Use Of MTX Research Articles

Drug-drug interaction assessment based on a large-scale spontaneous reporting system for hepato- and renal-toxicity, and thrombocytopenia with concomitant low-dose methotrexate and analgesics use

BackgroundMethotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment and is highly effective with low-dose intermittent administration. MTX is occasionally used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (APAP)/paracetamol for pain or inflammation control. With MTX treatment, the side effects, such as hepatotoxicity, renal failure, and myelosuppression should be considered. These are also seen with analgesics treatment.MethodsWe used a large spontaneously reported adverse event database (FAERS [JAPIC AERS]) to analyze whether the reporting of adverse events increased upon MTX and analgesic therapy in patients with RA.ResultsAfter identifying RA cases, the crude reporting odds ratios (cRORs) for hepatotoxicity, renal failure, and thrombocytopenia associated with the use of MTX, APAP, or NSAIDs were calculated by disproportionality analysis, which revealed significantly higher cRORs for these events. No analgesics showed consistent positive signals for drug-drug interaction (DDI) with concomitant low-dose MTX analyzed using four algorithms for DDI interaction (the Ω shrinkage measure, additive or multiplicative, and combination risk ratio models). However, in renal failure and thrombocytopenia, loxoprofen (Ω025 = 0.08) and piroxicam (Ω025 = 0.46), and ibuprofen (Ω025 = 0.74) and ketorolac (Ω025 = 3.52), respectively, showed positive signals in the Ω shrinkage measure model, and no consistency was found among adverse events or NSAIDs.ConclusionsStudies using spontaneous reporting systems have limitations such as reporting bias or lack of patient background; however, the results of our comprehensive analysis support the results of previous clinical or epidemiological studies. This study also demonstrated the usefulness of FAERS for DDI assessment.

E008 I feel a bit happier about going on it now: exploring the information needs of people starting methotrexate

Abstract Background/Aims Methotrexate (MTX) is recommended as initial disease-modifying anti-rheumatic drug (DMARD) therapy for people with rheumatoid arthritis (RA). Rheumatology nurses provide information about benefits, risks and safety monitoring requirements for methotrexate during DMARD counselling, which may be provided in different formats. This study sought to explore the information needs and experiences of people with RA commencing MTX. Methods Seventy-six adults with RA referred for MTX DMARD counselling attending two rheumatology units in the West Midlands were invited to take part in qualitative semi-structured interviews (either by phone or video) before and after receiving information about MTX. Research partners with RA helped to develop interview topic guides. Interviews were digitally recorded, transcribed and analysed using reflexive thematic analysis. Results Nineteen participants, (11 male, 8 female, White British, age 45-76 years, disease duration 6 weeks - 35 years) took part in telephone (n17) or video (n2) interviews (duration 34-82 minutes). Three main themes were identified: information delivery, necessity of MTX and concerns about MTX. Information delivery: most participants received telephone DMARD counselling which was helpful for people with mobility issues or work commitments. However, most acknowledged a preference for, and the importance of face-to-face communication. Information tended to be provided in a generic manner, using a checklist, and could feel rushed. Written MTX leaflets were received but not used by all participants. Some participants felt well informed whilst others felt overwhelmed with information. Many had difficulty recalling important safety information. Unmet information needs about monitoring, prescribing and follow-up arrangements were frequently reported. Inconsistent information about MTX from different sources could increase concerns. Rheumatology helplines were valued as a direct route to information and care. Necessity of MTX: most participants wanted more information on why they should take MTX, how and when MTX would help them and how long they would be required to take MTX for. Some wanted to know about other drug treatment options. Concerns about MTX: all participants had concerns about the likelihood and severity of side-effects including mouth ulcers, nausea and hair loss. Worries about the use of MTX as a cancer treatment were frequently reported. Whilst concerns remained about MTX most participants accepted the risk of side-effects because of the need to improve their symptoms. Conclusion DMARD counselling was valued by people with RA when starting MTX but was not always responsive to information needs. Addressing individual concerns about the necessity for MTX, concerns about side-effects and prioritising essential safety information is recommended. Practical issues around obtaining supplies of MTX, monitoring, follow-up arrangements and a follow-up telephone call may help address unmet information needs for some. Disclosure S.J. Logan: None. S. Hider: None. J. Green: None. S. Ryan: None.

