Methotrexate Users Research Articles

P-400 Methotrexate versus expectant management for treatment of tubal ectopic pregnancy: an individual participant data meta-analysis (IPD-MA)

Abstract Study question Is medical management with methotrexate superior over expectant management in the resolution of tubal ectopic pregnancy in clinically stable women and low serum hCG? Summary answer In women with tubal ectopic pregnancy and low serum hCG, methotrexate was not better than expectant management. There were no subgroups benefiting from methotrexate. What is known already Women with tubal pregnancy who are clinically stable and have low hCG concentrations can be treated medically with methotrexate, an anti-folate drug that has a range of adverse effects and requires women to avoid conceiving three months after administration due to teratogenic effects. Expectant management with close monitoring is as effective compared to methotrexate in this subgroup of women. There are three randomised controlled trials (RCTs) not showing a statistically significant difference in uneventful resolution of ectopic pregnancy between methotrexate and expectant management. These studies were too small to define if certain subgroups could benefit from either treatment. Study design, size, duration We performed an individual participant data meta-analysis (IPD-MA) of RCTs based on a search of international scientific databases. We selected RCTs comparing methotrexate and expectant management in women with suspected tubal ectopic pregnancy. The primary outcome was treatment success, defined as resolution of clinical symptoms and decline in level of serum hCG to < 20 IU/L or a negative urine pregnancy test by the initial intervention strategy, without any additional treatment. Participants/materials, setting, methods Analyses were performed on an intention-to-treat basis. A one-stage IPDMA was performed to assess overall treatment effects of methotrexate and expectant management to generate a pooled intervention effect. This included a random intercept (for baseline differences between studies) and random slope (for differences in treatment effect between studies). A log-binomial model for dichotomous outcomes yielded a risk ratio (RR) with 95% confidence interval (CI). Subgroup analyses were undertaken according to baseline serum β-hCG levels. Main results and the role of chance We obtained data from two relevant trials reporting on 153 women with suspected tubal ectopic pregnancy who were randomised to expectant management or methotrexate. The third RCT was excluded as their inclusion criteria required declining titres of hCG 48 hours prior to treatment. The success rate was 65/82 (79.3%) after methotrexate and 48/70 (68.6%) after expectant management (IPD RR 1.16, 95%CI 0.71-2.38). 9/82 (11%) in the methotrexate group and 9/70 (12.8%) after expectant required additional methotrexate. 8/82 (9.8%) in the methotrexate group and 13/70 (18.6%) in the expectant group required surgical intervention (RR 0.65, 95%CI 0.66-3.54). The mean time to success was 21.2 days (95%CI 17.4 to 25.6) after expectant management and 19.7 days (95%CI 17.1-22.2) after methotrexate (p = 0.25). There was no interaction with treatment of maternal age, parity, previous ectopic pregnancy, and serum β-hCG on success rate. Serum hCG <1000 IU/l was associated with a higher success rate in both groups. Only one woman in the expectant group required a blood transfusion. Methotrexate users had side effects (N = 7/49) including vomiting, diarrhoea, mucositis, conjunctivitis and photosensitivity that were not seen in the expectant group (N = 0/49). Limitations, reasons for caution One of the trials had a higher proportion of pregnancy of unknown location (PUL) which were presumed to be tubal ectopic pregnancies due to plateauing serum hCG levels and caution is therefore advised on the application of these findings to ectopic pregnancies visualised on ultrasound. Wider implications of the findings Initial expectant management might be the preferred strategy for women with suspected tubal ectopic pregnancy in clinically stable women with lower hCG levels in view of less adverse effects, less cost and enabling women who wish to conceive soon after resolution of ectopic pregnancy to do so. Trial registration number Prospero ID: CRD42021214093

Trajectories of systemic agent use and associated depression- and anxiety-related health care costs among patients with psoriasis

BackgroundSystemic treatment patterns and related mental health disorders and economic burden among patients with psoriasis are largely unknown.ObjectiveTo assess systemic treatment patterns and associated depression and anxiety-related health care costs among patients with psoriasis initiating a conventional systemic treatment (CST).MethodsUsing a retrospective cohort design with sequence and cluster analyses, we assessed systemic treatment trajectories (CST and tumor necrosis factor inhibitors or ustekinumab, [TNFi/UST]) over a 2-year period following CST initiation. We compared health care costs between trajectories using 2-part models.ResultsWe included 781 patients and identified 8 trajectories: persistent methotrexate users, persistent acitretin users, early CST discontinuation, late methotrexate discontinuation, switch to TNFi/UST, adding TNFi/UST, discontinuation then restart on methotrexate, and discontinuation then restart on acitretin or multiple CST switches. Overall, 165 (21%) patients incurred depression- and anxiety-related health care costs (median annual cost, CAN$56; quartiles, $14-$127). Compared with persistent methotrexate users, adding a TNFi/UST (cost ratio, 3.63; 95% CI, 1.47-5.97) and discontinuation then restart on acitretin or multiple switches between systemic agents (cost ratio, 13.3; 95% CI 5.76-22.47) had higher costs.LimitationsTrajectory misclassification may have occured. These date represent an association, and causality cannot be inferred, particularly given the risk of confounding.ConclusionDepression- and anxiety-related health care costs were high among patients adding TNFi/UST and those discontinuing then restarting on acitretin or experiencing multiple switches between systemic agents.

