Methotrexate Group Research Articles

The Influence of the MDR1 C3435T Polymorphism on Methotrexate Responsiveness in Rheumatoid Arthritis Patients

Background: Methotrexate (MTX) is most widely used for the treatment of rheumatoid arthritis (RA). However, different clinical responses have been observed in patients treated with MTX. Objective: The aim of the work was to determine the influence of the MDR1 C3435T polymorphism on Methotrexate responsiveness in RA patients. Patients and Methods: A cross sectional study included 90 RA patients. Demographics, clinical features, medication history, and the disease activity score (DAS28) were carefully recorded. Genotypes of the C3435T polymorphism were determined by real time polymerase chain reaction for all patients. According to disease activity score, patients were classified into 2 groups: group (1): MTX responders (DAS28 score ≤3.2) and group (2): MTX non-responders (DAS28 score >3.2). Results: Of the 90 RA patients, 80 were females (88.9%) and 10 were males (11.1%). No statistically significant difference was found in genotype or allele frequencies between MTX responders and non-responders groups. However, patients who had C allele were 1.65 times more likely to be non-responder to MTX treatment when compared to those who had the T allele. The most common MTX adverse effects reported were Gastrointestinal upset in 31.1% followed by undesirable hair loss in 11.1%. The probability of having GIT adverse effects was observed to be higher among the cases with (CT) genotype than the other genotypes but without statistical significance. Conclusion: It could be concluded that no significant association could be detected between MDR1 gene C3435T polymorphism and responsiveness to methotrexate in the studied rheumatoid arthritis patients.

The Influence of the MDR1 C3435T Polymorphism on Methotrexate Responsiveness in Rheumatoid Arthritis Patients

Background: Methotrexate (MTX) is most widely used for the treatment of rheumatoid arthritis (RA). However, different clinical responses have been observed in patients treated with MTX. Objective: The aim of the work was to determine the influence of the MDR1 C3435T polymorphism on Methotrexate responsiveness in RA patients. Patients and Methods: A cross sectional study included 90 RA patients. Demographics, clinical features, medication history, and the disease activity score (DAS28) were carefully recorded. Genotypes of the C3435T polymorphism were determined by real time polymerase chain reaction for all patients. According to disease activity score, patients were classified into 2 groups: group (1): MTX responders (DAS28 score ≤3.2) and group (2): MTX non-responders (DAS28 score >3.2). Results: Of the 90 RA patients, 80 were females (88.9%) and 10 were males (11.1%). No statistically significant difference was found in genotype or allele frequencies between MTX responders and non-responders groups. However, patients who had C allele were 1.65 times more likely to be non-responder to MTX treatment when compared to those who had the T allele. The most common MTX adverse effects reported were Gastrointestinal upset in 31.1% followed by undesirable hair loss in 11.1%. The probability of having GIT adverse effects was observed to be higher among the cases with (CT) genotype than the other genotypes but without statistical significance. Conclusion: It could be concluded that no significant association could be detected between MDR1 gene C3435T polymorphism and responsiveness to methotrexate in the studied rheumatoid arthritis patients.

Interventions for non-tubal ectopic pregnancy.

Interventions for non-tubal ectopic pregnancy.

Effects of Vitamin D3 on Methotrexate- Induced Jejunum Damage in Rats

Both methotrexate and vitamin D3 are used in combination for the treatment of various diseases. The aim of this study is to highlight the effect of vitamin D3 on methotrexate-induced jejunum damage using biochemical and histopathological studies. Seven groups of both sexes of rats were selected and treated as follows: (Group I and Group II) : control 1,control 2 (I.P normal saline) daily for 14 and 21 days respectively ; (Group III and Group IV) :vitamin D3 groups (500 IU/rat/day) orally for 14 and 21 days, respectively;(Group V): once daily dose of methotrexate 20mg/kg, I.P injected for 4 days;(Group VI):vitamin D3 (500 IU/rat/day) once daily for 14 days and methotrexate (20 mg/kg I.P) injected only at day 10;.(Group VII) vitamin D3 (500 IU/rat/day) orally for 21 days and methotrexate (20 mg/kg I.P) injected only at day 17; then the jejunum was removed and used for measuring malondialdehyde (MDA) content, total antioxidant capacity (TAOC) level; in addition histopathological study of jejunum tissue. Administration of vitamin D3 for 21 days and a single dose of methotrexate at day 17 resulted in non-significant difference (P>0.05) in MDA; while significant reduction (P<0.05) in the TAOC level in jejunum tissue; furthermore , sever villi damage ,crypts abscess, epithelial atrophy , mixed inflammatory cells infiltrate and goblet cells depletion were observed in comparison with methotrexate group. So the study demonstrates that vitamin D3 plays a synergistic role with methotrexate therefore the combined use of vitamin D3 and methotrexate may be used as a strategy to overcome dose limitations and side effects when use for the treatment of cancer, rheumatoid arthritis and psoriasis.
 Key words: Jejunum damage, Methotrexate, Oxidative stress, Rats, Vitamin D3.

Implication of baseline levels and early changes of C-reactive protein for subsequent clinical outcomes of patients with rheumatoid arthritis treated with tocilizumab

BackgroundRheumatoid arthritis (RA) is characterised by clinical joint swelling and elevation of acute phase reactant levels, typically measured by the C-reactive protein (CRP). Clinical and inflammatory responses are usually concordant,...

