Concurrent Use Of Methotrexate Research Articles

OA02 Real-world experience of dose tapering TNF inhibitors in rheumatoid arthritis: Long-term results

Abstract Background/Aims If sustained disease control is achieved in RA then tapering is supported by recommendations. However, this may cause loss of disease control with subsequent damage. A problem in assessing tapering is the short-term nature of studies. We wanted to explore the long-term use of tapering strategies. Methods Our biologics database has collected information since 2005. Our approach, refined with PPI, for people receiving TNF inhibitors (TNFi) has been to dose taper by one-third and then 50% if remission was achieved (DAS28<2.6 on 2 occasions >6 months apart, no corticosteroids). We initially required absence of power doppler (PD) in the hands (stopped in 2017). Failure of tapering was defined as a flare (DAS28>2.6, PD synovitis or patient-reported) resulting in a return to full dose, stopping the TNFi, or changing to another advanced therapy (bDMARD, tsDMARD). We explored associations between time on dose-reduction therapies and individual characteristics. Results 1180 patients started biological therapies during 2005-2021 with 668 receiving a TNFi. 119 (18%) were dose-tapered by one-third and of these 40 (30%) then by one-half. Over median follow-up of 2.2 years (IQR 0.7,5.9) with maximum follow-up of 8.93 years, tapering failed in 88 (74%). Of those failing, 50% achieved DAS28 remission, 18% low disease activity (LDA), 32% moderate (MDA) and none high (HDA) within 12 months. A Kaplan-Meier plot showed one-third of individuals failed tapering within the first year with two-thirds by 3 years. Logistic regression showed (Table 1) no significant effect of age, sex, time between diagnosis and TNFi, seropositivity, smoking, or DAS28 score. However, there was an association between concomitant use of methotrexate and reduced failure of tapering (HR 0.60 (CI 0.39,0.94) p = 0.03). Conclusion In a real-world setting, tapering is well accepted and occurred in around 20% of individuals. Two-thirds maintain tapering after 1 year with around one-third by 3 years. Predictors of success are limited although concurrent methotrexate use appears associated with continued tapering. However, around a third of patients who fail tapering do not return to remission/LDA when the full dose of TNFi is restarted. Disclosure M. Lwin: None. N. Nooh: None. C.R. Holroyd: Member of speakers’ bureau; Abbvie, BMS, Celltrion, Chugai, Galapagos/Gilead, Janssen, Lilly, Napp, Novartis, Pfizer, Roche and UCB. Other; Sponsorship / advisory board: Abbvie, BMS, Celltrion, Chugai, Galapagos/Gilead, Janssen, Lilly, Napp, Novartis, Pfizer, Roche and UCB. S.X. Lin1: None. D. Culliford: None. S.D. Fraser: None. C.J. Edwards: Member of speakers’ bureau; Abbvie, Astra Zeneca, BMS Celltrion Chugai, Gilead, Galapagos, GSK, Janssen, Eli Lilly, Pfizer, Roche, Sandoz, Samsung. Grants/research support; Abbvie, Astra Zeneca, BMS Celltrion Chugai, Gilead, Galapagos, GSK, Janssen, Eli Lilly, Pfizer, Roche, Sandoz, Samsung. Other; Advisory boards: Abbvie, Astra Zeneca, BMS Celltrion Chugai, Gilead, Galapagos, GSK, Janssen, Eli Lilly, Pfizer, Roche, Sandoz, Samsung.

Psoriasis rate is increased by the exposure to TNF inhibition in children with JIA

ObjectiveWe aimed to investigate the relationship between tumour necrosis factor inhibitors (TNFi) therapy and the onset of new psoriasis in children with juvenile idiopathic arthritis (JIA) using Childhood Arthritis and...

Tofacitinib versus tocilizumab in the treatment of biological-naïve or previous biological-failure patients with methotrexate-refractory active rheumatoid arthritis

ObjectivesTo compare effectiveness between tofacitinib and tocilizumab treatments for biological disease-modifying antirheumatic drug (bDMARD)-naïve patients or previous bDMARD-failure patients with active rheumatoid arthritis (RA) refractory to methotrexate (MTX).MethodsWe used two...

Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only

Treatment with contemporary chemotherapy-only protocols is associated with risk for neurocognitive impairment among survivors of childhood acute lymphoblastic leukemia (ALL). To determine whether concurrent use of methotrexate and glucocorticoids is associated with interference with the antioxidant system of the brain and damage and disruption of glucocorticoid-sensitive regions of the cerebello-thalamo-cortical network. This cross-sectional study was conducted from December 2016 to July 2019 in a single pediatric cancer tertiary care center. Participants included survivors of childhood ALL who were more than 5 years from cancer diagnosis, age 8 years or older, and treated on an institutional chemotherapy-only protocol. Age-matched community members were recruited as a control group. Data were analyzed from August 2017 to August 2020. ALL treatment using chemotherapy-only protocols. This study compared brain volumes between survivors and individuals in a community control group and examined associations among survivors of methotrexate and dexamethasone exposure with neurocognitive outcomes. Functional and effective connectivity measures were compared between survivors with and without cognitive impairment. The Rey-Osterrieth complex figure test, a neurocognitive evaluation in which individuals are asked to copy a figure and then draw the figure from memory, was scored according to published guidelines and transformed into age-adjusted z scores based on nationally representative reference data and used to measure organization and planning deficits. β values for neurocognitive tests represented the amount of change in cerebellar volume or chemotherapy exposure associated with 1 SD change in neurocognitive outcome by z score (mm3/1 SD in z score for cerebellum, mm3/[g×hr/L] for dexamethasone and methotrexate AUC, and mm3/intrathecal count for total intrathecal count). Among 302 eligible individuals, 218 (72%) participated in the study and 176 (58%) had usable magnetic resonance imaging (MRI) results. Among these, 89 (51%) were female participants and the mean (range) age was 6.8 (1-18) years at diagnosis and 14.5 (8-27) years at evaluation. Of 100 community individuals recruited as the control group, 82 had usable MRI results; among these, 35 (43%) were female individuals and the mean (range) age was 13.8 (8-26) years at evaluation. There was no significant difference in total brain volume between survivors and individuals in the control group. Survivors of both sexes showed decreased mean (SD) cerebellar volumes compared with the control population (female: 70 568 [6465] mm3 vs 75 134 [6780] mm3; P < .001; male: 77 335 [6210] mm3 vs 79 020 [7420] mm3; P < .001). In female survivors, decreased cerebellar volume was associated with worse performance in Rey-Osterrieth complex figure test (left cerebellum: β = 55.54; SE = 25.55; P = .03; right cerebellum: β = 52.57; SE = 25.50; P = .04) and poorer dominant-hand motor processing speed (ie, grooved pegboard performance) (left cerebellum: β = 82.71; SE = 31.04; P = .009; right cerebellum: β = 91.06; SE = 30.72; P = .004). In female survivors, increased number of intrathecal treatments (ie, number of separate injections) was also associated with Worse Rey-Osterrieth test performance (β = -0.154; SE = 0.063; P = .02), as was increased dexamethasone exposure (β = -0.0014; SE = 0.0005; P = .01). Executive dysfunction was correlated with increased global efficiency between smaller brain regions (Pearson r = -0.24; P = .01) compared with individuals without dysfunction. Anatomical connectivity showed differences between impaired and nonimpaired survivors. Analysis of variance of effective-connectivity weights identified a significant interaction association (F = 3.99; P = .02) among the direction and strength of connectivity between the cerebellum and DLPFC, female sex, and executive dysfunction. Finally, no effective connectivity was found between the precuneus and DLPFC in female survivors with executive dysfunction. These findings suggest that dexamethasone exposure was associated with smaller cerebello-thalamo-cortical regions in survivors of ALL and that disruption of effective connectivity was associated with impairment of executive function in female survivors.

Adherence, Persistence, and Expenditures for High-Cost Anti-Inflammatory Drugs in Rheumatoid Arthritis: An Exploratory Study.