Biologic Initiation Rate in Systemic-Naïve Psoriatic Arthritis Patients Starting Treatment with Apremilast vs Methotrexate: 1-Year Retrospective Analysis of a US Claims Database.

PurposeTo compare the rate of biologic initiation after commencing treatment with apremilast (APR) vs methotrexate (MTX), in systemic-naïve patients with psoriatic arthritis (PsA).Patients and MethodsSystemic-naïve patients with PsA who started treatment with either APR or MTX between 01/01/2015 and 12/31/2018 were analyzed using claims data from the IBM® MarketScan® Commercial and Medicare Supplemental databases (2014–2019). PsA patients were identified via diagnosis codes; the first prescription date for APR or MTX was the index date. Patient demographics, clinical characteristics, healthcare utilization during the year pre-index (baseline) and the year post-index (follow-up), and median time to biologic initiation were reported descriptively. The rates and risk of biologic initiation during follow-up were compared between APR and MTX users by logistic and Cox regressions, respectively. Models were adjusted for demographics, clinical and utilization measures during the baseline period.ResultsA total of 2116 patients with PsA newly treated with APR (n = 534) or MTX (n = 1582) were identified. Mean age was similar (50.5 vs 50.4; P = 0.938), and proportion of females was higher for APR vs MTX users (59.4% vs 54.0%; P = 0.031). Mean time to biologic initiation among patients who initiated during follow-up was 194.1 vs 138.7 days between APR vs MTX users (P < 0.001). After adjusting for confounders, the likelihood of biologic initiation was 58% lower (OR, 0.42 [95% CI, 0.32–0.54]; P < 0.001) with APR, with a significantly lower predicted rate of biologic initiation among APR users when compared to MTX users during follow-up (20.0% [95% CI, 16.6–23.9%] vs 37.5% [95% CI, 35.0–40.1%]). Additionally, APR users had a lower risk of biologic initiation than MTX users (HR, 0.46 [95% CI, 0.37–0.57]; P < 0.001) during the 1-year follow-up.ConclusionSystemic-naïve patients with PsA have a lower rate of, and longer time to, biologic initiation over one-year following APR initiation, compared to those initiating MTX.

P104 Comparative risk of infection for first-line csDMARD therapy in rheumatoid arthritis: a multinational cohort analysis of real world data

Abstract Background/Aims Infections on conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) are an important concern for rheumatoid arthritis (RA) patients, especially during the COVID-19 pandemic. However comparative safety data between csDMARDs have been conflicting and limited in power. The objective was to assess the comparative safety of serious, opportunistic and all infections (including non-serious) of first-line csDMARDs in RA through a large multinational observational study. Methods We evaluated first-line new users of methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SZ) and leflunomide (LEF) monotherapy. Data was obtained from four US databases (IQVIA US Ambulatory EMR (AMBER), Optum® De-identified Clinformatics® Datamart (Optum), IBM MarketScan® Medicare Supplemental Database (MDCR), and IBM MarketScan Commercial Database (CCAE)), one from Germany (IQVIA Disease Analyser Germany EMR (Germany)), and another from the UK (IQVIA UK The Health Improvement Network). Patients included were ≥18 years with a RA diagnosis between 2005-2019, without prior inflammatory arthritis, cancer or infection (in the preceding 30 days). Serious infections were defined as those requiring hospitalisation or resulting in death within 30 days; opportunistic infections were defined as per published EULAR consensus. Patients were followed from 1-day following treatment initiation to the earliest of treatment discontinuation, switching, or add-on plus 14 days, or loss to follow-up. Cox proportional-hazards models for MTX against each csDMARD with large-scale propensity score stratification were performed. A large set of negative control outcomes were used to calibrate hazard ratios (cHR) to account for potential residual confounding. Estimates were pooled where homogeneity across sources was adequate (I2&amp;lt;0.4). Results A total of 247,511 patients were included (MTX: 141,647; HCQ: 73,286, SSZ: 16,521, LEF: 16,057), with pooled incidence rates of serious, opportunistic and all infections across sources for MTX users of 33.7, 20.1 and 311.8 per 1,000 pyrs, respectively. With MTX as the referent, for all infections, the pooled cHR (with 95% Confidence Intervals) for SSZ was 0.73 (0.62, 0.86); HCQ, 0.96 (0.89, 1.04); and LEF, 0.74 (0.50, 1.08). The serious infection pooled cHR for SSZ was 0.75 (0.58, 0.97) and for LEF, 0.93 (0.61, 1.40). For opportunistic infections, pooled cHR for HCQ was 1.04 (0.92, 1.19). Conclusion SSZ, LEF and less consistently HCQ had a lower risk of all (including non-serious) infections, compared to MTX. SSZ and LEF were associated with a 25% reduction in the expected risk of all infections. SSZ was associated with a 25% lower risk of serious infections relative to MTX. In the first large scale observational network study assessing comparative risk of infection with csDMARDs there were differences between drugs in risk for all infections, with potential implications for clinical care. Disclosure M. Jani: None. E. Burn: None. J. Weaver: Corporate appointments; Janssen. L. Carmona: None. K. Chatzidionysiou: None. B. Illigen: None. D. Vizcaya: Corporate appointments; Bayer. T. Duarte-Salles: None. P. Ryan: Corporate appointments; Janssen. D. Prieto-Alhambra: None.