Efficacy of oral methotrexate (MTX) monotherapy vs oral MTX plus narrowband ultraviolet light B phototherapy in palmoplantar psoriasis.

Palmoplantar psoriasis (PPP) is a chronic, inflammatory dermatosis of the palms and/or soles with significant morbidity. It is notoriously difficult to treat and unresponsive to traditional topical agents. We aim to compare the effect of oral methotrexate (MTX) monotherapy vs MTX plus narrowband ultraviolet light B (NB-UVB) in the treatment of recalcitrant PPP. This was a comparative clinical trial involving 90 patients of PPP. Eligible patients were randomly assigned to one of the two treatment groups. We aim patients in group A received 10 mg oral MTX weekly, and patients in group B received oral MTX 10 mg weekly and NB-UVB sessions twice weekly for 12 weeks. There was a statistically significant difference in reduction of modified PPP Area Severity Index (m-PPPASI) of patients in MTX plus NB-UVB at week 12. The mean m-PPPASI at week 12 was 3.66 ± 2.11 in MTX plus NB-UVB group and 6.51 ± 2.04 in MTX only group (P < .001). Marked improvement (m-PPPASI 75) was achieved in 20 (44.44%) patients in MTX plus NB-UVB group compared with 6 (13.3%) in MTX monotherapy group (P < .001). Combination of MTX and NB-UVB phototherapy helps to attain a better clinical response (reduction in m-PPPASI score) than MTX monotherapy in the treatment of recalcitrant PPP.

Protective effect of melatonin against methotrexate-induced testicular damage in the rat model: An experimental study.

Background Methotrexate (MTX) has been shown to affect the testes adversely, especially the seminiferous epithelium. As melatonin, an endocrine hormone, has been shown to normalize testicular function, its ability to prevent MTX-induced testicular damage should be considered.ObjectiveBased on the antioxidant, anti-inflammatory, and antiapoptotic activities of melatonin, this study aimed to investigate its protective effect against testicular damage induced by MTX.Materials and MethodsForty adult male rats (200-230 g) were divided into five groups (n = 8/each). The rats in group I were injected with vehicle as a control. In group II, the rats were received intraperitoneal injections of melatonin (8 mg/kg) for 15 consecutive days. The rats in group III were intravenously injected with MTX (75 mg/kg) for 15 consecutive days. The remaining two groups received melatonin (8 mg/kgBW) for 15 (group IV) and 30 (group V) consecutive days, intraperitoneally, and then intravenously received MTX (75 mg/kgBW) on days 8 and 15 of the experimental period. Reproductive parameters, including epididymal sperm concentration, testicular tyrosine-phosphorylated protein expression, steroidogenic acute regulatory (StAR) protein expression, and caspase-3 and malondialdehyde levels, were examined.ResultsThe sperm concentrations (10/ml) of groups IV (58.75 1.28) and V (55.93 2.57) were improved significantly (p = 0.032) compared with that of group II (32.92 2.14). The seminiferous epithelium in groups IV and V also increased, while caspase-3 expression decreased. In the melatonin-treated groups, the expression of tyrosine-phosphorylated proteins at 32 kDa was decreased and that of proteins at 47 kDa was increased compared with the MTX group. StAR protein expression was not altered in any of the groups.ConclusionOur results indicate that melatonin improves the epididymal sperm concentration by decreasing the expression of caspase-3 and increasing that of tyrosine-phosphorylated proteins in MTX-treated testes.

Neuroprotective effects of hesperidin against methotrexate-induced changes in neurogenesis and oxidative stress in the adult rat

Methotrexate (MTX) induces the formation of reactive oxygen species (ROS) and leads to neurotoxicity. The drug also negatively impacts neurogenesis and memory. Hesperidin (Hsd) is a major flavanoid with multiple beneficial pharmacological effects such as anti-oxidation, anti-inflammation, and neuroprotective effects. The aim of our study was to investigate the neuroprotective effects of Hsd against MTX-induced alterations in oxidative stress and neurogenesis. Sprague Dawley rats were divided into four groups: 1) a vehicle group, which received saline and propylene glycol, 2) an Hsd group, which was orally administered with Hsd (100 mg/kg) for 21 days, 3) an MTX group, which received MTX (75 mg/kg) by intravenous injection on days 8 and 15, and 4) an MTX + Hsd group, which received both MTX and Hsd. After treatment with MTX, p21-positive cells had increased significantly and doublecortin (DCX) expression in the hippocampus had decreased significantly. Treatment with MTX also increased malondialdehyde (MDA) in both the hippocampus and prefrontal cortex and decreased levels of brain-derived neurotropic factor (BDNF) and nuclear factor erythroid 2-related factor 2 (Nrf2) in the hippocampus and prefrontal cortex. Additionally, there were significant decreases in superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) in the hippocampus and prefrontal cortex in the MTX group. However, co-treatment with Hsd ameliorated the negative effects of MTX on neurogenesis, oxidative stress, and antioxidant enzymes. These findings suggest that Hsd may be able to prevent neurotoxic effects of MTX by reducing oxidative stress and enhancing hippocampal neurogenesis.

Comparative efficacy and safety of 100mg and 200 mg filgotinib administered to patients with active rheumatoid arthritis: A Bayesian network meta-analysis of randomized controlled trials .

