Methotrexate Treatment Research Articles

The evaluation of success and failure of methotrexate treatment in ectopic pregnancy

Aim: Regardless of medical advancements, ectopic pregnancy (EP) is still an essential factor in the mortality rate of women of reproductive age. The main aim of this study was to determine predictive factors associated with the success of the response to treatment with single-dose and two-dose methotrexate (MTX) regimens in women with tubal EP. 
 Material and Method: This retrospective study examined the electronic records of 130 patients who underwent treatment due to EP were included in the study. The patients were divided into two groups: the successful MTX treatment group (n: 85) as the case group and the failure of MTX treatment group (n: 45) as the control group. 
 Results: Age-matched (30.62±4.36) and body mass index (BMI)-matched (24.37±2.29) patients diagnosed with EP were treated with MTX. The mean beta-human chorionic gonadotropin (β-hCG) value on the first day of treatment was 1639.84±524.96 mIU/mL in the successful and 5866.76±1875.51 mIU/mL in the unsuccessful group. 85 of 130 (65%) were successfully treated with MTX. Five of 45 (35%) failed medical treatment and required laparoscopic surgery. The longest ectopic mass diameter was significantly higher in the failure of MTX treatment group (p

Combination Therapy of Carnosic Acid and Methotrexate Effectively Suppressed the Inflammatory Markers and Oxidative Stress in Experimental Arthritis.

Background: Combination therapy with methotrexate (MTX) is the most common therapeutic strategy used for the treatment of patients with rheumatoid arthritis (RA). In this study, we combined the natural compound carnosic acid (CA) with MTX to reduce inflammation and oxidative stress in adjuvant arthritis (AA). Methods: AA was induced in 6–8 rats per group. MTX was administrated twice a week at a dose of 0.3 mg/kg b.w., while CA was administered daily at a dose of 100 mg/kg both in monotherapy and in combination with MTX. Plasma samples were collected on the 14th, 21st, and 28th day. Body weight and hind paw volume were measured once a week. Results: We found that, mainly, the CA + MTX combination significantly reduced the hind paw swelling, the levels of IL-17A, MMP-9, and MCP-1 in plasma, and GGT activity in joint homogenates. The mRNA expression of HO-1, catalase, and IL-1β in the liver were significantly improved by CA + MTX only. Our results indicate that adding CA to MTX treatment could be a good therapeutic option for patients suffering from RA. Conclusions: The addition of CA to methotrexate treatment significantly improved its efficacy in decreasing the development of AA by inhibiting the markers of inflammation and oxidative stress.

The Protective Effects of Nutraceutical Components in Methotrexate-Induced Toxicity Models-An Overview.

There are multiple concerns associated with methotrexate (MTX), widely recognized for anti-neoplastic and anti-inflammatory effects in life-threatening disease conditions, i.e., acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, psoriasis, and rheumatoid arthritis, due to long-term side effects and associated toxicity, which limits its valuable potential. MTX acts as an inhibitor of dihydrofolate reductase, leading to suppression of purine and pyrimidine synthesis in high metabolic and turnover cells, targeting cancer and dysregulated immune cells. Due to low discrimination between neoplastic cells and naturally high turnover cells, MTX is prone to inhibiting the division of all fast-dividing cells, causing toxicity in multiple organs. Nutraceutical compounds are plant-based or food-derived compounds, used for their preventive and therapeutic role, ascertained in multiple organ dysfunctions, including cardiovascular disease, ischemic stroke, cancer, and neurodegenerative diseases. Gut microbiota and microbiota-derived metabolites take part in multiple physiological processes, their dysregulation being involved in disease pathogenesis. Modulation of gut microbiota by using nutraceutical compounds represents a promising therapeutic direction to restore intestinal dysfunction associated with MTX treatment. In this review, we address the main organ dysfunctions induced by MTX treatment, and modulations of them by using nutraceutical compounds. Moreover, we revealed the protective mechanisms of nutraceuticals in MTX-induced intestinal dysfunctions by modulation of gut microbiota.

A 10-Year Review of Methotrexate Treatment for Ectopic Pregnancy in a Malaysian Tertiary Referral Hospital.