RHEUMATOID ARTHRITIS TREATED WITH DMARDS AND CARDIOVASCULAR DISEASE RISK

Rheumatoid arthritis (RA) is a disease characterized by joint inflammation and an increased risk of cardiovascular diseases (CVDs). This study examines possible associations between cardiovascular disease and the utilisation of conventional disease-modifying anti-rheumatic drugs (DMARDs) in patients with RA. MTX and SSZ with the latter to lesser extent were associated with a significant reduced risk of CVD than patients with RA who never used either of the drugs or combinations. This study suggests that the use of DMARD, in particular the use of MTX, results in potent suppression of joint inflammation. It also can reduce the development of atherosclerosis and associated CVDs.

Use of methotrexate and risk of skin cancer: a nationwide case–control study

BackgroundMethotrexate (MTX) use has been suspected of increasing the risk of skin cancer. The aim of this investigation was to examine the association between the use of MTX and the risk of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC) and cutaneous malignant melanoma (CMM).MethodsIn a nationwide Danish case–control study, we identified incident, histologically verified cases of BCC (n = 131,447), cSCC (n = 18,661) or CMM (26,068) from 2004 to 2018. We matched 10 controls to each case on sex and birth year using risk-set sampling and computed crude and adjusted odds ratios (ORs) using conditional logistic regression for the use of MTX (≥2.5 g) compared with never-use.ResultsUse of MTX was associated with increased risk of BCC, cSCC and CMM with adjusted ORs of (95% confidence interval) 1.29 (1.20–1.38), 1.61 (1.37–1.89) and 1.35 (1.13–1.61), respectively. For BCC and cSCC, ORs increased with higher cumulative doses. When restricting the study population to patients with psoriasis, the ORs were 1.43 (1.23–1.67), 1.18 (0.80–1.74) and 1.15 (0.77–1.72), respectively.ConclusionsWe observed an increased risk of BCC and cSCC associated with the use of MTX with evidence of a dose–response pattern; however, the association was not consistent when restricting the study population to patients with psoriasis.

Intraocular Methotrexate for the Treatment and Prevention of Proliferative Vitreoretinopathy: A Review.

To review the current literature on the use of intravitreal methotrexate (IVT MTX) for the treatment and prevention of proliferative vitreoretinopathy (PVR). All reports of IVT MTX to treat and prevent PVR published in PubMed, Google Scholar, and EBSCOhost were reviewed. The relevant current studies are included in this report. The literature search yielded 32 articles describing the use of MTX in PVR. These included preclinical studies, 1 case report, and several case series. Early studies found that IVT MTX is a promising medication for the treatment and prevention of PVR. MTX works as a potent anti-inflammatory agent through a new mechanism of action different from that of other medications for use in PVR. Few side effects have been reported and were mostly limited to mild reversible corneal keratopathy. There are 2 current ongoing randomized controlled clinical trials to further evaluate the efficacy of MTX for PVR. MTX is a safe and potentially efficacious medication for the treatment and prevention of PVR. Additional clinical trials are needed to further establish this effect.

Methotrexate, leflunomide and tacrolimus use and the progression of rheumatoid arthritis-associated interstitial lung disease.

To examine the association between MTX, LEF and tacrolimus use and the progression of RA-associated interstitial lung disease (ILD). The Korean RA-ILD cohort prospectively enrolled patients with RA-associated ILD at multiple centres from 2015 to 2018 and followed up with them for 3 years. ILD progression was defined by any of the followings: a decrease of ≥10% in forced vital capacity, a decrease of ≥15% in the diffusing capacity of the lung for carbon monoxide, or death from respiratory failure. Of 143 patients, 64 patients experienced ILD progression during a median follow-up period of 33 months. The use of MTX [adjusted hazard ratio (aHR), 1.06; 95% CI, 0.59, 1.89], LEF (aHR, 1.75; 95% CI, 0.88, 3.46) and tacrolimus (aHR, 0.94; 95% CI, 0.52, 1.72) did not increase the risk of ILD progression. However, the association between LEF use and the risk of ILD progression was significant in subgroups with poor lung function (aHR, 8.42; 95% CI, 2.61, 27.15). Older age, male sex, a shorter RA duration, higher RA disease activity and extensive disease at baseline were independently associated with ILD progression. None of the three treatments increased the risk of RA-associated ILD progression, except for LEF, which increased the risk of ILD progression in patients with severe ILD. The appropriate use of conventional synthetic disease-modifying antirheumatic drugs considering RA disease activity and ILD severity would be important for the management of RA-associated ILD.