We assessed the relative efficacy and safety of once-daily administration of 100 and 200 mg filgotinib (a JAK1-selective inhibitor) in patients with active rheumatoid arthritis (RA). We conducted a Bayesian network meta-analysis combining the direct and indirect evidence from randomized controlled trials (RCTs) that examined the efficacy and safety of filgotinib in patients with active RA. Five RCTs involving 3,920 patients met the inclusion criteria. There were 15 pairwise comparisons, including 8 direct comparisons and 7 interventions. The ACR20 response rate was significantly higher in the filgotinib 200 mg + methotrexate (MTX) group than in the placebo or placebo + MTX group (odds ratio (OR): 12.39, 95% credible interval (CrI): 3.36-45.98.10; OR: 2.68, 95% CrI: 1.80-4.39). Compared to the placebo group, the filgotinib 100 mg, adalimumab 40 mg + MTX, filgotinib 200 mg, and placebo + MTX groups showed a significantly higher ACR20 response rate. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated filgotinib 200 mg + MTX was likely to achieve the best ACR20 response rate (SUCRA = 0.902), followed by filgotinib 100 mg + MTX (SUCRA = 0.694), filgotinib 100 mg (SUCRA = 0.675), adalimumab 40mg + MTX (SUCRA = 0.661), filgotinib 200 mg (SUCRA = 0.305), placebo + MTX (SUCRA = 0.259), and placebo (SUCRA = 0.005). The safety based on the number of serious adverse events (SAEs) did not differ significantly among 6 six interventions. Filgotinib 100 and 200 mg administration once daily in combination with MTX was the most efficacious intervention for active RA, with no significant risk of SAEs.

FRI0228 TOFACITINIB IN THE TREATMENT OF SKIN AND MUSCULOSKELETAL INVOLVEMENT IN ADULT PATIENTS WITH EARLY SYSTEMIC SCLEROSIS, EVALUATED BY ULTRASOUND

Background:The whole management of systemic sclerosis (SSc) remains to be defined while trials mainly focus on the treatment of different organ involvement and disease-modifying treatments are still not available.Objectives:To assess the safety and efficacy of tofacitinib (TOF) treatment on skin and musculoskeletal involvement as compared to methotrexate (MTX) treatment in patients with early SSc.Methods:In this 52-week, prospective, investigator-initiated, open-label, single-centre study, 66 patients with SSc were enrolled. Thirty-three patients received 5mg of oral TOF twice a day; and thirty-three received 7.5-10 mg of MTX weekly. The primary outcome measures were: skin fibrosis improvement at week 26, assessed by the reduction in skin thickness - evaluated by the modified Rodnan skin score (mRSS) and the ultrasound (US) measured skin thickness; improvement in the musculoskeletal involvement, assessed by the reduction in the joint and tendon score (US10SSc score); and adverse events from baseline to week 26. The dynamics in the outcome measures within each group were examined through Wilcoxon tests and between-group comparisons were performed through Mann-Whitney U and Chi-square tests.Results:At baseline, both groups of patients had similar median scores with no significant differences on all measures: mRSS (p = 0.589), US measured skin thickness (p = 0.822), and US10SSc score (p = 0.918). At week 26, significant differences were observed between the two treatment groups as the TOF treated patients showed a greater reduction in mRSS and musculoskeletal manifestations. In the TOF group, the median mRSS score decreased by 50% from 24 to 12 (IQR = 7.50) versus a smaller decrease of 8.70% in the MTX group, from 23 to 21 (IQR = 8.00), p &lt; 0.001. The median US measured skin thickness in the TOF treated patients decreased by 12.87% from 1.71 to 1.49 (IQR =0.31) versus a decrease of 4.73%, from 1.69 to 1.61 (IQR =0.52) in the MTX group, p = 0.040. The US10SSc median score in the TOF group decreased by 56.25% from 16 to 7 (IQR = 6.50) versus a decrease of 12.5% in MTX group from 16 to 14 (IQR =10.50), p &lt; 0.001. There was no significant difference between the groups in the number of adverse events from baseline to week 26. No cases of herpes zoster and deep vein thrombosis were observed in the TOF group.Conclusion:The data show that in early SSc TOF may lead to a significant improvement of skin thickness, measured with the mRSS and US, and of the musculoskeletal involvement, measured by the US10SSc score. TOF has also shown a satisfactory safety profile.

SAT0100 ASSOCIATION BETWEEN LOW HEMOGLOBIN AND RADIOGRAPHIC PROGRESSION OVER 52 WEEKS IN PATIENTS WITH RHEUMATOID ARTHRITIS: RESULTS FROM A PHASE 3 TRIAL OF SARILUMAB

