Oral MTX Research Articles

Methotrexate for refractory adult atopic dermatitis leads to alterations in cutaneous IL-31 and IL-31RA expression

BackgroundMethotrexate (MTX) is an alternative treatment for patients with moderate/severe atopic dermatitis (AD). ObjectiveThe authors evaluated the effect of MTX on the cutaneous expression of cytokines and chemokines that are involved in the inflammatory response in adult AD patients who received treatment with methotrexate for 24 weeks. MethodsThe authors conducted a prospective single-institution cohort study with 12 adults with moderate/severe AD who received oral MTX (15 mg/wk for 24 wks) and 10 non-atopic matched controls. The comparison was made of skin biopsies of lesional and non-lesional skin, pre- and post MTX treatment. The authors analyzed mean epidermal thickness and expression of IL-31, IL-31RA, OSMR, TSLP, Ki67, IL-4 mRNA, IL-6, IL-10, TNF-α, IFN-γ, TARC, and CCL-22. ResultsThere was a reduction in mean epidermal thickness (p = 0.021), an increase in IL-31RA expression (immunohistochemistry) in the epidermis (p = 0.016) and a decrease in IL-31 gene expression (p = 0.019) on lesional AD skin post-MTX treatment. No significant changes in the cutaneous expression of the other evaluated markers were identified. Study limitationsSmall sample size and limited length of follow-up. ConclusionsTreatment with MTX in adults with moderate/severe AD reduced epidermal hyperplasia and changed the cutaneous expression of inflammatory cytokines and receptors that are mainly related to pruritus, including IL-31 and IL-31RA. Trial registrationClinicalTrials.gov Identifier: NCT03327116.

P106 Feasibility Study of Methotrexate use Improvement in Rheumatoid Arthritis using Biomarker Feedback: The MIRA Trial

Abstract Background/Aims MTX non-adherence is associated with reduced response, increased healthcare costs to the NHS and reduced quality of life for the patient. Often the prescriber is unable to determine if a patient is taking their medication as prescribed. There is a need to measure adherence directly to facilitate more precise and objective measurements of adherence to add to the clinicians tools and help to open up honest discussions and supportive interventions with patients. Our group has previously developed a sensitive biochemical assay for the detection of MTX adherence, MIRA is a feasibility trial designed to assess the feasibility of a randomised controlled trial of MTX biochemical adherence biofeedback. Methods MIRA is a prospective multi-centre randomised controlled trial to examine the feasibility of a fully powered randomised controlled trial to examine if a biochemical adherence guided intervention is superior to standard clinical care in RA patients prescribed MTX. RA patients prescribed oral MTX for ≥ two years were randomised 1:1 to receive biochemical adherence biofeedback or control. Clinico-demographics, biochemical MTX adherence and DAS-28 and were measured at baseline and three months. Participants in the intervention cohort were telephoned with their biochemical adherence results and adherence was explored. Ethical approval for MIRA was given by the North West - Haydock Research Ethics Committee (19/NW/0047) and all participants provided written informed consent. Results 57 participants were recruited, withdrawal rate was 14% and reasons given were intercurrent illness, lost contact, withdrawn consent and one patient died during follow-up leaving full outcome data available for 49 participants. Baseline clinico-demographics were similar in control and intervention cohorts (Table 1). Biochemical adherence worsened in the control cohort and improved in the intervention cohort (17 to 30%, 15 to 8% respectively). Change in DAS(CDP)-28 during the trial worsened in the control cohort but improved in the intervention cohort (-0.04 STD 1.26 and 0.38 STD 0.78 respectively). Conclusion The results of the MIRA trial have demonstrated that the use of a biochemical adherence blood test with biofeedback is feasible as part of a clinical trial. The intervention demonstrated early evidence for efficacy justifying the need for a full definitive trial. Disclosure J. Bluett: None. K.L. Hyrich: None. B. Keevil: None. P. Doran: None. A. Barton: None.

Ulcerations in Chronic Plaque Psoriasis: A Diagnostic Clue for Acute Methotrexate Toxicity

An elderly male patient, a known case of psoriasis vulgaris, presented with ulcerations in preexisting psoriatic lesions. The patient had fever with chills and severe pain and burning sensations in the lesions. There was a history of intramuscular methotrexate (Mtx) injection 15 mg followed by oral Mtx 7.5 mg once daily from next day for 5 days. Laboratory investigations revealed severe pancytopenia and abnormal renal and liver function tests. A diagnosis of acute Mtx toxicity was made and started treatment with intravenous leucovorin and subcutaneous granulocyte colony-stimulating factor (filgrastim) for 4 days. The patient responded to the treatment with improvement in skin lesions and laboratory parameters. The present case underlines the importance of patient counseling regarding the dosage schedule of the drugs and their adverse effects. The ulceration of preexisting lesions helps in early diagnosis, evaluation, and initiation of specific therapy.