Medicatiefouten met methotrexaat: casuïstiek en opportuniteiten door de bril van de ziekenhuisapotheker

Medication errors with methotrexate: new insights into an old drug Methotrexate (MTX) was first used in 1948 to treat childhood leukaemia. Nowadays, it is used for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), psoriasis, psoriatic arthritis and inflammatory bowel disease. MTX is a folic acid antagonist that binds dihydrofolate reductase and thereby inhibits the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and proteins. As an incontestable cornerstone in the treatment of RA, MTX should be started as soon as RA is diagnosed. The primary goal of the treatment is rapid and effective disease control to prevent long-term damage to the joints. For the treatment of patients with RA, the usual starting dose of MTX is 7.5-10 mg per week. Based on the clinical response, the dose could be increased to reach the optimal dose. The most common adverse drug events of MTX therapy are gastro-intestinal intolerance, haematological abnormalities, alopecia, hepatotoxicity and pulmonary toxicity. Overall, MTX is well tolerated. However, fatal cases of MTX intoxication have been reported in literature, mainly due to the daily intake and thus overdose of MTX. Despite the widespread experience with MTX, medication errors still occur with a risk of potentially severe adverse drug events. Clinical pharmacy interventions aim to detect these medication errors in inpatients. Based on a case series within a hospital population, the most common medication errors with MTX are presented. Subsequently, specific interventions to optimize medication safety with MTX therapy are described. The implementation of a specific chemotherapy module in the computerized physician order entry and clinical pharmacy interventions, such as medication reconciliation, the engagement of clinical pharmacists on hospital wards as part of the interdisciplinary team and prescription validation based on clinical rules, can contribute to a safer use of MTX.

Comparing Canadian paediatric rheumatology practice to the 2019 ACR Juvenile Idiopathic Arthritis guidelines: results from the CAPRI Registry.

To identify differences between baseline Canadian JIA practices and the 2019 ACR guidelines for JIA. Canadian paediatric rheumatologists were surveyed for their opinions on reasonable a priori target adherence rates for JIA guideline recommendations. Prospectively collected data for 266 newly diagnosed children from 2017 to 2019 were analysed to calculate observed adherence rates. Kaplan-Meier survival curves were used to estimate the cumulative incidence of starting synthetic or biologic DMARDs (sDMARD or bDMARD, respectively) for different patient groups. A total of 25/61 (41%) eligible physicians answered the survey. Most survey respondents (64%) felt that adherence targets should vary depending on the strength of the recommendation and quality of evidence, from a mean of 84% for strong recommendations with high-quality evidence to 29% for conditional recommendations with very low-quality evidence. Data showed 13/19 (68%) recommendations would have met proposed targets and 10/19 (53%) had ≥80% observed adherence. Exceptions were the use of subcutaneous vs oral MTX (53%) and infrequent treatment escalation from NSAIDs to bDMARDs in patients with sacroiliitis (31%) or enthesitis (0%). By 12 weeks, 95% of patients with polyarthritis received sDMARDs, 38% of patients with systemic JIA received bDMARDs and 22% of patients with sacroiliitis received bDMARDs. Canadian paediatric rheumatology practices were in line with many 2019 JIA guideline recommendations before their publication, except for frequent use of oral MTX and infrequent direct escalation from NSAIDs to bDMARDs in sacroiliitis and enthesitis.