Background:Anemia is a common comorbidity in patients with rheumatoid arthritis (RA).Objectives:Assess whether low hemoglobin (Hb) identifies a subgroup of patients at increased risk of joint damage progression, and investigate whether sarilumab modulates this risk.Methods:The 52-week, double-blind, Phase 3 MOBILITY trial (NCT01061736) in patients with active RA and inadequate response to methotrexate (n = 1197) demonstrated the tolerability and efficacy (clinical and radiographic) of subcutaneous sarilumab 150 and 200 mg every 2 weeks versus placebo, both in combination with methotrexate (MTX). In thispost hocanalysis, baseline characteristics and radiographic outcomes in MOBILITY were analyzed by baseline Hb category (low or normal) according to World Health Organization criteria, with low Hb defined as &lt;120 g/L for women and &lt;130 g/L for men. NominalPvalues are presented.Results:A total of 414 patients (35%) had low Hb at baseline. Patients with low Hb were more likely than patients with normal Hb to be female (86% vs 79%, respectively), Asian (14% vs 5%), younger (mean age 49 vs 51 years), and to have lower body weight (mean 69 vs 77 kg); all nominalP&lt;0.01. Duration of RA, prior biologic use, rheumatoid factor positivity, and baseline tender and swollen joint counts were similar between patients with low and normal baseline Hb, but there was a nominally significant difference in C-reactive protein (mean 30.2 [SD 28.5] vs 17.3 [18.5] mg/L;P&lt;0.0001). Patients with low Hb generally exhibited more joint damage progression over 52 weeks than patients with normal Hb (Table). In the sarilumab + MTX groups, joint damage progression was mitigated compared with placebo + MTX in patients with low Hb and in patients with normal Hb. Mean change from baseline in Hb at 52 weeks in the placebo + MTX, sarilumab 150 mg + MTX, and sarilumab 200 mg + MTX groups was +3.7 (SD 10.8), +14.7 (12.1), and +14.0 (10.5) g/L, respectively, in patients with low Hb at baseline, and –2.5 (9.9), +6.2 (9.3), and +8.0 (9.9) g/L in patients with normal Hb at baseline.Table.Mean change from baseline (SD) in radiographic measures of joint damagePlacebo+ MTXSarilumab 150 mg+ MTXSarilumab 200 mg+ MTXLow Hb (n = 140)Normal Hb (n = 258)Low Hb (n = 145)Normal Hb (n = 255)Low Hb (n = 129)Normal Hb (n = 270)mTSS3.75 (9.00)2.29 (6.98)1.20*** (5.58)0.73** (4.07)0.60*** (4.13)0.08*** (4.83)Joint space narrowing1.52 (3.71)1.22 (3.92)0.79* (3.17)0.30** (2.70)0.50** (2.93)0.06*** (3.33)Erosion score2.24 (6.24)1.07 (3.91)0.41*** (3.18)0.44* (2.05)0.10*** (2.13)0.02*** (2.19)NominalP*&lt;0.05, **&lt;0.01, ***&lt;0.001 versus placebo by rank ANCOVA model stratified by prior biologic use and region; mTSS, modified total Sharp scoreConclusion:Overall, sarilumab slowed joint damage progression in patients with RA. Additionally, in those patients with low Hb, who may suffer greater damage than those with normal Hb, sarilumab also increased Hb.Acknowledgments:Study funding and medical writing support (Matt Lewis, PhD, of Adelphi Communications Ltd, Macclesfield, UK) were provided by Sanofi Genzyme (Cambridge, MA, USA) and Regeneron Pharmaceuticals, Inc. (Tarrytown, NY, USA) in accordance with Good Publication Practice (GPP3) guidelines.Disclosure of Interests:Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Jean-Pierre Morello Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Owen Hagino Shareholder of: Sanofi, Employee of: Sanofi, Amy Praestgaard Employee of: Sanofi Genzyme, Stefano Fiore Shareholder of: Sanofi, Employee of: Sanofi, Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme

AB0785 REAL LIFE EXPERIENCE OF METHOTREXATE BASED DUAL COMBINATION DMARDS IN PSORIATIC ARTHRITIS- RESULTS FROM KARNATAKA PSORIATIC ARTHRITIS COHORT (KPsAC)

Background:Biologics have been the focus of recent treatment guidelines and ‘Treat to Target’ strategies for both psoriasis (PsO) &amp; psoriatic Arthritis (PsA). However, in day-today practice, combination DMARDs anchored around methotrexate are mainstay in majority of patients.Objectives:To describe experience and effectiveness of Methotrexate in combination with conventional DMARDs in Karnataka Psoriatic Arthritis Cohort.Methods:Treatment information was extracted from KPsAC (n=549) which is a cross sectional, non-interventional study conducted across 17 rheumatology practicing centres in Karnataka, India using a structured proforma. This study was approved by respective Ethical committee. Information on efficacy was extracted for various csDMARDs in combination with methotrexate. Standard disease activity outcome measures were used for assessing the response to therapy (DAPSA, PASI, HAQ, MDA5). All participating rheumatologists underwent training to calculate PASI and other outcome scores.Results:Nearly half of the patients in our cohort were on methotrexate (44%) monotherapy. Proportion of patients who received combination csDMARD anchored on methotrexate were 29%. The choice of add on csDMARD was as per clinician discretion or subject preference. Patients were divided in to three groups based on treatments they were receiving at the time of study: Methotrexate (Mtx)+Leflunomide (Lef), Mtx+Sulfasalazine (SSz) and Mtx+Apremilast(Apr). Their characteristics along with outcome measures are depicted in table 1. In Mtx+Apr group: remission or low disease activity was present in 42%, HAQ score of &lt;0.5 was seen in 82%, and only one patient had a PASI of &gt; 10. PASI was significantly lower in the Mtx+Apr group compared to Mtx+Lef group (p&lt;0.009) and Mtx +Ssz group (p &lt; 0.020)Conclusion:Apremilast is an orally administered, small molecule inhibitor of phosphodiesterase 4 (PDE4)**. In this observational study, 3 groups of methotrexate plus csDMARD- leflunomide, sulphasalazine and apremilast fared similarly for articular domain of PsA. However, in cutaneous domain, PASI was significantly lower in apremilast + methotrexate group. To our knowledge, this is the first real life report of the use of combination DMARDs in unselected PsA patients demonstrating effectiveness of apremilast in cutaneous domain. Methotrexate remains anchor DMARD for treatment of PsA in 2/3rdof PsA patients. Addition of apremilast to methotrexate inadequate responders appears to be beneficial in PsA with persistent cutaneous disease. However, being an observational study, this needs to be confirmed in controlled clinical trials.

