Efficacy and safety of tofacitinib by background methotrexate dose in psoriatic arthritis: post hoc exploratory analysis from two phase III trials

Objective Analyze tofacitinib efficacy and safety by background methotrexate (MTX) dose in patients with psoriatic arthritis (PsA). Methods This post hoc analysis pooled data from two phase III, double-blind trials (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) including patients receiving tofacitinib 5 or 10 mg twice daily (BID), or placebo, with stable MTX. Efficacy outcomes at month 3 stratified by MTX dose (≤ 15 month 3 stratified by MTX dose vs > 15 mg/week) were American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI); Psoriasis Area and Severity Index (PASI)50/75; change from baseline in HAQ-DI; physician’s global assessment of PsA (PGA-PsA-visual analog scale [VAS]); patient’s global joint and skin assessment (PGJS-VAS), Leeds Enthesitis Index (LEI); and Dactylitis Severity Score (DSS). Safety assessments included adverse events and laboratory parameters. Results Five hundred fifty-six patients received tofacitinib 5 mg BID (n = 186), 10 mg BID (n = 178), or placebo (n = 192), plus MTX (≤ 15 mg/week, n = 371; > 15 mg/week, n = 185). At month 3, tofacitinib efficacy was generally greater than placebo. Patients receiving tofacitinib 5 mg BID demonstrated greater numerical improvements in efficacy outcomes at month 3 with MTX > 15 mg/week vs MTX ≤ 15 mg/week; patients receiving tofacitinib 10 mg BID displayed the opposite. The safety profile was generally consistent between groups; headache was associated with MTX > 15 mg/week; decreased hemoglobin levels were observed in patients receiving tofacitinib 10 mg BID and MTX ≤ 15 mg/week. Conclusion Efficacy of tofacitinib was generally numerically greater than placebo, regardless of MTX dose. Tofacitinib 5 mg BID was generally more efficacious with MTX > 15 mg/week vs ≤ 15 mg/week; the opposite was observed for tofacitinib 10 mg BID. Headache was more frequent with MTX > 15 mg/week. Trial registration ClinicalTrials.gov. Identifier: NCT01877668 (registration: June 14, 2013) and NCT01882439 (registration: June 20, 2013). Key Points• Methotrexate is widely used in the treatment of psoriatic arthritis; however, there are limited data on the impact of varying background methotrexate doses on the efficacy and safety of Janus kinase inhibitors in patients with psoriatic arthritis.• This post hoc analysis assessed the impact of background methotrexate dose (≤ 15 or > 15 mg/week) on tofacitinib efficacy and safety in patients with psoriatic arthritis.• Results indicated that tofacitinib efficacy was generally numerically greater than placebo, regardless of methotrexate dose. Tofacitinib 5 mg twice daily, in combination with a higher dose of background methotrexate, was more efficacious compared with a lower dose of background methotrexate; the opposite was observed for tofacitinib 10 mg twice daily.• Headache was more frequent with the higher methotrexate dose. Data should be interpreted with caution due to the small sample sizes.

Incidence and Predictors of Fragility Fracture in Postmenopausal Rheumatoid Arthritis Patients Receiving Oral Bisphosphonates: A Longitudinal Observational Study