Methotrexate-associated Lymphoproliferative Disorder Presenting as an Ulcer With Tendon Exposure on the Dorsum of the Hand: A Case Report and Literature Review

Introduction. MTX-LPD is a complication that occurs during MTX treatment. Skin lesions in MTX-LPD are often subcutaneous nodules with occasional necrosis and ulceration. Although MTX-LPD regression is frequently observed upon discontinuation of oral MTX treatment, delayed diagnosis of MTX-LPD with associated ulceration may lead to ulcer enlargement and the need for surgical procedures such as skin grafts. Case Report. A 74-year-old female was diagnosed with RA and administered MTX for 3 years and 8 months. The patient presented with a 2-month-old ulcer on the dorsum of the hand. The ulcer size was 6.5 cm × 5 cm, and it was surrounded by an embankment tumor measuring 7 cm × 6 cm. Although a definitive diagnosis could not be made based on the biopsy specimen, excision of the ulcer-containing mass confirmed MTX-LPD diagnosis. MTX was discontinued, and free-flap reconstruction was performed 3 weeks after the first surgery. The postoperative period was uneventful, and MTX-LPD recurrence was not observed 10 months after the second surgery. Conclusion. Although MTX-LPD with ulceration is rare, it should be considered in cases of refractory ulcers in patients with RA. The discontinuation of MTX based on early MTX-LPD diagnosis is critical to avoid surgical procedures such as skin grafts and flap reconstruction.

Pharmacokinetics of oral and subcutaneous methotrexate in red and white blood cells in patients with early rheumatoid arthritis: the methotrexate monitoring trial

ObjectiveTo investigate the pharmacokinetics of methotrexate polyglutamate (MTX-PG) accumulation in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) in patients with early rheumatoid arthritis (RA) after oral and...

Adherence to methotrexate and associated factors considering social desirability in patients with rheumatoid arthritis: a multicenter cross-sectional study

BackgroundAssessing medication adherence in rheumatoid arthritis (RA) is clinically significant as low adherence is associated with high disease activity. Self-reported medication adherence surveys have been shown to have problems with overestimation of adherence due to social desirability bias. However, no MTX adherence studies adjusted for social desirability have been conducted to date. This study aimed to evaluate adherence to MTX and perform an investigatory search for factors associated with MTX adherence including social desirability.MethodsThis cross-sectional multicenter study was conducted among adult RA patients consuming oral MTX for ≥ 3 months. We examined the distribution of MTX adherence, according to the eight-item Morisky Medication Adherence Scale (MMAS-8). Social desirability was using the Social Desirability Scale (SDS). Furthermore, an exploratory factor analysis involving social desirability was examined to identify factors associated with MTX adherence using linear regression analysis. To deal with missing values, we used multiple imputations with chained equations methods.ResultsA total of 165 RA patients were enrolled. The median age was 64 years, and 86.1% were women. Based on the MMAS-8, low, medium, and high adherences were noted in 12.1%, 60.0%, and 27.9% of participants, respectively. High social desirability (coefficient, 0.14; 95% confidence interval [CI], 0.05–0.23; p < 0.05) and high age (coefficient per 10 years, 0.16; 95% CI, 0.01–0.03; p < 0.05) were associated with high MTX adherence, whereas full-time work was negatively associated with high MTX adherence (coefficient, -0.50; 95% CI, -0.95–-0.05; p < 0.05).ConclusionsA large proportion of patients with RA do not take MTX as prescribed. High social desirability, high educational level, and non-full-time work may be associated with high MTX adherence. Physicians should confirm MTX adherence before switching or adding disease-modifying anti-rheumatic drugs in cases of uncontrolled disease activity.

Prognosis Prediction Using Magnetic Resonance Spectroscopy and Oligoclonal Bands in Central Nervous System Methotrexate-associated Lymphoproliferative Disorder.

Central nervous system methotrexate-associated lymphoproliferative disorder (CNS-MTX-LPD) is rare, but its spontaneous regression has been observed in some patients after withdrawal of agents. We herein report three cases of primary CNS-MTX-LPD that received oral MTX for rheumatoid arthritis. Epstein-Barr virus and oligoclonal bands (OCBs) were positive, while proton magnetic resonance spectroscopy (1H-MRS) showed an elevated lipid peak and slightly elevated choline/N-acetylaspartate ratio in common. After MTX withdrawal, brain lesions showed spontaneous regression in all cases. Our patient's 1H-MRS findings and OCBs may reflect a non-monoclonal lymphoproliferative histology as benign-type lesions in CNS-MTX-LPD.