The development and validation of a Patient-Perceived Methotrexate Intolerance Scale for use in adult rheumatoid arthritis patients.

To develop a scale to measure methotrexate intolerance for use in adult rheumatoid arthritis (RA) patients and to describe its psychometric properties. A three-phase study was conducted. During Phase 1, we conducted individual interviews with RA patients (n=14) to inform our item development process. During Phase 2, we asked for RA patients' (n=10) feedback on item readability, clarity and the scale's ability to measure methotrexate intolerance. During Phase 3, we had patients with RA (n=204) complete the scale to develop a final version and to describe the scale's internal validity (Cronbach's alpha), test-retest reliability (intra-class correlation coefficients), construct validity and discriminant validity and the ability of the scale to discriminate between past and present methotrexate users. The newly developed, weighted scale (Patient-Perceived Methotrexate Intolerance Scale [PPMIS]) includes four subscales: Methotrexate Benefits, Methotrexate Risks-Side Effect Considerations, RA Risks and Methotrexate Risks-Willingness to Take Methotrexate Despite Risks. Cronbach's alpha ranged from 0.79 to 0.94. Test-retest reliability at 2weeks was 0.73-0.88. Construct validity was supported with significant logical relationships between subscale scores and the existing methotrexate intolerance scale and past/present methotrexate use. The PPMIS was able to correctly classify RA patients as a past versus present methotrexate user 77% of the time. At the cut point of 3.29, the sensitivity of the PPMIS is 74% and specificity is 72% to correctly classify patients into past/present methotrexate use. This is the first known scale with favourable measurement properties to evaluate methotrexate intolerance using a patient-centred perspective.

Patient-Reported Nausea and Fatigue Related to Methotrexate: A Prospective, Self-Controlled Study in the ArthritisPower® Registry.

IntroductionThe magnitude and frequency of temporally related methotrexate (MTX)-associated side effects in rheumatoid arthritis (RA) or psoriatic arthritis (PsA) patients are difficult to quantify using traditional research methods. As proof of concept designed in part to implement digital data collection for remote patient monitoring, we conducted a study implementing self-controlled case series analytic methods to understand MTX-related symptoms in RA or PsA.MethodsIn study phase 1, adults with RA or PsA from the ArthritisPower® Registry (past or current oral MTX users) participated in a cross-sectional survey. In phase 2, current MTX users participated in a longitudinal study and completed the Patient-Reported Outcomes Measurement Information System (PROMIS®) 1-day nausea/vomiting and fatigue measure. Within-person change in PROMIS scores between risk (6–36 h post-dose) and control (96–144 h post-dose) windows were compared using mixed models.ResultsThe baseline survey was completed by 671 participants (mean age: 54 years, 88% female, 92% white, 79% with RA). Among current MTX users (353/671 [53%]), most reported MTX-associated side effects (216/353 [61%]), most frequently fatigue (161/353 [46%]). Among phase 2 participants with (n = 39) and without (n = 84) baseline nausea, mean increase in PROMIS nausea was 5.1 units (P < 0.0001) and 0.7 units (P = 0.135), respectively; among those with (n = 51) and without (n = 72) baseline fatigue, mean increase in PROMIS fatigue was 3.9 units (P = 0.0003) and 0.4 units (P = 0.554), respectively.ConclusionsDigital remote patient monitoring presents an opportunity to detect and address medication tolerability in real time. Using a novel study design to control for between-person confounding, the magnitude of nausea and fatigue experienced by participants with RA and PsA temporally related to weekly MTX use was substantial.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00398-6.