Background Ectopic pregnancy was recorded as the fourth principal cause of maternal death in Malaysia in 2019. Early diagnosis and use of methotrexate treatment proved to be safe and effective alternatives to surgical treatment. This study investigates the success rate of methotrexate treatment for ectopic pregnancy in a tertiary hospital in Malaysia. Methods This was a retrospective review of 73 patients with ectopic pregnancies treated with methotrexate according to a single-dose protocol from January 2009 until November 2019. The diagnosis of ectopic pregnancy was made using a combination of transvaginal scan and serial serum β-hCG levels. Their clinical and demographic data were reviewed. Serum β-hCG levels were measured at pre- and post-treatment to determine the rate of successful resolution. Results The overall success rate was 87.7% (64/73 patients) with methotrexate treatment. Fifty-six patients (76.7%) were successfully treated with a single dose of methotrexate, and eight patients (11.0%) required a second dose of methotrexate. There was no relation between socio-demographic, pre-treatment β-hCG levels, ectopic mass size, and treatment efficacy. Smaller size of ectopic pregnancy (adjusted OR=29.23; 95% CI: 2.69, 317.90; P=0.006) and absence of free fluid at the pouch of Douglas (POD) (adjusted OR=27.31; 95% CI: 2.84, 262.32; P=0.004) was found to increase the likelihood of overall treatment success. Absence of fetal cardiac activities was found to increase the likelihood of first-dose methotrexate treatment success (OR=10.20; 95% CI: 1.93, 53.79; P=0.006). Conclusions Early diagnosis of ectopic pregnancy may reduce morbidity and mortality. In carefully selected cases, methotrexate treatment has been proven to be cost-effective and avoided risks associated with surgery and anaesthesia.

Clinical Factors and the Outcome of Treatment with Methotrexate in Rheumatoid Arthritis: Role of Rheumatoid Factor, Erosive Disease and High Level of Erythrocyte Sedimentation Rate.

To identify the clinical factors predicting the outcome of treatment with methotrexate in rheumatoid arthritis, we examined 312 patients (253 females, 59 males) with rheumatoid arthritis diagnosed according to the criteria of the American College of Rheumatology. All patients included in this analysis began treatment with a regimen of oral MTX 7.5 mg weekly, with the dosage increasing to 15 mg weekly after 4 weeks, in combination with folic acid (1 mg daily). Good responders were defined as patients who had a DAS28 of ≤2.4 at 6 months (patients with remission of disease symptoms). Poor responders were defined as patients who had a DAS28 of >2.4. In this study, we analyzed the association between clinical parameters such as sex of patients, age of patients, age at disease onset, disease duration, rheumatoid factor, anti-CCP antibodies, ESR values, presence of joints erosions, presence of extra-articular manifestations and the response to MTX in RA patients. Multivariate logistic regression analysis showed four independent factors significantly associated with good response to MTX treatment: older age at disease onset, low ESR, no erosive disease and negative RF. The results of our study suggest that a younger age at disease onset, the presence of RF, erosive disease, as well as a high level of ESR are associated with worse response to MTX therapy.

Biologics with or without methotrexate in treatment of polyarticular juvenile idiopathic arthritis: effectiveness, safety and drug survival.

To investigate the impact of additionally given MTX on biologic treatment of polyarticular JIA in terms of effectiveness, safety and drug survival. Patients suffering from polyarticular JIA and treated with either monotherapy with a first biologic or a combination of a biologic and MTX were selected from the BIKER registry. The TNF-α inhibitors (TNFi) adalimumab, etanercept and golimumab and the IL-6 inhibitor tocilizumab were considered. Upon a non-randomized study design, we adjusted the different cohorts using propensity score matching to improve comparability. A total of 2148 patients entered the analysis, who were treated by either combination therapy (n = 1464) or monotherapy (n = 684). Disease activity declined significantly more in patients upon combination therapy than upon biologic monotherapy. Comparison of adjusted cohorts revealed that patients who received TNFi gained more benefit from additionally given MTX than patients treated with tocilizumab. Median survival time of therapy with biologics was significantly longer upon combination therapy (3.1 years) than with monotherapy (2.7 years), as demonstrated by a Kaplan-Meier analysis (log rank test: P = 0.002). The safety profile was moderately affected by additional MTX due to increased incidence of gastrointestinal and hepatic adverse events. Serious adverse events occurred at an equal rate of 3.6 events per 100 patient-years in both cohorts. Additionally given MTX improves the effectiveness of biologic treatment in polyarticular JIA without seriously compromising treatment safety. Especially TNFi benefit from combination, while no improvement in outcome has been observed by combining tocilizumab with MTX.