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

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

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.

Subcutaneous administration, higher age and lower renal function are associated with erythrocyte methotrexate accumulation in Crohn’s disease: a cross-sectional study

BackgroundMethotrexate is an immunomodulatory drug for patients with Crohn’s disease. Erythrocyte MTX-polyglutamates (MTX-PG1-5) may be used for therapeutic drug monitoring (TDM) as MTX-PG is thought to mediate MTX’s efficacy. Information on determinants of the concentration of MTX-PG in patients with Crohn’s disease is lacking. We aim to identify clinical and biochemical determinants of the erythrocyte MTX-PG1-5 and MTX-PGtotal concentration in patients with Crohn’s disease.MethodsAdults with Crohn’s disease on methotrexate treatment who visited the outpatient clinic of Amsterdam UMC were included. Erythrocyte MTX-PGs were measured by tandem mass spectrometry.ResultsNineteen patients were included, with a median duration of MTX use of 77 months (range 7–202). Twelve patients received MTX monotherapy, whereas 7 patients were on concomitant TNF-α inhibitors. The mean dose of MTX was 15.5 mg (SD ± 2.8) and 12 (63%) patients used subcutaneous MTX. MTX-PG1-5 were successfully measured in 18 patients, showing substantial variability in concentrations of MTX-PGtotal and individual species. The median MTX-PGtotal was 117.1 nmol/L (range 46.4–258.7) with preferential accumulation of MTX-PG3 (43.1 nmol/L, range 15.3–96.1). Patients on subcutaneous compared to oral MTX had higher median MTX-PG(4,5) levels (55 versus 9 nmol/L, p = 0.01). Higher age (β = 0.71) and lower estimated glomerular filtration rate (β = − 0.52) were associated with a significantly higher MTX-PGtotal concentration (R2 = 0.60, p = 0.001).ConclusionMTX-PG concentrations display a considerable inter-individual variability. Higher MTX-PG accumulation is associated with subcutaneous administration, higher age, and lower renal function in Crohn’s disease patients.

HLA-DRB1 risk alleles for RA are associated with differential clinical responsiveness to abatacept and adalimumab: data from a head-to-head, randomized, single-blind study in autoantibody-positive early RA

BackgroundCertain risk alleles associated with autoantibody-positive rheumatoid arthritis (RA) have been linked to poorer prognoses. In patients with autoantibody-positive RA, abatacept shows differential efficacy to tumor necrosis factor inhibitors. Our aim was to investigate the relationship between clinical response to abatacept and to adalimumab and presence of risk alleles encoding human leukocyte antigen (HLA)-DRB1 shared epitope (SE) in RA.MethodsIn this head-to-head study, biologic-naïve adults with early (≤ 12 months), moderate-to-severe RA and inadequate response to methotrexate (MTX-IR), autoantibody-positive for both anti-cyclic citrullinated peptide 2 and rheumatoid factor, were randomized 1:1 to receive subcutaneous abatacept 125 mg weekly or subcutaneous adalimumab 40 mg every 2 weeks for 24 weeks with stable, weekly oral MTX. An open-label period to 48 weeks followed, during which adalimumab-treated patients were switched to abatacept. Patients were genotyped for HLA-DRB1 alleles and classified as SE-positive (≥ 1 SE allele) or SE-negative (no SE alleles). Efficacy was assessed at weeks 24 and 48.ResultsForty patients each received abatacept (9 SE-negative, 30 SE-positive, one unknown) or adalimumab (9 SE-negative, 31 SE-positive). Mean age and disease duration were 46.0 years and 5.5 months, respectively. At week 24, a greater percentage of abatacept patients achieved 50% improvement in ACR criteria (ACR50) compared with adalimumab patients (73% vs 45%, respectively) and estimate of difference (95% confidence interval [CI]), 28 (5, 48). In SE-positive patients, ACR50 estimate of difference (95% CI) was 32 (7, 55). During the open-label period, responses were sustained in the abatacept non-switch group and showed trends toward further improvement in the adalimumab-to-abatacept switch group at week 48, in both the overall and the SE-positive subpopulation. No new safety signals were identified.ConclusionsIn MTX-IR patients with early, autoantibody-positive RA, abatacept resulted in numerically higher efficacy responses versus adalimumab after 24 weeks, with more pronounced treatment differences in SE-positive patients. After 48 weeks, responses were sustained in patients who continued abatacept while those who switched to abatacept showed further clinical improvement, overall, and in SE-positive patients. This supports co-stimulation blockade as an effective treatment strategy for patients with early, autoantibody-positive RA, particularly among SE-positive patients.Trial registrationNIH US National Library of Medicine, NCT02557100. Registered on September 23, 2015.