Risk of Hematologic Events With Coadministration of Methotrexate and the Breast Cancer Resistance Protein Inhibitor Febuxostat.

The breast cancer resistance protein (BCRP) is a key drug transporter found in the liver, kidney, central nervous system, and gastrointestinal tract. Due to the wide expression of BCRP, interactions of other drugs with methotrexate (MTX) may differ in oral and intravenous MTX users, and understanding of these interactions may be useful in preventing severe adverse events. Febuxostat, a urate-lowering drug, inhibits BCRP. The objective of this study was to clarify the differences in the drug-drug interaction profiles of oral and intravenous methotrexate, associated with BCRP. We analyzed the Japanese Adverse Drug Event Report database and compared the frequency of hematologic events in patients taking oral and intravenous MTX, with or without the concomitant use of febuxostat or allopurinol. Hematologic events were defined as pancytopenia and neutropenia. Multiple logistic regression analysis was then used to identify the risk factors for hematologic events in oral and intravenous MTX users. We identified 8 453 oral and 810 intravenous MTX users with 546 and 126 cases of hematologic events, respectively. Compared with those not using febuxostat, a disproportionate number of hematologic events was observed in intravenous MTX users concomitantly using febuxostat (P < 0.01). The multivariate logistic analysis of intravenous MTX users showed that hematologic events were significantly associated with febuxostat use (P < 0.01) and age ≥ 60 years (P < 0.01). Our findings suggest that patients being treated with intravenous MTX who concomitantly use febuxostat may be at an increased risk of hematologic events, presumably due to BCRP-mediated drug-drug interaction.

Use of Methotrexate in Gynecologic and Obstetric Practice: What the Radiologist Needs to Know.

Methotrexate (MTX) is the primary pharmaceutical agent that is used for management of disorders arising from trophoblastic tissue. Its widespread international use is mostly attributable to its noninvasive, safe, and effective characteristics as a treatment option for ectopic pregnancy (EP) and gestational trophoblastic disease (GTD), with the large added benefit of fertility preservation. Although the effects of MTX usage are well documented in the gynecologic and obstetric literature, there is a scarcity of radiologic literature on the subject. Depending on the type of EP, the route of MTX administration and dosage may vary. US plays an essential role in the diagnosis and differentiation of various types of EPs, pregnancy-related complications, and complications related to MTX therapy, as well as the assessment of eligibility criteria for MTX usage. A knowledge of expected imaging findings following MTX treatment, including variability in echogenicity and shape of the EP, size fluctuations, changes in vascularity and gestational sac content, and the extent of hemoperitoneum, is essential for appropriate patient management and avoidance of unnecessary invasive procedures. A recognition of sonographic findings associated with pregnancy progression and complications such as tubal or uterine rupture, severe hemorrhage, septic abortion, and development of arteriovenous communications ensures prompt patient surgical management. The authors discuss the use of MTX in the treatment of disorders arising from trophoblastic tissue (namely EP and GTD), its mechanism of action, its route of administration, and various treatment regimens. The authors also provide a focused discussion of the role of US in the detection and diagnosis of EP and GTD, the assessment of the eligibility criteria for MTX use, and the identification of the sonographic findings seen following MTX treatment, with specific emphasis on imaging findings associated with MTX treatment success and failure. Online supplemental material is available for this article. ©RSNA, 2021.

Use of disease-modifying antirheumatic drugs and the subsequent risk of herpes zoster in older adults.

To examine the association between DMARD use and subsequent risk of herpes zoster in a large, heterogeneous and prospective population-based cohort. Using data from a cohort of adults (45 and Up Study) recruited between 2006 and 2009 and linked to pharmaceutical, hospital and death data (2004-2015), the effect of DMARD use on zoster risk was analysed using Cox proportional hazards models, adjusting for sociodemographic characteristics, comorbidities and corticosteroid use. Among 254 065 eligible participants, over 1 826 311 person-years follow-up, there were 6295 new DMARD users and 17 024 incident herpes zoster events. Compared with non-users, the risk of zoster was higher in those who used biologic (b)DMARDs, either alone or in combination with conventional synthetic (cs)DMARDs than in those who only used csDMARDs (adjusted hazard ratio [aHR] 2.53 [95% CI: 2.03, 3.16]) for bDMARDs vs 1.48 [95% CI: 1.33, 1.66] for csDMARDs, P-heterogeneity < 0.001; reference: non-users). Among users of csDMARDs, compared with non-users, zoster risks were highest in those using exclusively cyclophosphamide (aHR 2.69 [95% CI: 1.89, 3.83]), more moderate in those using azathioprine (aHR 1.57 [95% CI: 1.07, 2.30]) and hydroxychloroquine (aHR 1.43 [95%CI: 1.11, 1.83]) and not elevated in users of methotrexate (aHR 1.24 [95% CI: 0.98, 1.57]), sulfasalazine (aHR 1.00 [95% CI: 0.71, 1.42]) and leflunomide (aHR 0.41 [95% CI: 0.06, 2.88]). The risk of zoster was high among bDMARD and cyclophosphamide users. Also, the risk was increased in those using hydroxychloroquine alone and in combination with methotrexate but not methotrexate alone. Preventative strategies such as zoster vaccination or antiviral therapies should be considered in these populations if not contraindicated.

