Assessment of the toxic effects of levetiracetam on biochemical, functional, and redox parameters of salivary glands in male Wistar rats.

Levetiracetam (LEV) is an anticonvulsant for epilepsy. The toxic effects of this medication in tissues have been associated with redox state imbalance, which can lead to salivary gland dysfunction. Therefore, the current work investigated the effects of LEV on the biochemical, functional, and redox parameters of the parotid and submandibular glands in rats. For this, male Wistar rats (Rattus norvegicus albinus) were randomly divided into 3 groups (n = 10/group): Control (0.9% saline solution), LEV100 (100 mg/kg), and LEV300 (300 mg/kg). After 21 consecutive days of intragastric gavage treatments, pilocarpine stimulated saliva secretion was collected for salivary biochemical analysis. The extracted salivary glands were utilized for histomorphometry and redox state analyses. Our results showed that LEV300 increased plasma hepatotoxicity markers and reduced salivary amylase activity and the acinar surface area of the parotid gland. Total oxidant capacity and oxidative damage to lipids and proteins were higher in the parotid gland, while total antioxidant capacity and uric acid levels were reduced in the submandibular gland of the LEV100 group compared to Control. On the other hand, total oxidant capacity, oxidative damage to lipids and proteins, total antioxidant capacity, and uric acid levels were lower in both salivary glands of the LEV300 group compared to Control. Superoxide dismutase and glutathione peroxidase activities were lower in the salivary glands of treated animals compared to Control. In conclusion our data suggest that treatment with LEV represents a potentially toxic agent, that contributes to drug-induced salivary gland dysfunction.

The impact of disease severity and duration on cost, early retirement and ability to work in rheumatoid arthritis in Europe: an economic modelling study.

OBJECTIVE: RA is a progressive, chronic autoimmune disease. We summarize the impact of disease activity as measured by the DAS in 28 joints (DAS28-CRP scores) and pain on productivity and ability to work using the Work Productivity and Activity Impairment questionnaire (WPAI) scores, in addition to the impact of disease duration on the ability to work. METHODS: Data were drawn from the Burden of RA across Europe: a Socioeconomic Survey (BRASS), a European cross-sectional study in RA. Analyses explored associations between DAS28-CRP score and disease duration with stopping work because of RA, and regression analyses assessed impacts of pain and DAS28-CRP on early retirement and WPAI. RESULTS: Four hundred and seventy-six RA specialist clinicians provided information on 4079 adults with RA, of whom 2087 completed the patient survey. Severe disease activity was associated with higher rates of stopping work or early retirement attributable to RA (21%) vs moderate/mild disease (7%) or remission (8%). Work impairment was higher in severe (67%) or moderate RA (45%) compared with low disease activity [LDA (37%)] or remission (28%). Moreover, patients with severe (60%) or moderate pain (48%) experienced increased work impairment [mild (34%) or no pain (19%)]. Moderate to severe pain is significant in patients with LDA (35%) or remission (22%). A statistically significant association was found between severity, duration and pain vs work impairment, and between disease duration vs early retirement. CONCLUSION: Results demonstrate the high burden of RA. Furthermore, subjective domains, such as pain, could be as important as objective measures of RA activity in affecting the ability to work.

Cost-Effectiveness of a JAK1/JAK2 Inhibitor vs a Biologic Disease-Modifying Antirheumatic Drug (bDMARD) in a Treat-to-Target Strategy for Rheumatoid Arthritis.