P312 Erythrocyte methotrexate polyglutamate concentrations in patients with Crohn’s Disease: towards a new therapeutic drug monitoring tool

Abstract Background Methotrexate (MTX) is an immunomodulatory drug for patients with Crohn’s Disease (CD), used as first-line therapy, as a second-line in case of failure to thiopurine, and concomitantly with anti-TNFα agents to decrease production of anti-drug antibodies. Nevertheless, MTX is underutilised in the treatment of CD, despite its proven efficacy and good safety profile. This is for a large part due to the lack of therapeutic drug monitoring (TDM) of MTX because no stable plasma MTX levels are reached. Intracellular MTX-polyglutamates (MTX-PGs), formed after folylpolyglutamate synthetase attaches glutamate residues to MTX, could be used as a TDM tool as MTX-PG is thought to mediate MTX’s efficacy. We present the results of our cross-sectional study in CD patients, aiming to gain insight into erythrocyte MTX-PG levels. Methods CD adults on MTX treatment who visited the outpatient clinic of Amsterdam UMC between May 2019 and February 2020 were included consecutively. An established LC-ESI-MS/MS method1 was used to measure erythrocyte MTX-PGs. Results Nineteen patients were included. Mean disease duration was 17 years (SD±13.7). Montreal disease location and behaviour were as follows (n=): L1 = 2, L2 = 4, L3 = 13; B1 = 11, B2 = 5, B3 = 3. Only 4 patients had a flare according to Physician Global Assessment. Twelve patients received MTX monotherapy, whereas 7 patients were on concomitant anti-TNFα agents. The mean dose of MTX was 15.5 mg (SD±2.8) and 12 (63%) patients had subcutaneous (sc.) MTX. We successfully measured MTX-PG2-5 in 18 patients, showing substantial variability in measured concentrations of total MTX-PG(tot) and the individual species. The median MTX-PGtot was 117.1 nmol/L [min:46.4-max:358.7] with preferential accumulation of MTX-PG3 (43.1 [15.3-96.1]); the least predominant species being MTX-PG5 (9.4 [1.1-24.1]). Patients on sc. compared to oral MTX had higher MTX-PGtot levels (177.8 [58.8-358.7] vs. 93.2 [46.4-120.8] nmol/L, p=0.067) and significantly higher long-chain MTX-PG4-5 levels (55 [3.7-84.3] vs. 8.9 [2.4-15.0] nmol/L, p=0.010); see figure. Conclusion We showed that erythrocyte MTX-PGs can be measured in CD patients by tandem MS. Large variability in concentrations was demonstrated, similar to our previously published results in rheumatoid and juvenile arthritis2,3 which is a pre-requisite for MTX-PG use as a TDM tool. We showed for the first time that MTX-PG accumulation was higher in sc. MTX vs. oral MTX treatment. This work provides the first step towards establishing TDM for MTX in CD, a goal we aim to realize in our upcoming longitudinal study. References