THU0218 INCIDENCE AND RISK FACTORS FOR HERPES ZOSTER IN RHEUMATOID ARTHRITIS PATIENTS RECEIVING UPADACITINIB

Background:Upadacitinib (UPA) is an oral JAK inhibitor approved for the treatment of rheumatoid arthritis (RA). The background rate of herpes zoster (HZ) in patients (pts) with RA is around 0.98/100 person years (PY)1. Pts with RA receiving JAK inhibitors have been reported to have an increased risk of HZ.Objectives:To evaluate the incidence and risk factors for HZ in pts with RA receiving UPA relative to active comparators in the Phase 3 clinical trial program.Methods:The incidence rate of HZ was determined in pts receiving UPA (as monotherapy [mono] or combination therapy) in five randomized Phase 3 trials (SELECT-EARLY, SELECT-MONOTHERAPY, SELECT-NEXT, SELECT-COMPARE, and SELECT-BEYOND), of which 4 evaluated both the UPA 15 and 30 mg once-daily (QD) doses and 1 trial (SELECT-COMPARE) evaluated only the 15 mg QD dose. Incidence of HZ was also determined in pts receiving adalimumab (ADA) + methotrexate (MTX) in SELECT-COMPARE and MTX mono in SELECT-EARLY. Risk factors for HZ were assessed using univariate and multivariate Cox regression models. Data cut-off was 30 June 2019.Results:Overall, 2629 pts who received UPA 15 mg QD (4565.8 patient-years [PY]), 1204 pts who received UPA 30 mg QD (2309.7 PY), 579 pts who received ADA + MTX (768.6 PY), and 314 pts who received MTX mono (456.0 PY) were analyzed. Fewer than 5% of pts across the treatment groups reported prior HZ vaccination. HZ (n/100 PY [95% CI]) occurred in 142 pts (3.1 [2.6–3.7]) with UPA 15 mg, 126 pts (5.5 [4.5–6.5]) with UPA 30 mg, 8 pts (1.0 [0.4–2.1]) with ADA + MTX, and 5 pts (1.1 [0.4–2.6]) with MTX mono. Most of the HZ cases (~71%) with UPA (Table) and all cases with ADA + MTX and MTX mono involved a single dermatome. Ophthalmic involvement was seen in 6 (4.2%) and 3 (2.4%) cases in the UPA 15 and 30 mg groups, respectively, and unilateral involvement with multiple dermatomes was seen in 26 (18.3%) and 23 (18.3%) cases. There was a single case of HZ meningitis reported in a Japanese pt on UPA 30 mg. In multivariate analyses, prior history of HZ and Asian region were associated with an increased risk of HZ in both the UPA groups (p≤0.01;Figure). In addition, pts ≥65 years old had increased risk of HZ in the 15 mg group.Conclusion:HZ events in pts with RA receiving UPA were more common in the 30 mg vs 15 mg group, and in both UPA groups compared with the ADA + MTX and MTX groups.

OP0050 ADALIMUMAB INTRODUCTION VERSUS METHOTREXATE DOSE ESCALATION IN PATIENTS WITH INADEQUATELY CONTROLLED PSORIATIC ARTHRITIS: RESULTS FROM RANDOMIZED PHASE 4 CONTROL STUDY