МІСЦЕ ЛЕФЛУНОМІДА В ХВОРОБОМОДИФІКУЮЧІЙ ТЕРАПІЇ РЕВМАТОЇДНОГО АРТРИТУ: НОВІ АКЦЕНТИ

A new mechanism of lefl unomide (LEF) action was recently discovered, namely its ability to infl uence the intracellular mechanism of the infl ammatory process by inhibiting JAK kinases, which brings it closer to the new most eff ective group for treatment of rheumatoid arthritis (RA) – Janus kinase inhibitors. The article presents data from both our own and other authors’ studies on the eff ectiveness and safety of the drug in comparison with other synthetic and biological basic agents. The aim of our study was a comparative evaluation of LEF, methotrex- ate (MTX), sulfasalazine (SS) and their combinations (CDT) in 402 patients with RA. Obtained results showed advantages of LEF and СDT over the use of SS (at any RA duration) and MTX (at late RA). Adverse events were the lowest in the SS group, and disease-modifying anti-rheumatic drug (DMARD) discontinuation due to complications was the lowest in the LEF group. Based on the results of multifactor regression analysis, we developed a scheme of individualized selection of the most eff ective DMARD depending on the initial characteristics of RA patients. The article also presents international study data. It analyses the comparative effi cacy of LEF (10-20 mg/d) and low doses of rituximab (500 mg twice daily) in patients refractory to MTX therapy; effi cacy of LEF in monotherapy (5-40 mg/d) and combination with other DMARD; LEF at a dose of 100 mg/week and MTX at a dose of 10 mg/week; LEF at a dose of 50 mg once a week and 10 mg daily. The eff ect of LEF on uric acid levels and bone mineral density of the lumbar spine in patients with RA was studied.

Real-world evidence on methotrexate-free subcutaneous tocilizumab therapy in patients with rheumatoid arthritis: 24-week data from the SIMPACT study.

ObjectivesThe aim of the SIMPACT study was to evaluate the efficacy and safety of MTX-free s.c. tocilizumab (TCZ) therapy in RA patients.MethodsSIMPACT was an open-label, non-controlled, non-randomized, non-interventional study, in which RA patients for whom the treating physicians ordered s.c. TCZ were observed during a 24-week treatment period in Hungarian centres. Although the use of MTX was avoided during the study period, other conventional synthetic DMARDs, oral CSs and NSAIDs were allowed. Study endpoints included the change in DAS28 and clinical activity index (CDAI) scores, the proportion of patients achieving remission in the whole population and in subgroups defined based on prior RA treatment history, and age, weight or biological sex post hoc. The extent of supplementary medication use was monitored.ResultsThree hundred and thirty-seven RA patients were enrolled in 18 study centres. TCZ therapy significantly decreased the disease activity measured by both DAS28 (P = 0.0001) and CDAI (P = 0.0001). Clinical response was more pronounced in biologic-naïve patients and was lower in patients >75 years of age. In the whole population, DAS28 ESR or CRP and CDAI remission rates were 70.10%, 78.95% and 33.59%, respectively. In patients <45 years of age, the CDAI remission rate doubled (67.86%). A significant decrease in the frequency of co-administered medication was reported, including oral CSs and DMARDs.ConclusionReal-world clinical evidence on s.c. TCZ reported here is in line with the efficacy outcomes of randomized clinical trials. Subgroup analysis revealed that TCZ was more effective in biologic-naïve patients and in those <75 years old.Trial registrationClinicalTrials.gov, http://www.clinicaltrials.gov, NCT02402686.

Risk of New-Onset Diabetes Mellitus Associated with Antirheumatic Drugs in Patients with Rheumatoid Arthritis: A Nationwide Population Study.

Background: This study aimed to investigate the effect of disease-modifying antirheumatic drugs (DMARDs) on diabetes mellitus (DM) development in rheumatoid arthritis (RA). Methods: This nested case–control study with a cohort of 69,779 DM-naïve adult patients with RA was conducted from 2011 to 2019 in South Korea. Cases with incident DM were identified and individually matched to randomly selected controls (1:4). DMARDs use was measured for 1 year before the index date and stratified by exposure duration. The association of each DMARD use with DM risk was estimated using conditional logistic regression adjusted for comorbidities and concomitant drug use. Results: Of the patients, 5.4% were newly diagnosed with DM. The use of statins and a higher cumulative dose of corticosteroids were associated with an increased DM risk. In a multivariable-adjusted analysis, cumulative duration of exposure (CDE) >270 days/year, hydroxychloroquine (HCQ; adjusted odds ratio [aOR], 0.76) and methotrexate (MTX; aOR, 0.81) were associated with a significant decrease in DM risk, and tacrolimus (TAC; aOR, 1.27) was associated with an increased risk. Conclusions: Long-term use of HCQ and MTX (>270 days/year) was associated with a reduction in DM incidence as opposed to TAC.