AB0855 FIBROUS ARTHROPATHY AS THE KEY FEATURE OF JUVENILE SCLERODERMA - CASE REPORT

Background:Systemic sclerosis (SSc) is an autoimmune disease characterized by endothelial dysfunction, immunological disorders, and excessive synthesis of collagen and its deposition in various tissues and organs. The juvenile onset SSc before the age of 16 is very rare, with annual incidence of 0.27-0.5 cases per million children according to English and Finnish authors [1,2].Objectives:To present a clinical case of juvenile onset SSc, manifesting from the childhood predominantly with fibrous contractures.Methods:Patient K., 30 yo. Clinical presentation on admission to the Institute of Rheumatology in September 2020: thickening of the trunk and limbs skin (mRSS 10 scores), pronounced induration of subcutaneous tissues and muscles; contractures of the elbow, shoulder, hip and knee joints, short stature (height 142 cm) with proportional shortening of the limbs. ANA (HEp-2) 1/320, a-Scl-70, a-RNP-70 and ACA tests were negative. Ultrasonography revealed left-sided coxitis, esophagogastroduodenoscopy - Barrett’s esophagus. Chest CT, echocardiography, electrocardiography and capillaroscopy yielded no specific findings.The patient has been ill since the age of 3, when SSc manifested with skin thickening, “dry” arthritis and rapid development of contractures of the large joints. Thorough diagnostic elaboration ruled out such potential causes as phenylketonuria, glycogenosis, mucopolysaccharidoses, primary amyloidosis, and porphyria. Histological findings (2007) of a biopsied skin specimen containing subcutaneous fat and muscle tissue included focal vacuolization of keratinocytes, poor perivascular lymphocytic and histiocytic infiltration, fibrosis and hyalinosis of collagen fibers of varying intensity in the in mid- and deep dermis, infiltration of collagen fibers by fibroblasts, skin appendages atrophy – all of them representing a pattern of morphological changes characteristic of SSc. Therapeutic regimens including prednisone at 5-15 mg/day and D-penicillamine were ineffective.Results:In this case, in view of fibrotic arthropathy, a differential diagnosis was made with deep morphea and stiff skin syndrome. Visceral involvement, immunological disorders and biopsy findings substantiated a diagnosis of juvenile onset SSc. Oral MTX was initiated at 15 mg to target skin lesion and osteoarticular symptoms.Conclusion:Predominance of fibrotic arthropathy in presented case caused difficulties in establishing SSc diagnosis, as this patient did not have such inherent features as the Raynaud’s phenomenon, interstitial lung disease or pulmonary hypertension. Juvenile onset SSc manifesting before the age of 16 has its own clinical features, usually persisting through the adulthood, and therefore, such one-of-a-kind appearances of juvenile onset SSc should not be missed or misinterpreted.

The synergistic efficacy of hydroxychloroquine with methotrexate is accompanied by increased erythrocyte mean corpuscular volume.

ObjectivesTo determine whether concomitant HCQ modulates the increase in erythrocyte mean corpuscular volume (MCV) caused by MTX therapy, and whether this is associated with improved clinical response in RA.MethodsA retrospective observational analysis was conducted on two independent hospital datasets of biologic-naïve, early-RA patients who started oral MTX. Baseline characteristics, DAS28-ESR and monthly MCV after starting MTX were obtained. Conventional and machine-learning statistical approaches were applied to the discovery cohort (Cohort 1, 655 patients) and results validated using Cohort 2 (225 patients).ResultsHCQ therapy with MTX was associated with a 2-fold increase in the likelihood of response defined in this study as clinical remission or low disease activity at 6 months (P <0.001). The improved clinical outcome of combination HCQ and MTX therapy was associated with an accelerated rise in MCV from 2 months after commencing therapy. The increase in MCV at 3 months was equivalent to the contemporaneous reduction in the DAS (DAS28-ESR) in predicting clinical response at 6 months. Using latent class mixed modelling, five trajectories of MCV change over 6 months from baseline were identified. The odds ratio of response to treatment was 16.2 (95% CI 5.7, 46.4, P <0.001) in those receiving combination therapy classified within the MCV elevation >5 fl class, which contained the most patients, compared with MTX alone.ConclusionOur data provide mechanistic insight into the synergistic clinical benefit of concomitant HCQ with MTX, boosting the rise in MCV, which could serve as a companion biomarker of treatment response.

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.

FRI0129 DEVELOPMENT OF A PREDICTION MODEL FOR MAXIMUM METHOTREXATE (MTX) DOSE WITHOUT HEPATOTOXICITY USING AN INDEX OF ERYTHROCYTE MTX-POLYGLUTAMATE (MTXPG) LEVELS SPECULATED BY CLINICAL AND GENETIC MARKERS

Background:MTX is transported into cells and retained long after polyglutamation. MTXPG level can predict response and possibly adverse effects of MTX. We reported erythrocyte MTXPG concentrations efficiently discriminated patients with and without hepatotoxicity1. We also developed genetic and clinical prediction models for efficacy and hepatotoxicity of MTX2. In the present study, we firstly investigated the effects of clinical and secondly genetic variables on the concentration of total MTXPG and determined oral maximum MTX dose without hepatotoxicity using these variables.Objectives:To develop a prediction model for maximum MTX dose without hepatotoxicity.Methods:Concentrations of erythrocyte MTX-PG (PG1 to PG4) were detected by LC-MS/MS and calculated total MTXPG as sum of them. MTX-PGn levels were measured in 265 RA patients including 40 patients with elevated AST or ALT (≥ 60 U/L; 1.5 times of upper limits) and the 6 SNPs of 6 gens related to MTXPG metabolism were identified by RT-PCR.Results:Total concentrations of MTXPG were 141.3 ± 86.5 and 87.6 ± 47.8 nmol/L (mean±SD) in 40 RA patients with hepatotoxicity and 225 patients without, respectively (p&lt;0.0001). By ROC analysis, the two groups were most efficiently discriminated with cutoff concentration of 100.0 nmol/L (AUC 0.731). Next, genetic and clinical model to speculate the MTXPG concentration was established by multivariate analysis using 4 clinical and 3 genetic variables which were selected from 20 clinical and 6 genetic variables by univariate analysis (p&lt;0.1). Finally, a speculation model for MTXPG concentration by 4 clinical variables (MTX dose, BMI, RBC count, and creatinine) and one genetic variable (GGH c.452C&gt;T) was developed (Figure). When MTXPG concentration of 100 nmol/L was applied to the model, maximum MTX dose without hepatotoxicity was calculated for each patient asMTX dose (mg) = {100 (MTXPG) – 96 + 1.7*BMI + 28*RBC - 120*creatinine - 19.3*GGH(C/T)} / 7.7. Real dose of oral MTX exceeded the calculated dose in 23 of 40 patients (57.5%) with hepatotoxicity, whereas it exceeded in 95 of 223 patients (42.6%) without hepatotoxicity (OR 1.82, p=0.081).Conclusion:Maximum MTX dose without hepatotoxicity was speculated by several clinical and genetic markers without measurement of erythrocyte MTX-PG concentrations.