Treatment utilization and drug survival of systemic medications among commercially insured children with psoriasis.

Systemic medications and phototherapy are used to treat pediatric psoriasis, but real-world data on treatment utilization and persistence are limited. The study objective was to determine systemic and phototherapy treatment utilization and compare drug survival among systemics in pediatric psoriasis. Using United States commercial insurance claims data, a cross-sectional analysis was conducted to describe the prevalence of systemic treatment and phototherapy use among patients <18years old with psoriasis. We compared drug survival among new users of methotrexate, adalimumab, etanercept, and ustekinumab using a retrospective cohort design. Among 13759 patients, 14.6% used systemic or phototherapy treatment during 2001-2016, with rising utilization of systemics over this period. Among 579 new users of methotrexate, adalimumab, etanercept, and ustekinumab, the median durations of the initial treatment course were 141 (IQR 59-314), 179 (79-339), 175 (90-419), and 216 (64-435) days, respectively (P=.04). Drug discontinuation was less likely among ustekinumab (HR 0.47 [95% CI 0.27-0.83]), etanercept (0.74 [0.59-0.92]), and adalimumab (0.75 [0.55-1.02]) initiators than methotrexate initiators after adjustment for sociodemographic factors and psoriatic arthritis. Drug survival differences were limited to systemic-naïve patients. Potential limitations include short follow-up and residual confounding. Utilization of systemic therapies for pediatric psoriasis is increasing, but differences in drug survival exist.

Patterns of Anti-Inflammatory and Immunomodulating Drug Usage and Microvascular Endothelial Function in Rheumatoid Arthritis

Objectives: Specific anti-inflammatory and/or immunomodulating drugs (AIDs) can influence endothelial function which is often impaired in patients with rheumatoid arthritis (RA). We sought to determine whether overall patterns of AID usage are similarly associated with endothelial function.Methods: The reactive hyperaemia index (RHI), a marker of microvascular endothelial function, was measured in 868 RA patients reporting their intake of seven AIDs known to affect endothelial function. Latent class analysis (LCA) was performed to characterise patterns of AID usage. Models for 2–6 classes were compared using the AIC and BIC statistics and Lo-Mendell-Rubin likelihood ratio tests. Associations between the classes and RHI were adjusted for age, gender, body mass index, diabetes, HDL-cholesterol, LDL-cholesterol, family history of ischaemic heart disease, smoking status, RA duration, DAS28 score, steroid dose, existing hypertension, and C-reactive protein.Results: LCA identified five distinct AID usage classes: Class 1, generally low medication usage; Class 2, using either sulfasalazine or non-tumour necrosis factor (TNF) inhibitors; Class 3, methotrexate users; Class 4, TNF-inhibitor users; and Class 5, hydroxychloroquine users. The geometric mean for the RHI for subjects in classes 1 to 5 was 1.92, 1.81, 1.94, 2.10, and 2.07, respectively, with subjects in classes 4 and 5 having better endothelial function than subjects in class 2 (p = 0.003 for each). The glucocorticoid dosage did not influence the classes formed or the association between the classes and the RHI in sensitivity analyses.Conclusion: There were five broad patterns (classes) of AID usage in RA patients. The RHI was relatively lower in users of either sulfasalazine or non-TNF inhibitors. TNF inhibitors or hydroxychloroquine may counteract the negative effects of RA on endothelial function.

Risk of Chronic Obstructive Pulmonary Disease Exacerbation in Patients Who Use Methotrexate-A Nationwide Study of 58,580 Outpatients.