Background:Methotrexate (MTX) is often used as first-line therapy for patients (pts) with psoriatic arthritis (PsA) despite limited efficacy and data on appropriate dosage. Minimal Disease Activity (MDA) is suggested as an optimal treat-to-target outcome. Biologic disease-modifying antirheumatic drugs (bDMARDs) have demonstrated improved outcomes (including MDA rates) over MTX. However, more data are needed to define the optimal timing of bDMARD initiation and characterize efficacy of MTX dose escalation, to achieve optimal outcomes.Objectives:To compare achievement of MDA between adding adalimumab (ADA) vs escalating MTX dose in PsA pts with inadequate disease control after initial MTX therapy.Methods:The open-label, 2-part CONTROL study enrolled bDMARD-naive adult pts with active PsA (not in MDA at screening and ≥3 tender and ≥3 swollen joints) despite MTX 15 mg every wk (ew) for ≥4 wks. Pts were randomized to ADA 40 mg every other wk + MTX 15 mg (ADA+MTX) or escalated MTX to 20–25 mg ew or highest tolerable dose during 16-wk part 1 (Fig 1). The primary endpoint was achievement of MDA, defined as fulfilling ≥5 of the 7 criteria: tender joint count 68 (TJC68) ≤1, swollen joint count 66 (SJC66) ≤1, Psoriasis Area Severity Index (PASI) ≤1 or body surface area (BSA) ≤3%, pt’s pain (visual analogue scale [VAS] 0–100) ≤15, Pt’s Global Assessment of disease activity (PtGA) VAS ≤20, Health Assessment Questionnaire Disability Index (HAQ-DI) ≤0.5 and tender entheseal points (0–8) ≤1. Key secondary efficacy endpoints were achievement of ACR20 and PASI75 and change from baseline in HAQ-DI and Leeds Enthesitis Index (LEI) at wk 16.Results:Overall, 246 pts were randomized; 245 received treatment (ADA+MTX, n=123; escalated MTX, n=122); 117 (95%) pts and 110 (90%) pts, respectively, completed part 1. Baseline characteristics were similar between groups (Table). During part 1, the average dose of MTX was 21.8 mg/wk (55% on oral MTX) in the escalated MTX group. Significantly higher proportion of pts in ADA+MTX (42%) vs escalated MTX (13%) group achieved MDA at wk 16 (non-responder imputation [NRI]; difference [95% CI] 28% [18%–39%];P&lt;0.001;Fig 2). Observed case analysis confirmed the NRI analysis. Lower MDA rates at wk 16 were observed in the escalated MTX arm regardless of prior MTX duration (Fig 2). Significant improvements in key secondary endpoints were also observed with ADA+MTX vs escalated MTX (allP&lt;0.05;Fig 2). In part 1, the proportion of patients with adverse events was similar between groups (ADA+MTX, 62% vs escalated MTX, 57%); no opportunistic infections, tuberculosis, malignancies, or deaths were reported during part 1.Conclusion:A significantly higher proportion of pts achieved MDA at wk 16 after introducing ADA compared with escalating MTX dose; higher rates were observed regardless of prior MTX duration. Significantly higher responses in musculoskeletal, skin, and quality of life measures were observed with ADA+MTX vs escalated MTX. No new safety signals with ADA were identified in this pt population.Table 1.Baseline DemographicsCharacteristics, mean (SD)ADA+MTXn=123Escalated MTXn=122Female, n (%)64 (52.0)59 (48.4)Age, y51.4 (12.2)48.8 (12.7)BSA &gt;3%, n (%)74 (60.2)78 (63.9)Pt pain63.7 (19.5)62.3 (20.9)PtGA65.0 (19.9)62.9 (20.9)HAQ-DI1.2 (0.6)1.2 (0.7)LEI + plantar count3.5 (2.1)3.5 (2.1)Disclosure of Interests:Laura C Coates: None declared, William Tillett Grant/research support from: AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant of: AbbVie, Amgen, Celgene, Lilly, Janssen, Novartis, MSD, Pfizer Inc, UCB, Speakers bureau: AbbVie, Amgen, Celgene, Lilly, Janssen, Novartis, Pfizer Inc, UCB, Maria Antonietta D’Agostino Consultant of: AbbVie, BMS, Novartis, and Roche, Speakers bureau: AbbVie, BMS, Novartis, and Roche, Proton Rahman Grant/research support from: Janssen and Novartis, Consultant of: Abbott, AbbVie, Amgen, BMS, Celgene, Lilly, Janssen, Novartis, and Pfizer., Speakers bureau: Abbott, AbbVie, Amgen, BMS, Celgene, Lilly, Janssen, Novartis, Pfizer, Frank Behrens Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Lilly and Roche, Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai, Philip G Conaghan Consultant of: AbbVie, BMS, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, GSK, Novartis, Pfizer, Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer, Erin McDearmon-Blondell Shareholder of: AbbVie, Employee of: AbbVie, Xianwei Bu Shareholder of: AbbVie, Employee of: AbbVie, Liang Chen Shareholder of: AbbVie, Employee of: AbbVie, Mudra Kapoor Shareholder of: AbbVie, Employee of: AbbVie, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau

THU0197 SAFETY PROFILE OF UPADACITINIB UP TO 3 YEARS OF EXPOSURE IN PATIENTS WITH RHEUMATOID ARTHRITIS

Background:The safety and efficacy of upadacitinib (UPA), an oral JAK inhibitor, was evaluated in the phase 3 SELECT clinical program, which included 5 randomized, double-blind, controlled trials across a spectrum of rheumatoid arthritis (RA) patients (pts)1-5.Objectives:To describe the long-term integrated safety profile of UPA relative to active comparators in pts with RA treated in the SELECT program up to a cut-off date of 30 June 2019.Methods:Treatment-emergent adverse events (TEAEs: AE onset ≥first dose and ≤30 days after last dose) were summarized for the following: methotrexate (MTX, 1 trial, mean exposure 76 wks); adalimumab (ADA, 1 trial, mean exposure 69 wks); pooled UPA 15 mg (5 trials, mean exposure 90 wks); pooled UPA 30 mg (4 trials, mean exposure 100 wks). TEAEs are reported as exposure-adjusted event rates (EAERs; events/100 patient years [E/100PYs]).Results:3833 pts received ≥1 dose of UPA 15 mg [n=2629, 4565.8 PYs] or 30 mg [n=1204, 2309.7 PYs] QD, with no option to switch doses. More than half of pts received UPA for ≥96 wks (median: UPA 15, 101.9 wks; UPA 30: 111.7 wks). The EAERs of overall SAEs and AEs leading to discontinuation on UPA 15 mg were comparable to MTX and ADA; rates on UPA 30 mg were numerically higher than UPA 15 mg (Table). The most common AEs (≥5 E/100 PYs) reported with UPA 15 mg were upper respiratory tract infection (URTI), nasopharyngitis, urinary tract infection (UTI), bronchitis, increased CPK, and increased ALT. For UPA 30 mg, the most common AEs reported were URTI, UTI, increased CPK, nasopharyngitis, bacterial bronchitis, and herpes zoster (HZ). Overall rates of serious infections and opportunistic infections were comparable between UPA 15 mg, MTX, and ADA groups but were higher on UPA 30 mg (Figure). Rates of HZ were higher in both UPA groups (30 mg higher than 15 mg) vs MTX and ADA. The majority of HZ cases were non-serious (96%) and involved a single dermatome (74%). Rates of VTE were comparable across treatment groups (0.3-0.5/100 PYs), as were rates of adjudicated MACE and malignancies (excluding NMSC). Rates of NMSC in UPA 15 mg and ADA were similar, with numerically higher rates on UPA 30 mg. SMR analysis demonstrated that the number of deaths in pts with RA exposed to UPA was not higher than what would be expected for the general population.Conclusion:Through long-term follow-up, the integrated safety profile of UPA remained consistent with previous analyses, with no new signals identified.