AB0360 EFFICACY AND SAFETY OF THE PROSTAGLANDIN EP4 RECEPTOR ANTAGONIST CR6086 ADDED TO METHOTREXATE IN DMARD-NAÏVE EARLY RA PATIENTS: A PHASE 2 RANDOMIZED CONTROLLED TRIAL

Background:MTX is the first line treatment in early RA. There is robust evidence from cohort studies, but less from RCTs, that a “window of opportunity” exists over 12-16 weeks symptom duration. CR6086 is a selective prostaglandin EP4 receptor antagonist, with an immunomodulatory profile.Objectives:To test efficacy and safety of CR6086 added to MTX in early RA, DMARD-naïve patients.Methods:Patients with RA (ACR/EULAR 2010 criteria), &lt; 1 year from symptom onset and naïve to DMARDs were randomized to oral CR6086 30, 90, 180mg, or placebo bid and oral MTX (20mg weekly) for 13 weeks (NCT03163966). Primary endpoint was the ACR20 response rate: 240 patients were needed to detect a difference among groups, with 50% responders on placebo and 70% on the 90mg CR6086 target dose. Pairwise comparisons of proportions were performed, with nonresponder imputation for withdrawals. A subgroup of patients underwent dynamic contrast-enhanced (DCE) MRI for quantification of synovitis at MCP and wrist joints, evaluated as DEMRIQ-ME and DEMRIQ-vol.Results:The ITT population included all 244 randomized patients receiving at least one dose of study drugs (59 CR6086 30mg/MTX, 60 CR6086 90mg/MTX, 63 CR6086 180mg/MTX, 62 placebo/MTX). Safety was good with no increased rate of infections or other disorders; however, there were more minor upper GI adverse events (AEs) with CR6086, and increased dropouts due to AEs with the 180mg dose (9/63, 14.3% vs 1.7-3.4% in other groups). There were more ACR20 responders with MTX monotherapy than predicted (59.7%) and thus the 10.3% difference with the 90mg target dose (70.0%) was not significant. The low 30mg dose was no better than placebo (55.9%), while the high 180mg dose did not provide additional benefit compared with 90mg (74.0% net of dropouts). CR6086 90mg and 180mg induced a significant improvement in MRI, compared with placebo (Fig. 1). In a post-hoc analysis in patients &lt; 6 months from symptom onset (ACR definition of early RA: 98/244, 40.2%), MTX monotherapy exerted a large 76% ACR20 response rate that precluded potentiation. Conversely, in patients of 6-12 months disease duration (146/244, 59.8%) ACR20 responders were 48.6% with MTX monotherapy vs 68.4% with 90mg, i.e. a 19.8% difference as postulated, with proportional differences in secondary endpoints (Tab. 1).Conclusion:There was no benefit demonstrated for CR6086 added to MTX in the study cohort as a whole. However, in a post-hoc analysis, enhanced responses were observed with CR6086 90mg bid added to MTX in patients &gt;6 months disease duration. This generated the hypothesis that addition of CR6086 90mg bid may benefit in RA patients initiating MTX after the window of opportunity, to be tested in further studies.Table 1.Patient characteristics &amp; pregnancy outcomesSymptom onset &lt;12 months(principal analysis)Symptom onset 6-12 months(post-hoc analysis)*Placebo+MTX(N=62)CR6086 90mg+MTX(N=60)Placebo+MTX(N=37)CR6086 90mg+MTX(N=38)ACR20, %59.7%70.0%48.6%68.4%ACR50, %33.9%38.3%29.7%39.5%ACR70, %17.7%23.3%10.8%28.9%DAS28 (CRP) &lt;2.6, %12.9%20.0%8.1%18.4%CDAI ≤2.8, %8.1%11.7%5.4%15.8%SDAI ≤3.3, %6.5%10.0%2.7%15.8%Boolean-based remission, %6.5%6.7%2.7%10.5%*In patients with symptom onset &lt;6 months, MTX monotherapy exerted a large 76% ACR20 response, and correspondingly high secondary efficacy parameters, precluding potentiation in this subsetFigure 1.Change in MRI (DEMRIQ-ME#) after 13 weeksDisclosure of Interests:Karel Pavelka Consultant of: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Speakers bureau: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Ivanova Delina2 Delina: None declared, Minodora Mazur: None declared, Massimo D’Amato Employee of: Rottapharm Biotech, GIAMPAOLO GIACOVELLI Employee of: Rottapharm Biotech, Federica Girolami Employee of: Rottapharm Biotech, Marek Krogulec: None declared, René Østgård: None declared, Asger Reinstrup Bihlet Shareholder of: Nordic Bioscience A/S., Olga Kubassova Shareholder of: IAG, Image Analysis Group, Consultant of: Novartis, Takeda, Lilly, Employee of: IAG, Image Analysis Group, Lucio Rovati Shareholder of: Rottapharm Biotech, Employee of: Rottapharm Biotech, Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB

EP23 Subcutaneous methotrexate from the get-go: better adherence and tolerability

Abstract Background Several studies have shown subcutaneous methotrexate (s/c MTX) to be superior to oral for treatment of rheumatoid arthritis. However s/c MTX is rarely started first line. Methods We audited the first 67 patients started on s/c MTX at diagnosis and compared to a previous cohort of treat-to-target patients started on oral MTX. Results There was a significant difference in adherence: for every 1 patient staying on oral, 1.5 patients stayed on s/c MTX. There was no difference in final numbers in remission, escalation to biologics, or time to remission. Nearly half the patients on oral MTX had switched to s/c at 1 year, either for side effects or inefficacy. Conclusion Adherence to s/c MTX was better than adherence to oral MTX in our study. The large number of switches from oral to s/c suggests that adherence is improved due to improved tolerability and reduced side effects of s/c MTX. Disclosures C. Bevington None. K. Achilleos None. J. Smith Grants/research support; JS received £500 from Medac to carry out the audit. V. Smith: None.

Excellent Outcomes with Reduced Frequency of Vincristine and Dexamethasone Pulses in Children with National Cancer Institute (NCI) Standard-Risk B Acute Lymphoblastic Leukemia (SR B-ALL): A Report from Children's Oncology Group (COG) Study AALL0932

Background: A key component of COG maintenance chemotherapy for pediatric B-ALL has been the inclusion of vincristine/steroid pulses administered every 4 weeks. With the intensification of pre-maintenance therapy and modern risk stratification, there is uncertainty regarding the optimal frequency of these pulses in the context of modern ALL therapy. AALL0932 was designed to optimize maintenance therapy by asking two questions: (1) whether giving vincristine/dexamethasone (VCR/DEX) pulses every 12 weeks was non-inferior to every 4 week pulses; and (2) whether a starting weekly oral methotrexate (MTX dose) of 40 mg/m²/dose would be superior to the standard 20 mg/m2/dose. We previously reported that there was no benefit to intensifying oral methotrexate during maintenance therapy (ASH 2017). We now report on the outcomes of the VCR/DEX pulses. Methods: Average risk (AR) patients participating in the randomization had NCI SR B-ALL without CNS3 or testicular leukemia, unfavorable genetic characteristics or Down syndrome, AND either favorable genetics (trisomies of chromosomes 4 &amp;10 or ETV6/RUNX1 fusion) with Day 8 peripheral blood (PB) minimal residual disease (MRD) ≥ 0.01% or CNS2 status, Day 29 bone marrow (BM) MRD &amp;lt; 0.01%, OR if neutral cytogenetics, had Day 8 PB MRD &amp;lt; 1% and Day 29 BM MRD &amp;lt; 0.01%. AR patients were randomized to 1 of 4 Maintenance regimens using a 2 x 2 factorial design: (A): VCR/DEX pulses every 4 weeks and oral MTX 20 mg/m²/week (standard arm); (B): VCR/DEX pulses every 4 weeks and oral MTX 40 mg/m²/week; (C): VCR/DEX pulses every 12 weeks and oral MTX 20 mg/m²/week; and (D): VCR/DEX pulses every 12 weeks and oral MTX 40 mg/m²/week. Results from the MTX randomization have been previously reported (ASH 2017). Between 2010 and 2016, 2364 patients were randomized at the start of maintenance to VCR/DEX pulses every 4 weeks [Arms A and B (n=1186)] or VCR/DEX pulses every 12 weeks [Arms C &amp; D (n=1178)]. Results: The 5-year disease-free survival (DFS) (±SE) measured from the time of randomization for the AR subset of patients randomized to receive VCR/DEX pulse every 4 weeks vs. every 12 weeks was 94.1% ±1.0% vs. 95.1% ±0.9%, respectively (one-sided p=0.86 indicating no evidence of DFS inferiority for 12 week frequency). The 5-year overall survival (OS) (±SE) for the AR patients randomized to receive VCR/DEX pulse every 4 weeks vs. every 12 weeks was 98.3% ±0.5%, vs. 98.6% ±0.5%, respectively (one sided p=0.69). There was no evidence of significant interaction between the MTX and VCR/DEX pulses randomizations. Conclusions: AALL0932 demonstrated that the AR subset of patients with SR B-ALL who received VCR/DEX pulses every 12 weeks maintained outstanding outcomes similar to those who received pulses every 4 weeks. The decreased frequency of VCR/DEX pulses will be incorporated into frontline B-lineage COG ALL trials thereby dramatically improving patient and family quality of life. Disclosures Angiolillo: Servier Pharmaceuticals: Consultancy. Schore:Janssen Research &amp; Development, LLC: Research Funding; AMGEN INC: Research Funding. Zweidler-McKay:ImmunoGen: Employment. Borowitz:Beckman Coulter: Honoraria. Relling:Servier Pharmaceuticals: Research Funding. Raetz:Pfizer: Research Funding. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees. Hunger:Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Equity Ownership; Jazz: Honoraria; Novartis: Consultancy.