Re-recognition of methotrexate monotherapy in rheumatoid arthritis

With the in-depth research on treatment drugs of rheumatoid arthritis (RA), a variety of disease modifying anti-rheumatic drugs (DMARDs) have been approved for the treatment of RA. By now methotrexate (MTX) is still the anchor drug for RA treatment. The 2019 European League Against Rheumatism (EULAR) and 2021 American College of Rheumatology (ACR) recommendations for RA management both point out that for newly diagnosed RA patients, MTX monotherapy should be used as the first choice, which shows the importance of MTX monotherapy in DMARDs naïve RA. This paper mainly reviews the relevant researches on MTX in the treatment of RA in recent years, especially the relevant literature on the use of MTX monotherapy in initial treatment of RA. We summarize the development history, efficacy, treatment and adverse reactions of MTX to recognize the importance of MTX in the treatment of RA and the feasibility of MTX monotherapy.

Efficacy and safety of etanercept biosimilar rhTNFR-Fc in Chinese patients with juvenile idiopathic arthritis: An open-label multicenter observational study.

BackgroundEtanercept biosimilar recombinant human TNF-α receptor II: IgG Fc fusion protein (rhTNFR-Fc) has showed its efficacy and safety in Chinese patients with rheumatoid arthritis. However, data on rhTNFR-Fc's application in juvenile idiopathic arthritis (JIA) is limited.MethodsA prospective, observational, multicenter study was performed at 6 institutes in China from July 2020 to December 2021. In a 24-week follow-up, patients with JIA including polyarticular JIA and enthesitis related arthritis received rhTNFR-Fc plus methotrexate (MTX) treatment. The primary outcome parameters were improvements of cJADAS-10 (clinical Juvenile Arthritis Disease Activity Score), and the secondary outcome parameter was an inactive disease.Results60 patients completed at least 12-week follow-up, and 57 completed 24-week follow-up. They had high C reactive protein values (11.6 mg/L) and cJADAS-10 (14.6) at baseline. Thirteen patients had morning stiffness. 33 patients showed synovial thickening, and 34 showed bone marrow edemas on MRI. Ultrasonography demonstrated significant joint effusions in 43 patients. The cJADAS-10 sharply decreased from 14.66 at the baseline to 2.4 at 24 weeks of rhTNFR-Fc therapy, respectively (P < 0.01). About half of patients achieved inactive disease at 24 weeks of therapy. Compared with the baseline, the number of patients with morning stiffness, joint effusions, bone marrow edema and synovial thickening on MRI significantly decreased at 24 weeks. Adverse events were consistent with known side effects of biologic agents.ConclusionsThe present study indicated that the combination of rhTNFR-Fc and MTX significantly improve symptoms and disease activity of children with JIA. This study suggests etanercept biosimilar rhTNFR-Fc as an effective and safe therapy for children with JIA.

48 Juvenile dermatomyositis: the experience of Military Pediatrics Department of Tunis

BackgroundJuvenile dermatomyositis (JD) is a rare autoimmune disorder characterized by a non-infectious inflammatory state affecting of the muscles and skin associated with a vasculopathy which represents the essential of its physiopathogenesis.ObjectivesTo review the clinical and biological diagnosis of DMJ as well as its evolution under treatment based on the cases of two patients at the Military Pediatrics Department of Tunis.ObservationsCase 1: This was a three-and-a-half-year-old child with a history of a simple febrile seizure, admitted for a skin rash and myalgia that had been evolving for eight months. Skin examination revealed an erythematous rash of the face and upper eyelids with erythematous papular lesions in front of the proximal interphalangeal joint recalling Gottron's papules. Muscle testing was in favor of a proximal deficiency and the electromyogram (EMG) revealed a diffuse myogenic process more pronounced on the proximal muscles without signs of myositic activity. Biology analysis did not reveal a biological inflammatory syndrome but rather increased muscle enzymes levels up to 3- and 4-times normal values. On the immune status report, there was no evidence of DMJ-specific autoantibodies (ASM), but the anti-SRP antibodies associated with myositis were present. The diagnosis of DMJ was established in view of the association of typical cutaneous signs and 3 muscular signs (proximal deficit, elevation of muscle enzymes, myogenic tracing) and an evaluation of the activity of the disease according to a standardized scale by the Childhood Myositis Assessment Scale (CMAS) was required (which was at 7/52). Treatment with corticosteroids and methotrexate was started after a pretherapeutic evaluation and regular check-ups of the child showed a clear improvement of clinical and muscular signs (CMAS became at 41/52). Case 2: A 7-year-old boy, with no previous pathological history, admitted to our department to explore his gait disorder associated to erythematosquamous lesions. At the dermatological inspection, a localized erythema was noted on the upper eyelids, the nose, the cheeks and the chin area, as well as erythematosquamous lesions on the interphalangeal joints, metacarpophalangeal joints, elbows and knees (Gottron papules). The gait was waddling, the EMG was in favor of myogenic disorder and the muscular testing revealed a proximal muscular affection. The biology results showed an elevation of CPK and LDH to 1.5 times the normal values and a sedimentation rate at 40 mm/h. The antibodies determination showed the existence of anti-NXP2 antibodies specific to myositis. The progression under treatment (corticosteroids, methotrexate and adjuvant treatment) was favorable with a CMAS score of 39 (CMAS was 11 when admitted). The persistence of squamous lesions recalling calcinosis on the dorsal surfaces of the forearms was well correlated with the presence of anti-NXP2 antibodies.ConclusionThe positive diagnosis of DMJ in a child must be based on clinical and biological arguments. The immunological characterization of DMJ should be an important element in the disease management because it can explain the lesions associated with certain myositis specific antibodies as well as their evolution, which implies a particular follow-up depending on the detected antibodies (risk of cancer in anti-NXP2 AC positive patients)