Drugs for inflammatory conditions are one of the highest expenditure therapeutic classes for health plans. Published literature for adherence, persistence, nonadherence risk factors, and health care costs are incomplete for newer biologic agents. To (a) examine differences in adherence, persistence, switch patterns, and health care costs among high-cost specialty anti-inflammatory medications and (b) suggest risk factors for nonadherence in rheumatoid arthritis. In this exploratory retrospective cohort study, we used medical and pharmacy claims from 1.2 million enrollees in commercial health plans administrated by Premera Blue Cross, the largest not-for-profit health plan in the Pacific Northwest. We included members with rheumatoid arthritis who used the following high-cost disease-modifying antirheumatic drugs: abatacept, adalimumab, anakinra, apremilast, certolizumab, etanercept, golimumab, infliximab, rituximab, sekukinumab, tocilizumab, tofacitinib, and ustekinumab. Adherence was calculated via medication possession ratio. Persistence was calculated as the amount of days between the initial fill and final fill plus days supply. Switch rates for adalimumab and etanercept were calculated as the percentage of members who switched to another target drug during the observation period. Direct medical costs (total health care costs) and health care costs excluding specialty agents were calculated using the net allowable amount per claim for the duration of each therapy. Adherence, persistence, and costs of care were also examined for concurrent methotrexate use for the most used target drugs. The most commonly used drugs were abatacept (n = 47), adalimumab (n = 226), and etanercept (n = 252). Nonadherence in certain subgroups was associated with higher mean monthly health care costs, excluding specialty agents (etanercept cohort: +$1,063 for nonmethotrexate users; +$492 for nonadherent methotrexate users), but adherence was associated with higher total health care costs (+$883 for etanercept). Relative to specialty pharmacies, retail was associated with 9% higher nonadherence. Concurrent methotrexate use was associated with higher persistence (+307 and +192 days with adalimumab and etanercept). The most commonly switched-to drug after adalimumab/etanercept was abatacept (n = 39). This exploratory study raises signals suggesting that retail pharmacies may be associated with higher nonadherence; nonadherence may be associated with increased health care costs, excluding specialty agents; adherence may increase total health care costs; and methotrexate use may be associated with increased persistence. Future research should confirm these findings. This research was part of an internship awarded to Khilfeh by the AMCP Foundation/Pfizer Summer Internship Program and funded by Pfizer. Gross is an employee of Pfizer. The other authors have nothing to disclose. A portion of this research was presented at the AMCP Managed Care & Specialty Pharmacy Annual Meeting as a continuing education session entitled "The Evolving Role of Real-World Data in Health Care Decision Making" on March 29, 2017, in Denver, CO, and at AMCP Nexus 2016 as a poster on October 3-6, 2016, in National Harbor, MD.

Use and effectiveness of tocilizumab among patients with rheumatoid arthritis: an observational study from the British Society for Rheumatology Biologics Register for rheumatoid arthritis

The aims of the present study are to describe the characteristics of rheumatoid arthritis (RA) patients selected for tocilizumab (TCZ), compare the “real-world” effectiveness of TCZ and tumour necrosis factor inhibitors (TNFi) when used as a first biologic and assess the influence of past biologic exposure/concurrent methotrexate (MTX) therapy on post-TCZ treatment outcomes. The British Society for Rheumatology Biologics Register (BSRBR-RA) is a prospective cohort study following RA patients starting biologics in the UK. This includes patients starting TCZ as first or subsequent biologic, alongside biologic-naïve patients starting TNFi. Six-month disease activity and 1-year drug survival were compared between biologic-naïve patients starting TCZ versus TNFi and first-line versus subsequent TCZ users and TCZ users with MTX versus without using regression models adjusted by propensity score. Two hundred seventeen patients started TCZ, and 2419 started TNFi as first biologic. Seven hundred seventy-seven started TCZ after other biologics. First-line TCZ users had a higher prevalence of pulmonary fibrosis and cancer history than TNFi users. The first-line TCZ users were more likely to achieve DAS28 remission at 6 months than first-line TNFi, but other improvement markers were similar. The treatment response at 6 months was similar between subsequent-line TCZ users and first-line users after adjusting for baseline patient differences. Concurrent MTX use was not associated with treatment response in either first- or subsequent-line TCZ users. TCZ has been primarily used as subsequent-line biologic in the UK. When used as first line, the response appears similar to that observed in patients starting TNFi, suggesting that clinical response alone should not decide between initial biologic therapies.