P47 Successful treatment of two cases of refractory JIA uveitis with intravenous tocilizumab and subcutaneous methotrexate

Abstract Background There is a need for additional treatment options in refractory JIA uveitis which has responded inadequately to MTX and anti TNFα. There has been interest in the use of tocilizumab, the APTITUDE trial using SC tocilizumab in JIA uveitis and the STOP-Uveitis study comparing 2 dosing regimens of iv tocilizumab in adults. Anecdotal evidence reports JIA uveitis patients who were stable on IV tocilizumab flaring when switched to sc administration. We describe the successful use of IV tocilizumab and concurrent sc MTX in two cases. Methods Retrospective review of patient paper and electronic medical records. Results Case 1.: A five-year-old female presented with severe anterior uveitis in her right eye. She was diagnosed with idiopathic uveitis and treated with topical steroid, oral then SC MTX infliximab, mycophenolate and adalimumab, all with inadequate control of her uveitis. At the age of 12, on adalimumab, she developed arthritis and her diagnosis was changed to JIA uveitis. 7 years after initial diagnosis she was commenced on IV tocilizumab 8mgs/kg 4-weekly with improved control of her uveitis although initially still requiring some topical steroid. She required intra-articular steroids for active arthritis and agreed to restart SC MTX. On tocilizumab and MTX combined, her arthritis settled and her topical eye drops were weaned for the first time since diagnosis. From age 5 until 14 she was continually on topical steroids, consequently developing raised intraocular pressure and a dense cataract. With improved disease control she had cataract surgery aged 14. She has maintained good disease control for the last five years on the combination of IV tocilizumab and SC MTX and has not required any further steroids. Case 2: A 3 year old female with oligoarticular JIA had severe bilateral uveitis at presentation. Initial treatment was with oral prednisolone, topical steroid and SC MTX. 6 months after diagnosis her uveitis remained active and she was commenced on infliximab with additional IV methylprednisolone. Venous access was challenging, required a portacath to facilitate treatment. By the age of 6 she had developed a cataract requiring surgery and still had incomplete control of her uveitis. Infliximab was increased to 10mgs/kg 4 weekly with little further benefit and at the age of 7 she was changed to adalimumab. On this she developed macular oedema requiring pulse IV methylprednisolone. 5 years after diagnosis she was commenced on IV tocilizimab initially 4 weekly, increasing after three months to 2 weekly. Her methylprednisolone was weaned and she has subsequently maintained good disease control on IV tocilizumab 10mgs/kg 2 weekly with SC methotrexate. Conclusion We describe two cases of refractory JIA and uveitis in whom IV tocilizumab with SC methotrexate has provided good disease control. Further studies are required to determine the optimal dosing regimen. Conflicts of Interest The authors declare no conflicts of interest.