Immunogenicity of subcutaneous TNF inhibitors and its clinical significance in real-life setting in patients with spondyloarthritis

Key messagesConsiderable proportion of patients with SpA have been immunized to the subcutaneous anti-TNF drug they are using. Concomitant use of MTX protects from immunization, whereas SASP does not. Patients with SpA using subcutaneous anti-TNF drugs can benefit from monitoring of the drug trough levels.Immunization to biological drugs can lead to decreased efficacy and increased risk of adverse effects. The objective of this cross-sectional study was to assess the extent and significance of immunization to subcutaneous tumor necrosis factor (TNF) inhibitors in axial spondyloarthritis (axSpA) patients in real-life setting. A serum sample was taken 1–2 days before the next drug injection. Drug trough concentrations, anti-drug antibodies (ADAb) and TNF-blocking capacity were measured in 273 patients with axSpA using subcutaneous anti-TNF drugs. The clinical activity of SpA was assessed using the Bath AS Disease Activity Index (BASDAI) and the Maastricht AS Entheses Score (MASES). ADAb were found in 11% of the 273 patients: in 21/99 (21%) of patients who used adalimumab, in 0/83 (0%) of those who used etanercept, in 2/79 (3%) of those who used golimumab and in 6/12 (50%) of those who used certolizumab pegol. Use of methotrexate reduced the risk of formation of ADAb, whereas sulfasalazine did not. Presence of ADAb resulted in decreased drug concentration and reduced TNF-blocking capacity. However, low levels of ADAb had no effect on TNF-blocking capacity and did not correlate with disease activity. The drug trough levels were below the consensus target level in 36% of the patients. High BMI correlated with low drug trough concentration. Patients with low drug trough levels had higher disease activity. The presence of anti-drug antibodies was associated with reduced drug trough levels, and the patients with low drug trough levels had higher disease activity. The drug trough levels were below target level in significant proportion of patients and, thus, measuring the drug concentration and ADAb could help to optimize the treatment in SpA patients.

Methotrexate Reduces the Probability of Discontinuation of TNF Inhibitors in Seropositive Patients With Rheumatoid Arthritis. A Real-World Data Analysis

Tumor necrosis factor inhibitors (TNFi) are widely used for the treatment of patients with rheumatoid arthritis (RA), however a considerable percentage of patients discontinued the therapy. The aim of this study is to explore real-world TNFi survival, stratified for seropositivity, and to determine the factors that may influence it. This is a retrospective, observational and longitudinal study, using real-world data of patients, who started their first TNFi therapy between 1999 and 2018 from the RA-PAZ cohort. Patients were considered seropositive if they showed positive serum levels of either RF, ACPA, or both. Treatment survival was analyzed using Kaplan-Meier curves, and Cox proportional hazards models were used to compare the risks of TNFi discontinuation for seronegative and seropositive patients. Of the included 250 patients, 213 (85%) were seropositive. Results showed that TNFi survival did not depend on seropositivity status. However, median survival time was significant longer for seropositive patients who received concomitant MTX compared to patients who did not receive it (median [95% CI]: 3.3 yr. [2.3–4.2] vs. 2.6 yr. [1.7–3.6], respectively; p = 0.008). Furthermore, seropositive patients who received concomitant MTX were 49% less likely to discontinue TNFi therapy than patients who did not receive it (HR: 0.51; 95% CI: 0.35–0.74). In addition, we found that in seropositive patients, the use of prednisone throughout the TNFi treatment was associated with a higher likelihood of therapy discontinuation (OR: 2.30; 95% CI: 1.01–5.23). In conclusion, these data provide evidence to support the use of concomitant MTX in seropositive patients to prolong the effectiveness and the survival of the TNFi therapy. Moreover, the co-administration of prednisone in seropositive patients receiving TNFi was highly associated with TNFi discontinuation.