BACKGROUND: Baricitinib is a janus kinase (JAK1/JAK2) inhibitor developed for the treatment of patients suffering from rheumatoid arthritis (RA). Treating RA to the target of remission is current common practice. Cost-effectiveness of different treat-to-target (T2T) strategies, especially ones including new treatments is important for development and preference policy for treatment centers. European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) guidelines are currently unclear about preference between a JAK1/JAK2 versus a biological disease-modifying antirheumatic drug (bDMARD). OBJECTIVE: The main goal of this paper was to evaluate the cost-effectiveness of baricitinib versus first biological for methotrexate inadequate responders in a T2T strategy using a Markov model that incorporates hospital costs as well as societal costs. Costs and utilities over five years were compared between the two strategies. METHODS: A Monte Carlo simulation model was developed to conduct cost-utility analysis from the societal perspective over 5 years. Health states were based on the DAS28-erythrocyte sedimentation rate (ESR) categories. Effectiveness of baricitinib was retrieved from randomized controlled trials. Effectiveness of all other treatments, health state utilities, medical costs, and productivity loss were retrieved from the Dutch RhEumatoid Arthritis Monitoring (DREAM) cohorts. Annual discount rates of 1.5% for utility and 4% for costs were used. Probabilistic sensitivity analysis was employed to incorporate uncertainty and assess robustness of the results. RESULTS: Probabilistic sensitivity analysis results showed the baricitinib strategy yielded lower costs and higher utility over a 5-year period. Scenario analyses showed the baricitinib strategy to be cost-effective in both the moderate and severe RA populations. CONCLUSION: Results suggest that the use of a JAK1/JAK2 inhibitor instead of a bDMARD in a T2T approach is cost-effective in csDMARD refractory RA patients.

A modeling framework for the economic evaluation of baricitinib in moderate-to-severe rheumatoid arthritis.

Objectives: The approval in more than 50 countries of baricitinib, an oral Janus Kinase inhibitor for the treatment of Rheumatoid Arthritis (RA), warrants a framework for corresponding economic evaluations. To develop a comprehensive economic model assessing the cost-effectiveness of baricitinib for the treatment of moderately-to-severely active RA patients in comparison to other relevant treatments, considering the natural history of the disease, real world treatment patterns, and clinical evidence from the baricitinib trials.Methods: A systematic literature review of previously developed models in RA was conducted to inform the model structure, key modeling assumptions and data inputs. Consultations with rheumatologists were undertaken to validate the modeling approach and underlying assumptions.Results: A discrete event simulation model was developed to international best practices with flexibility to assess the cost-effectiveness of baricitinib over a lifetime in a variety of markets. The model incorporates treatment sequencing to adequately reflect treatment pathways in clinical practice. Outcomes assessed include cost and quality-adjusted life years, allowing for a full incremental analysis of cost-effectiveness of competing treatments and treatment sequences.Conclusion: The economic model developed provides a robust framework for future analyses assessing the cost-effectiveness of baricitinib for the treatment of RA in specific country settings.

Cost-effectiveness analysis of baricitinib versus adalimumab for the treatment of moderate-to-severe rheumatoid arthritis in Spain.

Background: Baricitinib is an oral janus kinase inhibitor for the treatment of rheumatoid arthritis (RA) and is approved in Europe for use in adults with moderately-to-severely active RA and an inadequate response or intolerance to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy. To date, no economic evaluations have assessed the cost-effectiveness of baricitinib in the Spanish setting. Objectives: To evaluate the cost-effectiveness of baricitinib versus adalimumab for the treatment of moderately-to-severely active RA in the Spanish setting. Methods: A discrete event simulation model was developed in Microsoft Excel. Costs and outcomes were estimated over a lifetime horizon using the Spanish national payer perspective. The model compared baricitinib 4 mg once daily in combination with methotrexate with adalimumab 40 mg every other week in combination with methotrexate. Effectiveness and physical function were captured using the American College of Rheumatology criteria and the Health Assessment Questionnaire-Disability Index, input values of which were derived from a phase 3, double-blind, placebo- and active-controlled trial (RA-BEAM; funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358). Costs are presented in Euros, 2018 values. Results: In the base case analysis, baricitinib was associated with a quality-adjusted life year gain of 0.09 years over a lifetime horizon, at an incremental cost of -€558 versus adalimumab. Results of various scenario analyses and probabilistic sensitivity analysis generally were consistent with the base case analysis. Conclusion: This analysis suggests that baricitinib is a cost-effective treatment option compared to adalimumab for Spanish patients with moderately-to-severely active RA and a previous inadequate response or intolerance to csDMARD therapy.