11 Evaluation of doctors’ knowledge (excluding rheumatologists and pediatricians) of juvenile idiopathic arthritis

BackgroundJuvenile idiopathic arthritis (JIA) is the most common pediatric inflammatory arthritis. However, this disease is not fully understood by all practitioners.ObjectivesThe objective of this survey is to assess the level of knowledge and attitudes of doctors excluding rheumatologists and pediatricians on the management of JIA.MethodsIn this cross-sectional descriptive study, an anonymous questionnaire composed of 20 questions, designed with the Google-Forms software, was sent via social networks to doctors from different specialties (excluding rheumatologists and pediatricians) and to interns and residents of the University Hospitals of Tunis.ResultsA total of 100 physicians responded to the questionnaire (61 women and 39 men). The mean age was 31.01 ± 5.64 [24–51] years. Fifty-seven percent of the participants were in training, 27% worked in public hospitals and 16% in private clinics. Most participants were general practitioners (32%), followed by ophthalmologists (9%), gynecologists (7%), and internists (5%). the mean length of service was 4.99 ± 4.5 [0–22] years. Thirty-six participants affirmed they have been confronted with patients with JIA. Twenty percent of participants believed they have knowledge about JIA. Among them, 25% believed they have sufficient knowledge, the others had superficial knowledge. Thirty-four percent of participants knew the definition of the disease according to the age, 17% knew its frequency and 18% had an idea about its various sub forms. The most frequent sub form was known only by 32 participants.Regarding the complications of JIA, only 25% of the participants thought of the macrophage activation syndrome in case of deterioration of the general state, fever, and pancytopenia. In addition, 44% of participants knew that JIA can be complicated by ocular involvement.Concerning the presence of rheumatoid factors and anti-nuclear antibodies during JIA, 64% and 60% respectively answered that their presence was not necessary.Concerning the care of JIA, 64% of participants referred these patients to rheumatologists, 31% to a pediatrician, and 5% took care of them themselves.The interest of methotrexate and biological treatments were known by 48% of the participants. However, 37% of participants had no idea of the therapeutic management of JIA.Concerning the prognosis, only 25% of the participants know the sub forms of bad prognosis. However, 48% had no idea about the prognosis of the disease.ConclusionThe level of knowledge of doctors on JIA is low to average. Training for physicians on this potentially serious disease is needed.

Combination of Methotrexate and Leflunomide Is Efficient and Safe for 60 Patients with Rheumatoid Arthritis.