Patients with severe chronic obstructive pulmonary disease (COPD) experience frequent acute exacerbations and require repeated courses of corticosteroid therapy, which may lead to adverse effects. Methotrexate (MTX) has anti-inflammatory properties. The objective of this study was to describe the risk of COPD exacerbation in patients exposed to MTX. In this nationwide cohort study of 58,580 COPD outpatients, we compared the risk of hospitalization-requiring COPD exacerbation or death within 180 days in MTX vs. non-MTX users in a propensity-score matched study population as well as an unmatched cohort, in which we adjusted for confounders. The use of MTX was associated with a reduction in risk of COPD exacerbation in the propensity-score matched population at 180 days follow-up (HR 0.66, CI 0.66–0.66, p < 0.001). Similar results were shown in our sensitivity analyses at 180-day follow-up on unmatched population and 365-day follow-up on matched and unmatched population (HR 0.76 CI 0.59–0.99, HR 0.81 CI 0.81–0.82 and HR 0.92 CI 0.76–1.11, respectively). MTX was associated with a lower risk of COPD exacerbation within the first six months after study entry. The finding seems biologically plausible and could potentially be a part of the management of COPD patients with many exacerbations.

POS0935 DO PERIPHERAL AND EXTRA MUSCULOSKELETAL MANIFESTATIONS HAVE AN IMPACT ON BIOLOGIC DMARD PRESCRIBING PATTERNS IN AXIAL SPONDYLOARTHRITIS: THE RESULTS OF TREASURE EXPERIENCE

Background:Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease mainly affecting sacroiliac joints and spine. Peripheral arthritis, dactylitis and enthesitis may also occur. Extra musculoskeletal manifestations (EMMs; uveitis [AAU], inflammatory bowel disease [IBD] and psoriasis [Pso] are among the most common ones) are important features and might have an impact on the disease burden in patients with axSpA. The presence of EMM, in particular IBD and AAU could influence the choice of TNFi however little is known regarding the role of peripheral manifestations together with the EMM on the prescribing patterns in axSpA patients.Objectives:To examine the frequency of peripheral and EMMs in a real-world axSpA cohort and their effect on the choice of first advanced treatment.Methods:In total 1687 axSpA patients (58% male and the mean age (±SD) was 38.5 ± 10.9) who initiated his/her first biologic were included in the present analysis. The data for the current study was obtained from the TReasure web-based registry; in which RA and SpA patients treated with bDMARDs from different regions of Turkey. Baseline demographic, disease related characteristics, peripheral and EMMs were extracted. Characteristics of patients with and without peripheral/extra-musculoskelatal involvement were compared as well as factors/covariates associated with the choice of first TNFi and secukinumab was analysed.Results:Enthesis (28.2%) was found the most common peripheral manifestations and peripheral arthritis (26.4%) and hip arthritis (24.4%) followed it. Symptom duration to the first advanced treatment initiation was significantly shorter in axSpA patients with peripheral arthritis, enthesitis, dactylitis and psoriasis and longer in hip arthritis and AAU. HLA-B27 positivity was significantly lower in patients with arthritis, psoriasis and IBD and higher with hip arthritis and AAU. In multivariate analysis the presence of IBD is significantly associated with the preference of monoclonal TNFi (mab) over etanercept (ETA) (OR 5,770; 95%CI 1.788-18.616). However ETA was preferred in patients with hip arthritis (p=0.003), longer symptom duration (p=0.049), and using sulfasalazine (p=0.043). In comparison with mabs, secukinumab (SEC) prescription was found to be significantly associated with higher age (p=0.001), sulfasalazin (p=0.001) and methotrexate usage (p=0.053) among axSpA patients need their first advanced treatment.Conclusion:The results of the current study confirm the pathophsyologic associations of peripheral involvement and EMM in axSpA patients. Apart from hip arthritis the presence of IBD has an impact on the prescription of advanced treatment in real-life.Table 1.Clinical characteristics of patients in cohortAll patients(n=1678)Peripheral arthritis(n=445)Dactilitis(n=81)Enthesis(n=476)Uveitis(n=193)Psoriazis(n=152)IBD(n=78)Hip involvemet(n=412)Age, mean±SD38,5±10,938,3±11,637,4±11,137,9±10,741,3±11,439,9±11,341,6±12,239,2±11,2Male sex,n (%)974 (57,7)184 (41,3)34 (42)238 (50)96 (49,7)54 (35,5)43 (55,1)272 (66)Symptom duration, mean month±SD108,5±98,996,9±92,979,1±76,5100,4±92,7144,7±110,287,7±9494,5±98133,3±108,2HLA B27 positivity, n (%)621 (53,7)142 (46,3)27 (51,9)174 (49,4)104 (77)34 (36,2)16 (27,1)186 (59,8)Concomitant cDMARD usage (yes), n (%)420 (24,9)170 (38,2)39 (48,1)133 (27,9)53 (27,5)58 (38,2)24 (30,8)99 (24)BASDAİ,mean±SD5,1±2,55,1±35,3±3,15,3±2,94,7±2,55,6±2,44,8±2,35,3±2,1ASDAS-CRP, mean±SD3,1±1,52,6±1,92,5±1,82,8±1,72,9±1,73,4±1,33,1±1,53,7±1,4Disclosure of Interests:None declared

Clinicopathological characteristics of lymphoproliferative disorders in 232 patients with rheumatoid arthritis in Japan: A retrospective, multicenter, descriptive study.