The Effect of Dehydroepiandrosterone on Ovarian Reserve in Ovarian Damage Caused by Methotrexate

To determine the possible detrimental effects of multiple methotrexate doses has on the ovarian reserve and to determine the beneficial effects of dehydroepiandrosterone supplementation. The rats (n:24) divided into three groups; Group 1: control group, Group 2: dehydroepiandrosterone and methotrexate group (6mg/kg dehydroepiandrosterone dissolved in 0.1 ml sesame seed oil subcutaneously for ten days and 1mg/kg intramuscular methotrexate at the 1st, 3rd, 5th and 7th days) and Group 3: methotrexate group (1mg/kg intramuscular methotrexate at the 1st, 3rd, 5th and 7th day). The groups compared in regards to their histopathological ovarian damage scores and AMH values. It established that multiple methotrexate applications had a considerable effect on reducing vascular congestion in the ovarian tissue. Both in groups 2 and 3 AMH values found to be significantly lower. When this decline in the ovarian reserve examined comparatively; while both the group 2 and 3 reported having a considerable and continuous reduction in the AMH levels correlative to the control group; the primordial, primary and total follicle counts shown to stay statistically the same in the group 2 (p

The Effect of Dehydroepiandrosterone on Ovarian Reserve in Ovarian Damage Caused by Methotrexate

To determine the possible detrimental effects of multiple methotrexate doses has on the ovarian reserve and to determine the beneficial effects of dehydroepiandrosterone supplementation. The rats (n:24) divided into three groups; Group 1: control group, Group 2: dehydroepiandrosterone and methotrexate group (6mg/kg dehydroepiandrosterone dissolved in 0.1 ml sesame seed oil subcutaneously for ten days and 1mg/kg intramuscular methotrexate at the 1st, 3rd, 5th and 7th days) and Group 3: methotrexate group (1mg/kg intramuscular methotrexate at the 1st, 3rd, 5th and 7th day). The groups compared in regards to their histopathological ovarian damage scores and AMH values. It established that multiple methotrexate applications had a considerable effect on reducing vascular congestion in the ovarian tissue. Both in groups 2 and 3 AMH values found to be significantly lower. When this decline in the ovarian reserve examined comparatively; while both the group 2 and 3 reported having a considerable and continuous reduction in the AMH levels correlative to the control group; the primordial, primary and total follicle counts shown to stay statistically the same in the group 2 (p<0.0167). The dehydroepiandrosterone supplementation, while did not have a significant effect on reducing ovarian damage induced by methotrexate, also was not shown to provide any considerable increase in AMH levels. However, prolonged usage of dehydroepiandrosterone by contributing to the antral follicle pool considered promising in increasing the AMH levels conceivably

Post-transplant cyclophosphamide as graft-versus-host disease prophylaxis in HLA matched sibling donor stem cell transplantation for patients with acute leukemia.