The risk of hospitalized infection following initiation of biologic agents versus methotrexate in the treatment of juvenile idiopathic arthritis.

BackgroundIn the present study, we compared the incidence of hospitalized infection among children with juvenile idiopathic arthritis (JIA) following initiation of treatment with biologic agents versus methotrexate (MTX).MethodsWe used national Medicaid claims data from 2000 through 2010 to create cohorts of children with JIA who were new users of tumor necrosis factor inhibitors (TNFi), anakinra, and MTX (without concurrent biologic agent use) as defined by a 6-month baseline period of nonuse. Because most anakinra users have systemic juvenile idiopathic arthritis (SJIA), we used claims to identify MTX users who likely had SJIA. Among TNFi users, concurrent MTX use was a time-varying covariate. The study outcome was a primary hospital discharge diagnosis of infection. We calculated adjusted hazard ratios (aHRs) to compare infection rates between biologic agents and MTX.ResultsWe identified 3075 new MTX users (160 with SJIA), 2713 new TNFi users, and 247 new anakinra users. There was no increased risk of infection associated with TNFi monotherapy versus MTX (aHR 1.19, 95 % CI 0.72–1.94) or with TNFi + MTX combination therapy versus MTX (aHR 1.23, 95 % CI 0.69–2.17). Baseline high-dose oral glucocorticoid use (≥10 mg/day of prednisone) was associated with infection (aHR 2.03 [95 % CI 1.21–3.39] versus no oral glucocorticoid). Anakinra was associated with infection versus MTX (aHR 3.53 95 % CI 1.83–6.82), but less so compared with MTX users with SJIA (aHR 2.69, 95 % CI 0.82–8.82).ConclusionsNeither TNFi monotherapy nor TNFi + MTX combination therapy was significantly associated with hospitalized infection compared with MTX. Anakinra was significantly associated with infection, but there was likely residual confounding by disease phenotype.

Hyper-Acute Methotrexate Pneumonitis in a Patient With Crohnʼs Disease

Case: A 64 year-old female with Crohn's colitis presented with 2 weeks of fevers, drenching night sweats, malaise, dry cough and dyspnea. She had developed a severe flare of Crohn's colitis 4 months earlier that was refractory to infliximab, necessitating surgical management with colectomy and diverting ileostomy. Post-operatively, she developed peristomal pyoderma gangrenosum for which she was to receive adalimumab and methotrexate(MTX) 10 mg oral every week. Two days after her first dose of MTX, she developed the presenting symptoms that worsened after her second dose. This occurred prior to initiation of adalimumab. On presentation, patient was tachycardic to 120s, hypoxic and febrile to 101°F. Rales were audible over both lung fields. Laboratory values were within ranges of normal except mild renal insufficiency. Chest CT (figure 1) showed diffuse ground glass opacities with centrilobular prominence. Non-invasive workup for infectious etiologies was negative. On bronchoscopy and bronchoalveolar lavage (BAL), antigen testing and cultures did not reveal evidence of bacterial, viral, mycobacterial or fungal infection. Elevated lymphocyte (54%) and eosinophil (11%) counts were noted on the BAL fluid cell differential. A diagnosis of MTX-induced pneumonitis (MIP) was made. She was started on 40 mg/day prednisone with tapering over 5 weeks. After 4 weeks on corticosteroids, the patient's symptoms resolved. A follow-up chest CT (figure 2) showed resolution of radiographic abnormalities.Figure 1Figure 2Discussion: MTX is an immunosuppressive with efficacy as monotherapy in induction and remission of Crohn's disease. Concurrent use of MTX with anti-TNFα agents can prevent anti-drug antibody formation and foster higher drug levels. MTX is associated with serious lung toxicity with MIP as the most common manifestation. MIP presents with non-specific acute or gradually progressive symptoms of cough, dyspnea, fevers and can progress to respiratory failure. MIP generally occurs after months of low-dose oral MTX therapy. Of the only two previous case reports of MTX-related pulmonary disease reported in Crohn's disease(CD) symptom onset was at 2-18 months after initiation of MTX. This is the first case of hyper-acute MIP in CD with symptom onset within a few days of MTX initiation. MIP diagnosis is made based on a composite of clinical history, radiological findings and BAL results. CT chest imaging can demonstrate diffuse groundglass opacities with or without consolidation, centrilobular nodules or traction bronchiectasis. BAL findings have lymphocytic and eosinophilic predominance with increase in the CD4/CD8 ratio. The treatment of MIP is MTX withdrawal. Corticosteroid therapy can be considered based on severity, duration and progression of symptoms.