To describe the clinicopathological characteristics of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA). In this multicenter case series, we retrospectively reviewed the medical records of RA patients who were newly diagnosed as having LPDs with or without biopsy confirmation between 2000 and 2017 in eight hospitals in Japan. We included 232 patients with LPDs. The median age was 67 years (interquartile range [IQR], 60-73 years), and 77.1% were female. At the time of LPD diagnosis, 94.8% and 62.6% of the patients were methotrexate users and in remission or had low RA disease activity, respectively; lymphadenopathy and extranodal involvement were present in 77.1% and 51.9%, respectively. Major extranodal sites were the lungs and oral/oropharyngeal mucosa. The most common LPD pathological subtype was diffuse large B-cell lymphoma (40.5%), followed by classic Hodgkin lymphoma (10.8%), Epstein-Barr virus-positive mucocutaneous ulcer (7.7%), and reactive lymphoid hyperplasia (6.2%). The clinical and laboratory characteristics varied across the pathological subtypes. LPD occurred mainly in methotrexate users, while RA disease activity did not seem to be associated with LPD development. Although the clinical manifestations vary among pathological subtypes, manifestations of LPD in patients with RA can include lymphadenopathy, extranodal mass, and mucocutaneous ulcer.

Choriocarcinoma in Cesarean Scar Site: A Case Report

Background & aim: Cesarean scar pregnancy is an ectopic pregnancy implanted in the myometrium at the site of a previous cesarean section scar and is the rarest kind of ectopic pregnancy. The present study present a case of choriocarcinoma (CC) in the cesarean scar. The clinical course, findings, and treatment plan are discussed. Case report: A 41-years old multi-gravid woman with a history of one previous cesarean section and three subsequent abortions was admitted to the hospital. She suffered from an unknown abnormal vaginal bleeding for two months. Β-HCG titer was 1,000 IU/L and the report of sonography showed no gestational sac. Accordingly, the patient was diagnosed with ectopic pregnancy in the cesarean scar site and, therefore, weekly usage of methotrexate was prescribed for her. Since she did not respond to the treatment, she was referred to our department in the Faculty of Medicine. The evaluation showed mass invasion through the entire uterine wall. The uterus preservation was not possible, therefore, total hysterectomy was performed. The pathology report confirmed CC in the cesarean scar. Conclusion: Based on previous studies, as the number of cesarean sections increases, the possibility of complications rises, as well. Cesarean scars implantation of CC is one of the rare complications of caesarean section. The probability of a gestational trophoblastic disease should be considered in any woman during her pregnancy. Early detection and proper management of the complications can result in a decrease in morbidity and mortality.

Hyaluronic Acid-Coated MTX-PEI Nanoparticles for Targeted Rheumatoid Arthritis Therapy

Methotrexate (MTX) is an anchor drug for the treatment of rheumatoid arthritis (RA); however, long-term and high-dose usage of MTX for patients can cause many side effects and toxic reactions. To address these difficulties, selectively delivering MTX to the inflammatory site of a joint is promising in the treatment of RA. In this study, we prepared MTX-PEI@HA nanoparticles (NPs), composed of hyaluronic acid (HA) as the hydrophilic negative electrical shell, and MTX-linked branched polyethyleneimine (MTX-PEI) NPs as the core. MTX-PEI@HA NPs were prepared in the water phase by a one-pot method. The polymeric NPs were selectively internalized via CD44 receptor-mediated endocytosis in the activated macrophages. In the in vivo mice mode study, treatment with MTX-PEI@HA NPs mitigated inflammatory arthritis with notable safety at a high dose of MTX. We highlight the distinct advantages of aqueous-synthesized NPs coated with HA for arthritis-selective targeted delivery, thus verifying MTX-PEI@HA NPs as a promising MTX-based nanoplatform for treatment of RA.

Oral Methotrexate Monotherapy for Severe Alopecia Areata: A Single Center Retrospective Case Series.