Background: Although many studies have reported the predictors of fractures in patients with rheumatoid arthritis (RA) who are not receiving anti-osteoporotic treatments or who are receiving unspecified treatments, studies focusing on the predictors of fracture in patients with RA who are currently being treated with oral bisphosphonates (BP) are quite scarce. This study aims to investigate the incidence and predictors of fragility fracture in postmenopausal patients with RA receiving oral BP.Methods: This retrospective longitudinal observational study comprised 98 postmenopausal RA patients receiving oral BP for a minimum of 6 months between April 2015 and December 2020. The cumulative incidence of fragility fractures including vertebral and nonvertebral fractures was investigated using the Kaplan–Meier method. Cox proportional hazards analysis was used to analyze baseline predictors of future fragility fractures. To determine a cutoff value of continuous predictors, the receiver-operating characteristic curve was applied.Results: Twenty patients developed fractures during the study period, with a cumulative incidence of 6.1% at 12 months, 10.5% at a median follow-up of 28 months, and 14.4% at 36 months. Multivariable Cox hazards analysis showed a history of prior vertebral fracture (hazard ratio [HR]: 6.26, 95% confidence interval [CI]: 1.99‒19.68, P = 0.001) and dose of methotrexate (HR: 0.87, 95% CI: 0.76‒0.99, P = 0.041) to be independent predictors. The cutoff value for methotrexate dose was 4 mg/week.Conclusions: We found a cumulative incidence of any fractures of 10.5% at 28 months in patients with RA currently being treated with oral BP. A history of prior vertebral fractures and methotrexate dose were positive and negative predictors for fractures, respectively. Practitioners should consider selecting another anti-osteoporotic drug in patients with RA who remain at risk despite receiving oral BP.

AB0136 ASSESSING THE RELATIONSHIP AMONG OBESITY, GENETIC POLYMORPHISM, AND CLINICAL PARAMETERS IN PATIENTS WITH RHEUMATOID ARTHRITIS

Background:Several study suggested body mass index(BMI) may influence development of rheumatoid arthritis(RA). There are conflicting reports concerning the impact of high BMI on development of RA, but several reports of obese on drug resistance and functional impairment. The relationship of genetic polymorphism on obesity is unclear in RA.Objectives:To examine the relationship among BMI, genetic polymorphism of obesity, disease activity of RA, laboratory parameters, and therapeutic agent of RA.Methods:We have carried out a retrospective observational study by systematically analyzing medical records of total 289 patients diagnosed with RA in Shinko Hospital between March 2016 and December 2019. We also conducted genotyping single nucleotide polymorphisms (SNPs) including FTO (rs1558902 and rs9939609), UCP1 (rs1800592), ADR2(rs1042713) and ADR3(rs4994) after informed consent. Obesity was defined as BMI over than 25 and patients were divided between obese (“Ob”) and non-obese (“non-Ob”). These SNPs, DAS28CRP, laboratory parameters, methotrexate dose, use of biological DMARDs were compared between Ob and non-Ob patients.Results:Of these 289 patients, 82.7% was female, mean age was 61.9 years and BMI was 22.4. Univariate logistic regression showed differences (p<0.1) between Ob and non Ob groups in UCP1 gene mutation(63.6% vs 78%, P=0.018), DAS(2.24 vs 1.99, P=0.033),triglyceride abnormality(23.8% vs 9.3%, P=0.021), HDL(56 vs 71, P=0.00009), HbA1c abnormality(26.5% vs 12.1%, P=0.019),γGTP(32 vs 21, P=0.00037), ALP (253 vs 230, P=0.0058), ALT (26.5 vs 20, P=0.029),and MTX dose(6 vs 8, P=0.066). Multivariate logistic regression showed that Ob group was significantly associated with HDL(OR=0.976, 95%CI 0.958 to 0.995), UCP1 gene mutation(OR=0.446, 95%CI 0.202 to 0.984), γGTP(OR=2.321, 95%CI 1.269 to 4.245), and MTX dose(OR=0.866, 0.784 to 0.957).Conclusion:Obesity in patients with RA had significant positive correlation with γGTP, and negative correlation with HDL, UCP gene mutation and MTX dose.Disclosure of Interests:None declared

The association between increased body mass index and response to conventional synthetic DMARD treatment in rheumatoid arthritis: Results from the METEOR database