Benefits of Methotrexate Use on Cardiovascular Disease Risk Among Rheumatoid Arthritis Patients Initiating Biologic Disease-modifying Antirheumatic Drugs.

Methotrexate (MTX) has been associated with reduced risk for cardiovascular disease (CVD) events among patients with rheumatoid arthritis (RA) not exposed to biologic disease-modifying antirheumatic drugs (bDMARDs). The effect of concomitant MTX on CVD risk among RA patients initiating bDMARDs remains unknown. A retrospective cohort study was conducted to assess the effect of MTX on CVD risk using 2006-2015 Medicare claims data for patients with RA initiating bDMARD. The main exposure was current use of MTX, updated in a time-varying fashion. The primary outcome was a composite of incident myocardial infarction (MI), stroke, and fatal CVD. Secondary outcomes were each event that comprised the primary outcome. Incidence rates (IR) and 95% CI were calculated using Poisson regression. Associations between MTX and risk of CVD were assessed using Cox regression. A total of 88,255 bDMARD initiations and 1861 CVD events were included in this study. Mean age was 64.6 (12.3) years, 84.0% were female, and 68.2% were non-Hispanic White. The crude IRs (95% CI) for CVD were 17.9 (16.9-18.8) and 12.1 (11.1-13.2) per 1000 patient-years among MTX unexposed and exposed, respectively. The multivariable adjusted HR (95% CI) for CVD events associated with MTX was 0.76 (0.68-0.85). Multivariable adjusted HRs were 0.78 (0.66-0.91), 0.74 (0.62-0.88), 0.77 (0.68-0.86), and 0.82 (0.73-0.93) for MI, stroke, MI or stroke, and a composite CVD outcome, respectively. Results were robust in sensitivity and subgroup analyses. Among patients with RA receiving biologics, concomitant MTX use was associated with a 24% lower risk for CVD events.

High frequency of methotrexate intolerance in longstanding rheumatoid arthritis: using the methotrexate intolerance severity score (MISS)

BackgroundMethotrexate (MTX) intolerance is frequent, and its early identification may impact treatment, leading to timely changes in medication that may promote patient compliance and better control of rheumatoid arthritis (RA). The objective of this study was to identify the frequency of, and risk factors for, MTX intolerance using the Brazilian Portuguese version of the Methotrexate Intolerance Severity Score (MISS) questionnaire in patients with RA.MethodsThis cross-sectional study was performed between April 2018 and April 2019 and enrolled patients with RA in regular use of oral or subcutaneous MTX for at least 3 months. Patients were invited to answer the Brazilian Portuguese version of the MISS questionnaire, and MTX intolerance was defined by a score ≥ 6 points. Age, sex, disease duration, time of MTX use, dose, route of administration, concomitant medications, comorbidities, smoking, and Disease Activity Score for 28joint (DAS28) data were collected from institutional medical records.ResultsAmong 120 patients, 103 (85.8%) were female, the mean age was 61 (±12.5) years, the mean duration of disease was 16 (±10.3) years, and the average duration of MTX use was 7 (±5.5) years. The frequency of MTX intolerance was 21.6%. The most frequent symptoms reported after the use of MTX were nausea (92.3%), abdominal pain (46.1%), and vomiting (30.7%). Behavioral symptoms occurred in 96.1% of patients with MTX intolerance, the most frequent being restlessness and irritability. Patients who used corticosteroids were more likely to develop MTX intolerance than those not using corticosteroids (odds ratio = 2.73; 95% confidence interval, 1.06 to 7.06; p = 0.038). Conversely, increasing age showed marginally significant association with decreased risk of MTX intolerance (p = 0.059).ConclusionsThe use of the MISS questionnaire disclosed high frequencies of anticipatory, associative, and behavioral symptoms in MTX-intolerant patients, and the use of corticosteroid increases the risk of MTX intolerance. We suggest that the MISS questionnaire be used routinely in clinical practice.