Although several therapeutic options have been suggested for alopecia areata (AA), none of them are consistently effective, thus making the management of severe or refractory cases challenging. Several studies have recently reported the usage of methotrexate (MTX) in AA; however, the pure effect of MTX monotherapy remains elusive. To evaluate efficacy and safety of oral methotrexate monotherapy for AA. We retrospectively reviewed the clinical course of AA patients including pediatric cases treated with MTX monotherapy. Their detailed clinical data including original severity of AA, final treatment outcome, the duration until the maximum response, and side effects, were assessed. Statistical analysis was performed to evaluate if the clinical factors including the duration of current alopecia, age, the presence of body hair loss, and sex were associated with treatment response. All included patients had severe AA and failed standard therapies. Thirteen out of 15 cases demonstrated improvement during the monotherapy, and all responders demonstrated the maximum response within 1 year. Female patients had significantly better outcomes than male patients. Other factors did not significantly influence on the treatment outcome. None of the patients experienced side effects that were severe enough to terminate the treatment. Our results support MTX monotherapy as a feasible option for severe AA patients who fail other standard therapies or for whom systemic corticosteroids are contraindicated.

Patients with rheumatoid arthritis have impaired long-term outcomes after myocardial infarction: a nationwide case-control registry study.

ObjectiveTo investigate the long-term outcomes of patients with RA after myocardial infarction (MI).MethodsAll-comer, real-life MI patients with RA (n = 1614, mean age 74 years) were retrospectively compared with propensity score (1:5) matched MI patients without RA (n = 8070) in a multicentre, nationwide, cohort register study in Finland. The impact of RA duration and the usage of corticosteroids and antirheumatic drugs on RA patients’ outcomes were also studied. The median follow-up was 7.3 years.ResultsRA was associated with an increased 14-year mortality risk after MI compared with patients without RA [80.4% vs 72.3%; hazard ratio (HR) 1.25; CI: 1.16, 1.35; P <0.0001]. Patients with RA were at higher risk of new MI (HR 1.22; CI: 1.09, 1.36; P =0.0001) and revascularization (HR 1.28; CI: 1.10, 1.49; P =0.002) after discharge from index MI. Cumulative stroke rate after MI did not differ between RA and non-RA patients (P =0.322). RA duration and corticosteroid usage before MI, but not use of methotrexate or biologic antirheumatic drugs, were independently associated with higher mortality (P <0.001) and new MI (P =0.009). A higher dosage of corticosteroids prior to MI was independently associated with higher long-term mortality (P =0.002) and methotrexate usage with lower stroke rate (P =0.034). Serological status of RA was not associated with outcomes.ConclusionRA is independently associated with poorer prognosis after MI. RA duration and corticosteroid usage and dosage were independent predictors of mortality after MI in RA. Special attention is needed for improvement of outcomes after MI in this vulnerable population.

A Systematic Review of Vaccinations in Methotrexate Users

With several COVID-19 vaccines now available, many questions regarding immunization within patients on immune modifying agents have been surfacing. One critical question is what effect methotrexate (MTX), a known inhibitor of antibody formation, may have on vaccine response during the pandemic. In particular, does holding methotrexate during the vaccination period have improved outcomes on vaccine response? A systematic review was conducted of previous randomized controlled trials and clinical trials of vaccine studies for methotrexate use. Studies were limited to the adult population and to those with autoimmune rheumatic conditions. 29 studies were included for review. There was heterogeneity in vaccinations used including pneumococcal, influenza (H1N1, H3N2, and various B strains), tetanus toxoid, hepatitis A, and varicella zoster. Measurement of vaccine response was non-uniform among the studies. Methotrexate dosing in some studies was not reported, and in many studies was variable. 82.8% of the studies demonstrated methotrexate users were able to meet the study defined vaccine response in the majority of methotrexate users in at least 1 endpoint. Two studies examined vaccine disruption for influenza vaccines and demonstrated improved vaccine response to methotrexate users who discontinued therapy. Dosing of methotrexate was identified in 3 studies as having an impact on vaccine response. Based off review of previous vaccine literature, a temporary hold of methotrexate in the post vaccination period may be a reasonable option to try boost the immune response to a novel vaccine.

Risk of haematological events and preventive effect of folic acid in methotrexate users with chronic kidney disease and rheumatoid arthritis: Analysis of the Japanese Adverse Drug Event Report database.

Although methotrexate (MTX) for rheumatoid arthritis (RA) sometimes causes severe haematological toxicities in users with chronic kidney disease (CKD), data are limited regarding the risk of these events and the preventive effect of folic acid. This study evaluated the risk of haematological toxicities and the efficacy of folic acid in MTX users with CKD using the Japanese Adverse Drug Event Report. In total, 5,648 oral MTX users with RA were identified, including 630 with haematological toxicities. MTX users with CKD had significantly increased risk of haematological toxicities compared with those without CKD when folic acid was not used (OR 3.72; 95% CI 2.87-4.81; P < 0.01). Multivariate logistic analysis showed that the risk of haematological toxicities was significantly decreased by only folic acid (OR 0.16; 95% CI 0.04-0.62; P < 0.01). This result provides useful information for preventing severe haematological toxicities in MTX users with CKD and RA.