Recent trends in medication usage for the treatment of juvenile idiopathic arthritis and the influence of tumor necrosis factor inhibitors.

Using administrative data from a large commercial US health insurer, we investigated temporal trends in medication use among children diagnosed with juvenile idiopathic arthritis (JIA). Children with ≥ 1 physician diagnosis code for JIA in the calendar years 2005 through 2012 were included. Use of tumor necrosis factor inhibitors (TNFi), methotrexate (MTX), nonsteroidal antiinflammatory drugs (NSAID), and oral glucocorticoids (GC) was determined. Temporal changes in medication usage were evaluated with the Cochran-Armitage test for trend. We used paired t-tests to evaluate the use of NSAID and GC in the 6 months before and after new TNFi use. We identified 4261 unique individuals with JIA. The proportion of patients receiving TNFi increased from 8.7% in 2005 to 22.4% in 2012 (p < 0.0001). MTX use increased from 18.4% to 23.2% (p = 0.02). NSAID use decreased from 49% to 40% (p = 0.02). GC use was relatively unchanged. Following new TNFi use, the mean number of NSAID prescriptions (among prevalent users) decreased from 2.8 to 2.0 (p < 0.0001), and the mean daily GC dose (among prevalent users) decreased from 7.3 mg/day to 3.9 mg/day (p < 0.0001). Many new TNFi users (57%) had not used MTX in the previous 6 months, and only 37% had any concurrent MTX use in the 6 months following new TNFi use. TNFi use in the treatment of JIA increased 2- to 3-fold over the last 8 years. New TNFi use was associated with decreased NSAID and GC use. TNFi may be replacing, rather than complementing, MTX in the treatment of many patients.

Concurrent use of methotrexate and celecoxib increases risk of silent liver fibrosis in rheumatoid arthritis patients with subclinical reduced kidney function.

We evaluated the effects of concurrent use of methotrexate and celecoxib on silent liver and kidney damages in rheumatoid arthritis (RA) patients. We enrolled 92 RA patients with normal laboratory results related to liver and kidney functions, who had received methotrexate and celecoxib concurrently over 6 months. Liver stiffness measurement (LSM) using transient elastography and ultrasonography were performed along with blood and urine tests. Estimated glomerular filtration rate (eGFR) was calculated by both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) equations. Initial eGFR represented kidney function at the time of the initiation of celecoxib. The cutoff for abnormal LSM values was adopted as 5.3 kPa. The optimal cutoff of each eGFR for abnormal LSM values was also calculated. The median age of patients was 55 years old (74 women). The median LSM was 4.4 kPa and the median eGFRs and median initial eGFRs ranged from 89 to 99 mL/min/1.73 m(2). The cumulative doses of methotrexate and celecoxib and their concurrent administration duration did not affect LSM values and eGFRs. Both eGFRs were significantly associated with LSM values. Patients with initial eGFR(CKD-EPI), initial eGFR(MDRD), and eGFR(CKD-EPI) below each optimal cutoff had significantly high risks for silent liver fibrosis (RR 9.4, 10.3, and 4.4, p < 0.001, respectively). Both initial eGFRs (CKD-EPI and MDRD) and eGFR (CKD-EPI) were significant predictors for the development of silent liver fibrosis in RA patients who had received methotrexate and celecoxib concurrently for at least 6 months.

SAT0157 Concurrent Use of Methotrexate and Celecoxib Increases Risk of Silent Liver Fibrosis in Rheumatoid Arthritis Patients with Reduced Kidney Function

ObjectivesWe evaluated the effects of concurrent use of methotrexate and celecoxib on silent liver and kidney damages in rheumatoid arthritis (RA) patients.MethodsWe enrolled 92 RA patients with normal liver and...