The present work is aimed at exploring the clinical efficacy and safety of methotrexate (MTX) and leflunomide (LEF) combination therapy for rheumatoid arthritis. From June 2019 to June 2021, a total of 120 individuals with rheumatoid arthritis received a diagnosis. Sixty patients each were randomly assigned to the control and observation groups. The observation group received MTX and LEF combo medication while the control group only received MTX treatment. Clinical efficacy, complication incidence, and the alleviation of inflammatory markers, joint pain, and clinical symptoms were compared between the 2 groups. Posttreatment, the observation group had overall response rate of 96.66%, while the control group had 86.67%, with significant differences. Compared with pretreatment, both control and observation group patients showed decreasing trends of IL-1 levels and increasing trends of IL-10 levels posttreatment, with significant differences (P < 0.05). Compared with the control group, patients in the observation group had lower IL-1 and TNF-α levels with significant differences (P < 0.05) and higher levels of IL-10 with significant difference (P < 0.05). In both groups, the pain score and the number of painful joints were much lower than they were prior to treatment. Following treatment, the observation group displayed significantly lower levels of erythrocyte sedimentation rate, rheumatoid factor, and C-reactive protein than the control group (P < 0.05). Clinical measures in the observation group were all lower than those in the control group with statistically significant differences (P < 0.05). Moreover, the incidence rate of adverse reactions showed no significant difference between these 2 groups (P > 0.05). In conclusion, the combination therapy of MTX and LEF is efficacious for rheumatic arthritis.

Is local methotrexate therapy effective in the treatment of cesarean scar pregnancy? A retrospective cohort study.

To evaluate the success of local methotrexate (MTX) treatment, the side-effect profile and its fertility effect in patients diagnosed with cesarean scar pregnancy. This retrospective cohort study included 56 cesarean scar pregnancy patients who applied to Erciyes University Faculty of Medicine, Department of Obstetrics and Gynecology between January 2012 and January 2022 and were treated with ultrasound-guided local MTX. The results of 56 patients with cesarean scar pregnancy who underwent transvaginal ultrasound-guided single-dose local MTX treatment were evaluated. First, the contents of the sac were aspirated, and then 50 mg of MTX was injected into the gestational sac. The median gestational age at diagnosis was 7 weeks 2 days. The mean beta human chorionic gonadotrophin level was 31 345 ± 37 838 (range: 113-233 835 mIU/mL). Fifty-four patients were successfully treated with local MTX therapy. The interval between the first MTX injection and the normalization of beta human chorionic gonadotrophin was 55.2 ± 41.0 days. None of our patients required surgical treatment. Beta human chorionic gonadotrophin values did not decrease in one patient and she was treated with systemic MTX. Local MTX therapy could not be applied to one patient for technical reasons. Only one patient needed blood transfusion after local MTX. Thirteen patients become pregnant after treatment (76%). No systemic side effects related to MTX were observed in any of the patients. Transvaginal ultrasound-guided single-dose local MTX treatment is an effective, safe, and fertility-preserving treatment method for cesarean scar pregnancy.

ACTIVE MANAGEMENT OF PERSISTENT PREGNANCIES OF UNKNOWN LOCATION RESULTS IN A SHORTER TIME TO RESUME FERTILITY TREATMENT

To demonstrate that active management of persistent pregnancies of unknown location (PPUL) with dilation and curettage (D&C) followed by methotrexate (MTX) treatment if needed results in a shorter time to resume treatment when compared to empiric MTX for a presumed diagnosis of ectopic pregnancy.

Pausing methotrexate prevents impairment of Omicron BA.1 and BA.2 neutralisation after COVID-19 booster vaccination

ObjectiveThe level of neutralising capacity against Omicron BA.1 and BA.2 after third COVID-19 vaccination in patients on paused or continuous methotrexate (MTX) therapy is unclear.MethodsIn this observational cohort study, neutralising...

Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing diseases

Immune system and blood–brain barrier dysfunction are implicated in the development of Alzheimer’s and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827 immune system- and blood–brain barrier-related biomarkers and identified 127 potential causal risk factors for dementia-causing diseases. Pathway analyses linked these biomarkers to amyloid-β, tau and α-synuclein pathways and to autoimmunity-related processes. A phenome-wide analysis using Mendelian randomization-based polygenic risk score in the FinnGen study (n = 339,233) for the biomarkers indicated shared genetic background for dementias and autoimmune diseases. This association was further supported by human leukocyte antigen analyses. In inverse-probability-weighted analyses that simulate randomized controlled drug trials in observational data, anti-inflammatory methotrexate treatment reduced the incidence of Alzheimer’s disease in high-risk individuals (hazard ratio compared with no treatment, 0.64, 95% confidence interval 0.49–0.88, P = 0.005). These converging results from different lines of human research suggest that autoimmunity is a modifiable component in dementia-causing diseases.

