the end of induction, the uptake ratios of bleomycin-injected regions on the back-to-muscle (R/M) and lung-to-muscle (L/M) derived from SPECT images were 7.27 ± 0.50 and 4.25 ± 0.15, respectively. The radioactivity uptakes could be blocked by excessive folic acid (FA), and R/M and L/M obviously decreased to 2.78 ± 0.57 and 2.51 ± 0.79, respectively. R/M (2.22 ± 0.71) and L/M (1.62 ± 0.28) decreased very close to those of the control mice group (R/M = 1.99 ± 0.36, L/M = 1.50 ± 0.14) when macrophages had been depleted in advance. After being treated with cyclophosphamide (CTX) or methotrexate (MTX), R/M and L/M decreased to 3.58 ± 0.52 and 2.03 ± 0.32 (CTX treatment) or 2.48 ± 0.64 and 1.83 ± 0.06 (MTX treatment). R/M and L/M were highly correlated with pathological changes. The trend of hydroxyproline content in lungs at the later non-inflammatory phase of each group was similar to the uptake values of the lung in the 4th week from the beginning of induction. [99mTc]Tc-HYNFA had an ideal uptake in SSc lesions. R/M and L/M had a high consistency with pathological changes. SPECT imaging-targeted FR could monitor the therapeutic effect of CTX and MTX. It is expected to be an effective means to evaluate SSc.

B7-H4 Polymorphism Influences the Prevalence of Diabetes Mellitus and Pro-Atherogenic Dyslipidemia in Patients with Psoriasis.

The co-inhibitory molecule B7-H4 is located in the genomic regions associated with type 1 diabetes (T1D) susceptibility. However, the correlation of B7-H4 with glycometabolism and dyslipidemia has never been studied. To explore the influence of B7-H4 polymorphism on the prevalence of diabetes mellitus (DM) and dyslipidemia in psoriasis. In this single-center cross-sectional study, we recruited 265 psoriatic patients receiving methotrexate (MTX) treatment. Thirteen single-nucleotide polymorphisms (SNPs) in B7-H4 were genotyped. Serum levels of total cholesterol (TC), triglycerides (TG), lipoprotein (a) (LP(a)), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein (LDL), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB) were measured at baseline and week 12. The GG genotype carriers of rs12025144 in B7-H4 had a higher prevalence of DM (57.14% vs. 17.71% vs. 18.67%, p = 0.0018), and had a poorer response to MTX in diabetic patients (p &lt; 0.05), compared with AA or AG genotype carriers. The AG genotype of rs2066398 was associated with higher levels of pro-atherogenic lipids. MTX significantly downregulated the level of anti-atherogenic lipid ApoA1 in AA genotype carriers of rs2066398. The genotypes rs12025144 and rs2066398 in B7-H4 were correlated with a higher prevalence of DM and dyslipidemia in psoriasis, respectively.