FRI0277 Predicting Future Response to Tumor Necrosis Factor Inhibitors by the Distribution of Affected Joints in Rheumatoid Arthritis Patients

BackgroundAchieving remission is essential for avoiding joint destruction and disability in patients with rheumatoid arthritis (RA). Tumor necrosis factor inhibitors (TNFi) therapies represent an important advancement in therapy for RA....

OP0281 Recent Trends in Medication Usage for the Treatment of Juvenile Idiopathic Arthritis in the United States and the Influence of Tnf Inhibitors

BackgroundThe pharmacologic management of JIA has changed dramatically over the last decade with the advent of tumor necrosis factor inhibitors (TNFi), but the impact of TNFi on medication usage in...

Safety of Nonsteroidal Antiinflammatory Drugs and/or Paracetamol in People Receiving Methotrexate for Inflammatory Arthritis: A Cochrane Systematic Review

To systematically review the literature on the safety of using nonsteroidal antiinflammatory drugs (NSAID) and/or paracetamol in people receiving methotrexate (MTX) for inflammatory arthritis (IA), as an evidence base for generating clinical practice recommendations. A systematic literature review was performed using the Cochrane Library, Medline, Embase, and conference proceedings for the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) for 2008-2009. The search aimed to identify studies describing adverse events (AE) with the concurrent use of paracetamol and/or NSAID in people taking MTX for IA. Articles fulfilling our predefined inclusion criteria were systematically reviewed and quality appraised. Seventeen publications out of 8681 identified studies were included in the review, all of which included people with rheumatoid arthritis (RA) using various NSAID; there were no identified studies for other forms of IA or with paracetamol. Of the studies examining concurrent use of MTX and NSAID, there were no reported adverse effects on lung, liver, or renal function, and no increase in MTX withdrawal or in major toxic reactions. However, transient thrombocytopenia was demonstrated in 1 study. Looking at specific NSAID, there were no clinically significant AE with concomitant piroxicam or etodolac, and only mild AE with celecoxib or etoricoxib. Antiinflammatory dose aspirin was demonstrated to have an adverse effect on liver and renal function. In the management of RA, concurrent use of NSAID with MTX appears to be safe, provided appropriate monitoring is performed. The use of antiinflammatory doses of aspirin should be avoided.

Feasibility Trial of Methotrexate–Paclitaxel as a Second Line Therapy in Advanced Urothelial Cancer

To evaluate the clinical value of the concurrent use of methotrexate administered immediately before paclitaxel, we investigated the efficacy and toxicity of this two-drug combination administered as palliative second line therapy in patients with advanced urothelial cancer. The design of the schedule and sequence used was based on our previous preclinical data from a comparative study on sequential combinations of paclitaxel and methotrexate in a human bladder cancer cell line. As a confirmation study, we further extended our analysis of in vitro synergism. Twenty patients with advanced transitional cell carcinoma of the urinary tract previously treated with platinum-based therapy, with adequate renal function and a performance status ≥60 were considered eligible. They received therapy with methotrexate 30 mg/m2 administered as an intravenous bolus, followed immediately by paclitaxel 175 mg/m2 given as a 3-hr infusion, both on day 1 every 21 days. Therapy was given on a compassionate-use basis until either disease progression was documented or the patient became intolerant to therapy. In vitro data were further analyzed using the median-effect principle and the combination index method. Twenty patients with metastatic (16 patients) or locally advanced disease (four patients) received a median of three cycles of therapy. Of the 19 patients assessable for response, there were six partial responses and seven disease stabilizations with no complete responses. Median duration of response was 3 months (range, 2–7) and median survival was 5 months. Three patients developed grade 3–4 neutropenia, one patient had grade 3 anemia, four patients had grade 2–3 sensory neuropathy, and three patients had myalgias. Eighteen patients developed alopecia. Gastrointestinal toxicity was mild. One patient died after the first cycle due to pulmonary thrombo-embolism and could not be evaluated for response. The synergistic in vitro effect of the concurrent combination was confirmed in analyses performed under mutually exclusive and mutually nonexclusive criteria. In conclusion, the combination of methotrexate and paclitaxel at this dose and sequence is feasible and active as a palliative therapy in patients with advanced urothelial cancer previously treated with platinum-based therapies. This schedule merits further investigation in a phase-II trial.