Effect of Folic Acid Conjugated Silver Nanoparticles in Treatment of RA Like Adjuvant Arthritis in Rats

Objective: Nano medicine has become one of the promising research areas, opening new horizons in disease diagnosis and treatment. Recent years have witnessed a surge in the development of Nano medicine for combating rheumatoid arthritis (RA), the most common autoimmune arthritis. RA is characterized by progressive inflammation and persistent synovitis, leading to joint destruction, functional incapability, and ultimately disability. Although there has been a tremendous evolution in disease assessment and treatment, many patients still fail to attain remission. Therefore, developing new drugs that specifically target inflamed joints and simultaneously attenuate other possible damages to healthy tissues is indispensable. This study was done to evaluate the potential of folic acid conjugated silver nanoparticles (FA-AgNPs) as RA therapy. Methods: In the CFA-arthritic rat model, FA-AgNPs &amp; methotrexate were administered for 8 consecutive weeks. Therapeutic efficacy was evaluated by measuring paw volume, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6) levels. For safety concerns, complete blood picture (CBC), liver and renal function tests were evaluated. Joints histological assessment was also carried out. Results: FA-AgNPs significantly reduced paw volume, paw weight, ESR, CRP, RF, TNF-α, and IL-6 levels compared with arthritic non-treated rats, demonstrating good anti-inflammatory activity. Likewise, histology of tarsal joints depicted comparatively lesser inflammatory cellular infiltration and diminished cartilage erosions. Methotrexate displayed comparable results. In contrast to methotrexate, FA-AgNPs showed normal CBC &amp; significantly improved liver and renal function tests. Conclusion: FA-AgNPs exhibited substantial anti-arthritic activity. This notable anti-arthritic potential of FA-AgNPs was as good as the current standard treatment of methotrexate (MTX) with higher biosafety.

Retinal changes of primary vitreoretinal lymphoma after intravitreal methotrexate

BackgroundTo identify retinal changes using spectral-domain optical coherence tomography (SD-OCT) and ultra-widefield images in eyes with primary vitreoretinal lymphoma (PVRL) during intravitreal methotrexate (MTX) treatment. MethodsThis study retrospectively reviewed 111 eyes of 58 patients with vitreous cytology-proven confirmed PVRL, who received intravitreal injections of MTX.ResultsAt the initial visit, the OCT manifestations included vitreous cells (105 eyes, 94.6%), intraretinal infiltration (44 eyes,39.6%), subretinal infiltration (45 eyes, 40.5%,), retinal pigment epithelium (RPE) abnormalities (66 eyes, 59.5%), disruption of the ellipsoid zone (58 eyes, 52.3%), subretinal fluid (4 eyes, 3.6%), RPE detachment (PED) (28 eyes, 25.2%), epiretinal membrane (ERM) (8 eyes, 7.2%), macular edema (10 eyes, 9%). After therapy, tumor regression was achieved in all eyes. Between the initial presentation and regression, the vitreous cells (94.6% vs. 0%, P < 0.001), intraretinal infiltration (39.6% vs. 0%, P < 0.001), RPE abnormalities (59.5% vs.19.8%, P < 0.001), PED (25.2% vs.0%, P < 0.001), and subretinal infiltration (40.5%vs.16.2%, P < 0.001) were significantly reduced. The fundus photography findings all improved after therapy. The mean Logarithm of the Minimum Angle of Resolution (logMAR) for the best corrected visual acuity (BCVA) at presentation was 0.79 ± 0.81 (range, 0–2.9), which improved to 0.70 ± 0.97 (range, 0–2.9, P = 0.01) at the final visit.ConclusionsSD-OCT combined with ultra-widefield imaging, which can reflect retinal changes, are valuable tools for monitoring the effect of PVRL treatment.

Analysis of Key Factors Associated with Response to Salvage High-Dose Methotrexate Rechallenge in Primary Central Nervous System Lymphoma with First Relapse