Long-term clinical, functional, and cost outcomes for early rheumatoid arthritis patients who did or did not achieve early remission in a real-world treat-to-target strategy.

OBJECTIVE: To retrospectively compare the long-term clinical, functional, and cost outcomes for early RA patients (symptoms < 1 year) who did or did not achieve early remission in a treat-to-target strategy. METHOD: Five-year data of 471 patients included in the DREAM remission induction cohort were used. Patients were treated according to a pre-specified 28-joint Disease Activity Score (DAS28) remission driven step-up treatment strategy starting with methotrexate, addition of sulfasalazine, and exchange of sulfasalazine for biological medication in case of failure. Two- and 3-year healthcare costs were available for selected subsamples of patients only. RESULTS: DAS28 remission was achieved in 27.7%, 38.2%, and 51.6% of patients at 2, 3, and 6 months, respectively. Achieving DAS28 remission at 2, 3, or 6 months was consistently associated with significantly lower DAS28 and Health Assessment Questionnaire-Disability scores at 1, 3, and 5 years of follow-up (all P values < 0.02). Patients in remission at 2, 3, or 6 months also had significantly lower medication costs per patient over the first 2 and 3 years of treatment, mainly due to lower biologic use, but differences in total healthcare resource costs (hospital admissions plus consultations) were less pronounced. Mean total medication and total healthcare resource costs at 3 years were €1131 and €1757 for patients in remission at 6 months vs. €7533 (P < 0.01) and €2202 (P = 0.09) for those not in remission. CONCLUSION: Achieving early remission was associated with beneficial clinical outcomes for early RA patients and lower costs in the long term. Key Points • Previous studies in rheumatoid arthritis patients have demonstrated that early good response is associated with sustained remission and better long-term clinical outcomes. • This study extents these findings by examining the long-term benefits of achieving early remission on clinical, patient-reported, and economic outcomes in a real-world cohort of patients with very early rheumatoid arthritis treated according to treat-to-target principles. • The findings of this study clearly demonstrate that aiming for early remission in rheumatoid arthritis patients is beneficial in the long-term in terms of better clinical and functional outcomes and lower healthcare costs.

Treatment patterns, health care resource utilization and costs of rheumatoid arthritis patients in Italy: findings from a retrospective administrative database analysis.

OBJECTIVES: This study aimed to: 1) describe treatment patterns and drug utilization profile (in terms of therapeutic strategy used, switch, persistence and drug consumption variation) among adult patients affected by rheumatoid arthritis (RA), and 2) estimate the health care resource utilization and its associated direct cost for the management of RA patients. METHODS: A retrospective cohort analysis, using administrative databases of six Local Health Units in Italy, was performed. All adult patients with a confirmed diagnosis of RA between January 1, 2010 and December 31, 2014 were enrolled. The date of the first RA diagnosis according to the study criteria during the study period represented the index date (ID) for each patient. Patients enrolled were observed from the ID for at least 12 months (follow-up period), and their clinical characteristics were investigated for 12 months prior to the ID. RESULTS: A total of 10,401 patients with a confirmed RA diagnosis were included. Mean age was 63.0 years and 25% were male; 67% of patients were untreated at ID. During the followup period, 67.8% of patients treated with biologic agents were persistent with initial therapy, compared to 45.7% for patients on conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), while 11% of patients treated with biologic agents switched during the follow-up period, compared to 17.6% of csDMARDs-treated ones. At the end of the follow-up period, 14.7% of all patients in the analysis had an increase and 12.6% of them had a decrease in their initial drug consumption. The mean cost per RA patient was €3,743. CONCLUSION: Our study showed that there is still much that needs to be learned about the prescription of csDMARDs and biologics to RA patients in Italy and to identify areas for future research. The knowledge of RA management in a real-life clinical setting could offer an opportunity to improve the management of RA in Italy.