e19523 Background: Graft-versus-host disease (GVHD) is a life-threatening complication of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT). Calcineurin inhibitor (CNI) and methotrexate (MTX) have been used as the standard GVHD prophylaxis in HLA-matched HSCT. Promising clinical trial data using high dose post-transplant Cyclophosphamide (PT-Cy) with or without additional immunosuppressive agents (IS) have shown that it’s an effective, well tolerated alternative. However, experiences are limited with controversial results. Methods: We analyzed 62 patients with Acute Leukemia (39 males, 23 females) with age ranges from 18 to 60 years underwent allogeneic HSCT from matched sibling donors (MSD) using reduced intensity chemotherapy at Maadi Armed Forces Medical Hospital after informed consent. They were randomized into 2 groups according to GVHD prophylaxis regimen. The 1st group (40 patients) received MTX in the following doses; day+2 (15mg), day +4 (10 mg), day +6 (10 mg) with Cyclosporine (5mg/kg) from day -3 till day +90 and Mycophenolate (MMF) (2 -3gm/day) from day +1 till day +30. The 2nd group(22 patients) received PT-Cy (45 mg/kg/day) on days +3 and +4 with Cyclosporine (5mg/kg) from day +5 till day +30 &amp; MMF:(2-3gm /day) from day +5 till +30. Results: At median 1 year Post Allo, PT-Cy was associated with statistically significant lowering of chronic GVHD (cGVHD) incidence compared to MTX group (22.7%, 56.4%) respectively (P = 0.011). Incidence of acute GVHD (aGVHD) at day +100 was (40%, 22.7%) in group 1, 2 respectively (P = 0.169). 92% of patients in group 1 and 86.4 % of patients in group 2 were engrafted with full donor chimerism on day +30 (P = 0.659). The cumulative incidence of relapse at 4 years after transplantation was 17.9 % for group 1 and 36.4 % for group 2 (P &gt; 0.05). Relapse related mortality were 16.2% among MTX group while 27.3% in PT-Cy group (P = 0.10). Transplant related mortality (TRM) in MTX group were; Severe aGVHD (8%), cGVHD (10%), Hepatic Toxicity (8%), Nephrotoxicity (2.7%) &amp; ARDS (5.4%). In PT-Cy group TRM were; septicemia (18%), severe aGVHD (4.5%) &amp; ARDS (4.5%). Cumulative 4 years Disease Free Survival (DFS) &amp; Overall survival (OS) in PT-Cy group were (51.8 %, 46.4%) respectively while (69.3%, 39%) in MTX group which is statistically non-significant (P &gt; 0.05). Conclusions: For GVHD prophylaxis in MSD, PT-Cy is a safe alternative that reduces the risk of cGVHD in comparison with MTx based regimen without affecting Relapse rate, DFS or OS.

Comparison of combination therapy of methotrexate with etanercept and etanercept alone in psoriasis in Tertiary care center in South India

Psoriasis is a disorder of chronic nature. But the present day systemic therapies for psoriasis of moderate to severe nature are associated with toxicity and also have a greater level of displeasure in the patients. Hence the current focus for treatment is with intermittent or combination therapy that helps to overcome the loss of effectiveness in treatment over time and decrease the side effects as a result of cumulative toxicities during monotherapy. To assess the effectiveness of oral Methotrexate and Etanercept combination therapy in comparison to Etanercept monotherapy for treatment of moderate to severe plaque type of psoriasis among patients. This was a prospective analytical study conducted in dermatology OPD of Madras Medical College, a tertiary care centre in south India between August 2015 and July 2016. About Forty subjects clinically diagnosed with plaque type of psoriasis based upon the clinical history and morphology of the dermatological lesions were included in this hospital based study depending on inclusion and exclusion criteria and were randomly allocated into two groups. Group C: Combination therapy with oral methotrexate and Etanercept and Group M:Monotherapy with Etanercept alone. All the patients were reviewed every 4 weeks at intervals of 0,4,8 and 12 weeks for complaints and for assessment of clinical response using PASI scoring and DLQI scoring and other investigations. Data was compiled and analyzed with the help of Statistical Package for Social Science (SPSS) Version 20.0. Mean age of the study population was 37.43 ± 10.1 years. Twenty two subjects were males (55%) and eighteen subjects were females (45%). The subjects who received Group C (Methotrexate and Etanercept combination therapy) therapy achieved 75% reduction of PASI in comparison to subjects who received Group M (Etanercept monotherapy) after 8 weeks (30% vs 5%) and after 12 weeks (100% vs 50%). Also Group C showed good response to treatment after 12 weeks in comparison to Group M (85% vs 50%) and this difference in proportion of treatment response between the two groups was statistically significant. Subjects who received Group C showed greater decline (77.4% vs 68.7) in DLQI score after 12 weeks in comparison to subjects who received Group M.

Protective effects of apocynin on damaged testes of rats exposed to methotrexate

Background/aimMethotrexate (MTX), widely used as a drug in cancer, has many adverse effects on tissues. Apocynin (APO) is a NADPH oxidase inhibitor and is known with many antioxidant properties. In this study, we aimed to evaluate the adverse effects of MTX on testicular tissue and the protective effects of APO at two different doses (20 mg/kg and 50 mg/kg) on MTX-induced testicular damage.Materials and methodsFifty adult male Wistar albino rats (8 weeks old and weighing 200–250 g) were divided into five groups of 10 rats each: 1. saline control, 2. dimethyl sulfoxide (DMSO) control, 3. MTX, 4. APO-20 + MTX, and 5. APO-50 + MTX. All injections were performed intraperitoneally. At the end of day 28, all rats were sacrificed under anesthesia. The testes were evaluated histologically and the blood samples were analyzed biochemically.ResultsAccording to histological and biochemical analyses, there was no significant difference between the DMSO and control groups. In terms of the histological findings, MTX group was significantly the worst affected group compared to the others, and in this group, apoptotic cell number (P = 0.011) was significantly increased in comparison with the control group. Except MTX, there was no significant difference in apoptotic cell number of the other groups compared to the control group. In the MTX group, malondialdehyde (MDA, P = 0.017) and myeloperoxidase (MPO, P < 0.001) levels were significantly increased in tissue and in blood (MDA P < 0.001, MPO P < 0.001), while tissue glutathione (GSH, P < 0.05) and serum testosterone levels (P < 0.01) were decreased compared with the control group. APO + MTX treatment groups exhibited better testis morphology, and apoptotic cells were also significantly decreased compared to MTX group (P < 0.001).Conclusion Our results suggest that MTX induced defects on testis via oxidative stress and APO reversed the effects of MTX with its antioxidant properties.