Background: Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin’s lymphoma that occurs in the central nervous system. Although sensitive to chemotherapy, 35–60% of PCNSL patients still relapse within 2 years after the initial treatment. High-dose methotrexate (HD-MTX) rechallenge is generally used in recurrent PCNSL, especially for patients who have achieved a response after initial methotrexate (MTX) treatment. However, the overall remission rate (ORR) of HD-MTX rechallenge is about 70–80%. Additionally, the side effects of HD-MTX treatment endanger the health of patients and affect their quality of life. Methods: This is a retrospective study of patients with first relapse PCNSL at Huashan Hospital, Fudan University between January 2000 and November 2020. By comparing the clinical characteristics and radiological manifestations of first relapsed PCNSL patients with remission and non-remission after receiving HD-MTX rechallenge, we screened out the key factors associated with HD-MTX rechallenge treatment response, to provide some help for the selection of salvage treatment strategies for patients with recurrent PCNSL. Additionally, patients with remission after HD-MTX rechallenge were followed up to identify the factors related to progression-free survival of the second time (PFS2) (time from the first relapse to second relapse/last follow-up). The Kruskal–Wallis and Pearson chi-square tests were performed to examine the univariate association. Further, multivariable logistic regression analysis was used to study the simultaneous effect of different variables. Results: A total of 207 patients were enrolled in the study based on the inclusion criteria, including 114 patients in the remission group (RG) and 81 patients in the non-remission group (nRG), and 12 patients were judged as having a stable disease. In Kruskal–Wallis and Pearson chi-square tests, progression-free survival rates for first time (PFS1) and whether the initial treatment was combined with consolidated whole brain radiotherapy (WBRT) were related to the response to HD-MTX rechallenge treatment, which was further validated in regression analysis. Further, after univariate analysis and regression analysis, KPS was related to PFS2. Conclusions: For PCNSL patients in their first relapse, HD-MTX rechallenge may be an effective salvage treatment. PFS1 and whether initial treatment was combined with consolidation WBRT were associated with HD-MTX rechallenge treatment response. In addition, patients with higher KPS at the time of the first relapse had a longer PFS2 after HD-MTX rechallenge treatment.

Withholding methotrexate after vaccination with ChAdOx1 nCov19 in patients with rheumatoid or psoriatic arthritis in India (MIVAC I and II): results of two, parallel, assessor-masked, randomised controlled trials.

BackgroundThere is a necessity for an optimal COVID-19 vaccination strategy for vulnerable population groups, including people with autoimmune inflammatory arthritis on immunosuppressants such as methotrexate, which inhibit vaccine-induced immunity against SARS-CoV-2. Thus, we aimed to assess the effects of withholding methotrexate for 2 weeks after each dose of ChAdOx1 nCov-19 (Oxford–AstraZeneca) vaccine (MIVAC I) or only after the second dose of vaccine (MIVAC II) compared with continuation of methotrexate, in terms of post-vaccination antibody titres and disease flare rates.MethodsMIVAC I and II were two parallel, independent, assessor-masked, randomised trials. The trials were done at a single centre (Dr Shenoy's Centre for Arthritis and Rheumatism Excellence; Kochi, India) in people with either rheumatoid arthritis or psoriatic arthritis with stable disease activity, who had been on a fixed dose of methotrexate for the preceding 6 weeks. Those with previous COVID-19 or who were positive for anti-SARS-CoV-2 nucleocapsid antibodies were excluded from the trials. People on high-dose corticosteroids and rituximab were also excluded, whereas other disease-modifying antirheumatic drugs were allowed. In MIVAC I, participants were randomly assigned (1:1) to stop methotrexate treatment for 2 weeks after each vaccine dose or to continue methotrexate treatment. In MIVAC II, participants who had continued methotrexate during the first dose of vaccine were randomly assigned (1:1) to withhold methotrexate for 2 weeks after the second dose of vaccine or to continue to take methotrexate. The treating physician was masked to the group assignments. The primary outcome for both MIVAC I and MIVAC II was the titre (absolute value) of anti-receptor binding domain (RBD) antibody measured 4 weeks after the second dose of vaccine. All analyses were done per protocol. The trials were registered with the Clinical Trials Registry- India, number CTRI/2021/07/034639 (MIVAC I) and CTRI/2021/07/035307 (MIVAC II).FindingsBetween July 6 and Dec 15, 2021, participants were recruited to the trials. In MIVAC I, 250 participants were randomly assigned and 158 completed the study as per the protocol (80 in the methotrexate hold group and 78 in the control group; 148 [94%] were women and 10 [6%] were men). The median post-vaccination antibody titres in the methotrexate hold group were significantly higher compared with the control group (2484·0 IU/mL, IQR 1050·0–4388·8 vs 1147·5 IU/mL, 433·5–2360·3; p=0·0014). In MIVAC II, 178 participants were randomly assigned and 157 completed the study per protocol (76 in the methotrexate hold group and 81 in the control group; 135 [86%] were women and 22 [14%] were men). The methotrexate hold group had higher post-vaccination antibody titres compared with the control group (2553·5 IU/ml, IQR 1792·5–4823·8 vs 990·5, 356·1–2252·5; p<0·0001). There were no reports of any serious adverse events during the trial period.InterpretationWithholding methotrexate after both ChAdOx1 nCov-19 vaccine doses and after only the second dose led to higher anti-RBD antibody titres compared with continuation of methotrexate. However, withholding methotrexate only after the second vaccine dose resulted in a similar humoral response to holding methotrexate after both vaccine doses, without an increased risk of arthritis flares. Hence, interruption of methotrexate during the second dose of ChAdOx1 nCov-19 vaccine appears to be a safe and effective strategy to improve the antibody response in patients with rheumatoid or psoriatic arthritis.FundingIndian Rheumatology Association.