First-line csDMARD monotherapy drug retention in psoriatic arthritis: methotrexate outperforms sulfasalazine

ObjectivesConventional synthetic DMARDs (csDMARDs) are the first-line treatment for PsA, but there is conflicting data regarding their efficacy and scarce reports describing the duration of use (drug retention) of csDMARD in this population. Their position in treatment recommendations is a matter of growing debate due to the availability of alternative treatment options with higher levels of evidence. We aimed to study drug retention and predictors for drug retention among PsA patients receiving first-line csDMARD monotherapy.MethodsRetrospective cohort study in DMARD-naïve adult PsA patients in whom a first csDMARD was prescribed as monotherapy primarily to treat PsA-related symptoms. The main outcome was time to failure of the csDMARD (i.e. stopping the csDMARD or adding another DMARD).ResultsA total of 187 patients were included, who were mainly prescribed MTX (n = 163) or SSZ (n = 21). The pooled median drug retention time was 31.8 months (interquartile range 9.04–110). Drug retention was significantly higher in MTX (median 34.5 months; interquartile range 9.60–123) as compared with SSZ-treated patients (median 12.0 months; interquartile range 4.80– 55.7) (P =0.016, log-rank test). In multivariable Cox regression, the use of MTX and older age were associated with increased retention. The main reasons for treatment failure were inefficacy (52%) and side effects (28%). Upon failure, MTX treated patients were more commonly, subsequently treated with a biologic DMARD compared with SSZ (P < 0.05).ConclusionMTX outperforms SSZ as a first-line csDMARD in DMARD-naïve PsA patients with respect to monotherapy drug retention in daily clinical practice.

Pre-operative withholding of infliximab and the risk of infections after major surgery in patients with rheumatoid arthritis.

Withholding TNF inhibitors (TNFI) before surgery has been recommended due to concern for post-operative infection. We examined the risks of post-operative infections and mortality in patients with RA in relation to the pre-operative timing of infliximab infusion. In this population-based retrospective cohort study, we used US Medicare claims data from 2007 to 2015 to identify patients with RA who underwent coronary artery bypass grafting (CABG), aortic or vascular surgery, or bowel resection, and who were treated with infliximab in the 90 days prior to surgery. We examined associations between the timing of infusion and infections and mortality in the 30 days after surgery. We adjusted for the predicted probability of post-operative infection or death, demographic characteristics, use of MTX, post-operative blood transfusion and hospital volume. We studied 712 patients with CABG, 244 patients with vascular surgery and 862 patients with bowel resections. Post-operative pneumonia occurred in 7.4-11.9%, urinary tract infection in 9.0-15.2%, surgical site infection in 3.2-18.9%, sepsis in 4.2-9.6% and death in 3.5-7.0% among surgery cohorts. There was no association between the time from last infliximab dose to surgery and the risk of post-operative infection or mortality in any surgical cohort. No subgroups were identified that had an increased risk of infection with more proximate use of infliximab. Among elderly patients with RA, risks of infection and mortality after major surgery were not related to the pre-operative timing of infliximab infusion.

The Effect of Folinic Acid (FA) Rescue Following MTX Gvhd Prophylaxis on Regimen Related Toxicity and Transplantation Outcome: A Double Blind Randomized Controlled Study

<h3>Background</h3> The use of MTX for GVHD prophylaxis is associated with increased rates of oral mucositis (OM), delayed engraftment, hepatotoxicity and nephrotoxicity. Based on limited data, the EBMT and ELN working group recommend the use of FA-rescue to reduce MTX toxicity after alloHCT. We aimed to determine whether FA-rescue reduces the rate of MTX-induced toxicity in patients who receive post-transplant MTX for GVHD prophylaxis. <h3>Methods</h3> This is a double blind RCT conducted in 3 centers. We enrolled patients undergoing alloHCT from MSD or MUDs with a MAC regimen and PBSC grafts, and GVHD prophylaxis consisting CSA/MTX, plus ATG for MUDs. Patients were randomized to oral FA or placebo, stratified by center and conditioning intensity (standard <i>vs.</i> reduced toxicity MAC). FA administration started 24h after each MTX dose: 15 mg TID after MTX administration on day +1 and QID after MTX administration on days +3 and +6. The primary endpoint was the rate of grade 3-4 OM according to the WHO scale. A sample size of 58 subjects in each group was estimated to detect a difference in grade 3-4 OM of 50% <i>vs.</i> 25%. <h3>Results</h3> From 2/2016 through 7/2019, 52 patients with acute leukemia in CR (n = 45), MDS (n=6) or NHL in CR (n=1) were randomized to FA (n=28) or placebo (n=24). Patient characteristics were similar between groups (table). After enrolment of 52 patients, interim analysis revealed that the rate (46.6% <i>vs.</i> 45.8%, P=0.97) and duration (4 <i>vs.</i> 4 days) of grade 3-4 OM and the rate of OM of any severity (83.3% <i>vs.</i> 77.8%, P=0.65) were similar in both groups. Also, time to neutrophil and platelet engraftment, rates of febrile neutropenia and blood stream infections, VOD, need for opiates or TPN and time from HCT to discharge were not significantly different between groups. With a median follow-up of 9 months we did not observe any difference in rates of acute or chronic GVHD, DFS and OS. <h3>Conclusions</h3> The interim results, showing similar rates of grade 3-4 OM and secondary outcomes, do not support continuation of the study. FA-rescue following MTX GVHD prophylaxis does not seem to decrease regimen related toxicity and affect transplant outcomes.