Background Few data exist on the association between increased BMI and response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) in rheumatoid arthritis (RA). We aimed to explore the association between increased (overweight or obese) BMI on csDMARD-prescribing, methotrexate-dose and disease activity over 12-months. Methods Participants in an international RA database were stratified into early (&lt;1year post-diagnosis) and established RA. EULAR response, DAS28 remission and treatments were recorded at baseline, 6-months and 12-months. Increased BMI was explored in early and established RA, as predictors of good EULAR response, DAS28 remission, number of csDMARDs and methotrexate-dose, using logistic and linear regression. Results Data from 1313 patients, 44.3% with early RA, were examined. In early RA, increased BMI was not significantly associated with remission. In established RA, obese patients on monotherapy were significantly less likely to achieve good EULAR response or DAS28 remission at 6 months and more likely to be treated with combination csDMARDs, compared with normal BMI. In patients taking methotrexate, overweight and obese patients with early and established RA were exposed to higher methotrexate doses (mono- and combination-therapy), with a mean dose of 20mg/week, compared to 15mg/week in those of normal BMI. Conclusion We observed, compared to patients with normal BMI, overweight and obese individuals experienced more intensive csDMARD exposures. Similar response rates were observed in early RA but increased BMI was associated with reduced response in established RA. Optimisation of targeted RA treatment remains important, particularly in those with increased BMI where response in established disease may be attenuated.

COVID-19 pandemic and biological therapy in rheumatologic disorders: how to deal with?

The outbreak of coronavirus disease 2019 (COVID-19) has involved more than 159 countries and more than 5 million people worldwide. A 40-year-old man with a history of rheumatoid arthritis treated with prednisolone, Disease-Modifying Anti-Rheumatic Drugs (DMARDs), and biologic agents was admitted with chief complaints of fever, chills, malaise, myalgia, and dyspnea. Chest computed tomography showed bilateral subsegmental atelectasis and diffuse ground-glass opacities in both lungs inducing the suspicion of COVID-19 infection. The oro-nasopharynx swab sample for COVID-19 polymerase chain reaction was positive. In addition to supportive care, lopinavir/ritonavir 400/100 mg twice daily and oseltamivir (75 mg) twice daily were started in combination with a starting dose of hydroxychloroquine (400 mg). The methotrexate dose was decreased, and the dose of prednisolone was increased to 30 mg for 10 days. Azathioprine and adalimumab were continued at previous doses. The use of biologic agents and DMARDs in rheumatic patients is a serious challenge in the COVID-19 pandemic. In conclusion, during the COVID-19 pandemic, due to the key roles of cytokines in the promotion of the disease, the rheumatic patients may benefit from continuing their previous treatment, which may have protective effects.

BASIC FIBROBLAST GROWTH FACTOR AND ADIPONECTIN IN ADOLESCENCE WITH JUVENILE IDIOPATHIC ARTHRITIS TREATED WITH METHOTREXATE

Methotrexate has been applied clinically for juvenile idiopathic arthritis (JIA) treatment for decades. It is recommended for use globally, according all modern guidelines. Despite the fact that fibrosis molecular mechanisms as well as methotrexate (MTX) elimination and fibrosis indexes were studied a lot there is still not enough information for adolescence. Adiponectin, fibroblast growth factor and fibrosis indexes in adolescents with JIA treated with methotrexate were studied in this work. The aim was to study dynamics of molecular-cellular mechanisms activation of fibrotic processes development in the liver in adolescents with juvenile idiopathic arthritis treated with methotrexate. Materials and methods: A total of 68 children with juvenile idiopathic arthritis, were enrolled in the study. 25 boys (36.8 %) and 43 girls (63.2 %) were examined. Children were divided into three groups in accordance with the methotrexate dose. The following data were analyzed: ESR (mm/hour), C-reactive protein (mg/l), Hemolytic activity (CU), circulating immune complexes, (g/l), ALT (U/l), AST (U/l), Adiponectin (mcg/ml), BFGF (pg/ml), APRI index, FIB-4 Score. Results: According to our results when patients start using MTX they have significantly positive effect. Therefore, when analyzing all parameters liver pathologies may occur before MTX use. When MTX used, its proinflammation and antifibrotic effects lead to normalization of all organs and systems, as well as joints and liver. Also, long-term MTX use can lead to adverse effects. Conclusions: So, it is important to control possible liver disorders in adolescence treated with MTX. According to our study results we find out that there are decreasing of liver damage parameters in patients which started using MTX.