Contraceptive efficacy and safety of the 52-mg levonorgestrel intrauterine system for up to 8 years: findings from the Mirena Extension Trial

The 52-mg levonorgestrel-releasing intrauterine system is an established, long-acting contraceptive option with approved use for up to 7 years. The Mirena Extension Trial evaluated the efficacy and safety of the 52-mg levonorgestrel-releasing intrauterine system during extended use beyond 5 and up to 8 years. This was a multicenter, single-arm study in the United States, enrolling existing users of the 52-mg levonorgestrel-releasing intrauterine system, aged 18 to 35 years, who have had the system for 4.5 to 5 years. We assessed the contraceptive efficacy (Pearl Index) and cumulative failure rate (using the Kaplan-Meier method) of the 52-mg levonorgestrel-releasing intrauterine system during extended use. We also evaluated bleeding outcomes and adverse events. Of the 362 participants starting year 6, 243 entered and 223 completed 8 years of 52-mg levonorgestrel-releasing intrauterine system use. Just more than half the participants were parous. The mean (standard deviation) age was 29.2 (±2.9) years, and all participants were aged ≤36 years at the end of year 8. Two pregnancies occurred, both with the device in situ. The year 6 pregnancy was of undetermined location and resolved spontaneously. The pregnancy in year 7 was ectopic and resolved with methotrexate treatment. In both cases, the 52-mg levonorgestrel-releasing intrauterine system was removed and the participants left the trial. For years 6 to 8, the 3-year Pearl Index (95% confidence interval) was 0.28 (0.03-1.00) with a 3-year cumulative failure rate of 0.68% (0.17-2.71). Pearl Indexes for years 6, 7, and 8 were 0.34 (0.01-1.88), 0.40 (0.01-2.25), and 0.00 (0.00-1.90), respectively. The 3-year (years 6-8) ectopic pregnancy Pearl Index was 0.14 (0.00-0.77). We found treatment-emergent adverse events in 249 of 362 participants (68.8%), with 65 (18.0%) events considered to be related to the 52-mg levonorgestrel-releasing intrauterine system. The discontinuation rate was 38.4% (139/362), most commonly because of desire for pregnancy (12.2%, 44/362). During extended use beyond 5 years and up to 8 years, participants reported a decrease in the mean number of bleeding or spotting days with approximately half of the women experiencing amenorrhea or infrequent bleeding. We did not enroll a sufficient number of women using the 52-mg levonorgestrel-releasing intrauterine system for contraception and heavy menstrual bleeding to assess extended use for that indication. At the end of year 8, most (98.7%, 220/223) of the participants who completed the study remained satisfied with the continued use of the 52-mg levonorgestrel-releasing intrauterine system. Of the 31 women who discontinued early because of desire for pregnancy with evaluable data for return-to-fertility analysis, 24 reported a posttreatment pregnancy within 1 year, giving a 12-month return-to-fertility rate of 77.4%. The 52-mg levonorgestrel-releasing intrauterine system, initially approved for 5 years, maintains high contraceptive efficacy, user satisfaction, and a favorable safety profile through 8 years of use. Participants reported 26 posttreatment pregnancies in total, of which 24 occurred in women who had discontinued the 52-mg levonorgestrel-releasing intrauterine system because of a desire for pregnancy. Of note, among women who elected to continue use through 8 years, bleeding patterns remained highly favorable. These findings support continued 52-mg levonorgestrel-releasing intrauterine system use for up to 8 years in women who wish to continue treatment.