Multicenter, observational clinical study of abatacept in Japanese patients with rheumatoid arthritis

The aim of this study was to assess abatacept in rheumatoid arthritis (RA) patient. Patients (20 men, 89 women, aged 61.9 ± 10.4 y) who responded inadequately to conventional synthetic disease-modifying anti-rheumatic drug were treated with abatacept for 24-months. Disease activity score in 28 joints (DAS28-CRP) was evaluated. Of 109 patients, 82 (75.2%) were on methotrexate (MTX; mean dosage 9.0 ± 2.7 mg/week); 48 (44.0%) were naive to biologics and 61 (56.0%) had failed biologics. The 1- and 2-year retention rates were 77% and 53%, respectively. At 24-months, the DAS28-CRP remission rates were 62.8% in the biologic-naïve patients, and 33.3% in the biologic-failure patients (p < .01), while the structural remission rates were 83.9% and 73.1%, respectively (p = .461). Abatacept was equally effective in RA patients who were and were not on concomitant MTX. Biologic-naïve was associated with better clinical outcome. Abatacept was effective in patients who showed decreasing anti-CCP antibody titers or serum MMP-3 levels during treatment. Infection was the most frequent adverse effect of abatacept therapy. In conclusion, abatacept is more effective in biologic-naïve than in biologic-failure RA patients with or without concomitant use of MTX. Abatacept is more effective in RA patients with than without decreasing serum MMP-3 or anti-CCP antibody titers during treatment.

Using subcutaneous methotrexate to prolong duration of methotrexate therapy in rheumatoid arthritis.

Our study aims to determine whether the use of subcutaneous methotrexate (SC MTX) is associated with prolonged MTX use and lower incidence of hepatotoxicity in rheumatoid arthritis (RA) patients on MTX monotherapy and multiple drug therapy. We conducted a retrospective cohort study using national databases of a large hospital system. Subjects had been diagnosed with RA and treated with MTX between September 30, 1999, and October 1, 2009. Outcomes of interest were the amount of time on MTX monotherapy or multiple disease-modifying anti-rheumatic drug (DMARD) therapy before addition of additional DMARDs or biologic agents, respectively. We conducted Cox regressions and Kaplan-Meier curves for association between SC MTX use and length of time before therapeutic change. We conducted chi-square tests for association between SC MTX use and elevated liver function tests (LFT). MTX monotherapy: SC MTX was associated with a significantly lower likelihood of therapeutic change (HR 0.64, 95% CI 0.52-0.78). Multiple DMARD therapy: SC MTX was not associated with a lower risk of adding a biologic (HR 1.13, 95% CI 0.97-1.31). Liver enzymes: There was no significant association between use of SC MTX and decreased frequency of abnormal LFTs [p=0.09 for alanine aminotransferase (ALT), p=0.924 for aspartate aminotransferase (AST)]. Use of SC MTX is associated with longer duration of MTX monotherapy before addition of other DMARDs/biologic agents in RA patients. Use of SC MTX is not associated with significantly longer duration of multiple DMARD therapy before addition of biologic agents. Use of oral MTX is not significantly associated with increased frequency of elevated LFTs.