Oral prednisolone suppresses skin inflammation in a healthy volunteer imiquimod challenge model

Imiquimod (IMQ) is a topical agent that induces local inflammation via the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in healthy volunteers for proof-of-pharmacology trials. The aim of this study was to profile the cellular, biochemical, and clinical effects of the marketed anti-inflammatory compound prednisolone in an IMQ model. This randomized, double-blind, placebo-controlled study was conducted in 24 healthy volunteers. Oral prednisolone (0.25 mg/kg/dose) or placebo (1:1) was administered twice daily for 6 consecutive days. Two days after treatment initiation with prednisolone or placebo, 5 mg imiquimod (IMQ) once daily for two following days was applied under occlusion on the tape-stripped skin of the back for 48 h in healthy volunteers. Non-invasive (imaging and biophysical) and invasive (skin punch biopsies and blister induction) assessments were performed, as well as IMQ ex vivo stimulation of whole blood. Prednisolone reduced blood perfusion and skin erythema following 48 h of IMQ application (95% CI [-26.4%, -4.3%], p = 0.0111 and 95% CI [-7.96, -2.13], p = 0.0016). Oral prednisolone suppressed the IMQ-elevated total cell count (95% CI [-79.7%, -16.3%], p = 0.0165), NK and dendritic cells (95% CI [-68.7%, -5.2%], p = 0.0333, 95% CI [-76.9%, -13.9%], p = 0.0184), and classical monocytes (95% CI [-76.7%, -26.6%], p = 0.0043) in blister fluid. Notably, TNF, IL-6, IL-8, and Mx-A responses in blister exudate were also reduced by prednisolone compared to placebo. Oral prednisolone suppresses IMQ-induced skin inflammation, which underlines the value of this cutaneous challenge model in clinical pharmacology studies of novel anti-inflammatory compounds. In these studies, prednisolone can be used as a benchmark.Drug Delivery Technolog

Targeted treatment in early rheumatoid arthritis

With the implementation of new treatment options, including biologicals and the early, agressive start of target-steered treatment the outlook for rheumatoid arthritis patients improved considerably the past decades. This thesis describes several aspects of modern rheumatoid arthritis treatment from the perspective of the BeSt study, a randomised controlled trial comparing four treatment strategies. The main findings from BeSt were that initial combination therapy, including high dose prednisone or the tumour necrosis factor inhibitor infliximab led to an earlier improvement in functional limitations and quality of life, earlier clinical remission and less joint damage after 5 years of follow-up than initial monotherapy. From one year onwards clinical outcomes were comparable across the groups. Drug free remission was possible in up to 20% of patients. Besides the primary outcomes of the BeSt study, this thesis de scribes the association between disease activity and functional capacity, the association between clinical signs of synovitis and joint damage progression at joint level, a comparison between disease activity measures and remission criteria, a comparison between radiological scoring methods, an evaluation of the effect of discontinuation of medication in case of low disease activity and remission and the association between disease activity, treatment and blood pressure.The research was financially supported by the Dutch College of Health Assurances with additional funding by Scheringh-Plough B.V. and Centocor Inc.UBL - phd migration 201

Recent advances in the management of rheumatoid arthritis

Pathophysiology and treatment of rheumatic disease

Pharmacokinetics of intravenous and inhaled salbutamol and tobramycin: An exploratory study to investigate the potential of exhaled breath condensate as a matrix for pharmacokinetic analysis

Concentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath condensate (EBC) as a matrix for pharmacokinetic analysis of inhaled and intravenous medication. A 4-way crossover study was conducted in 12 volunteers with tobramycin and salbutamol intravenously and via inhalation. EBC and plasma samples were collected postdose and analysed for drug concentrations. Sample dilution, calculated using urea concentrations, was used to estimate the epithelial lining fluid concentration. Salbutamol and tobramycin were largely undetectable in EBC after intravenous administration and were detectable after inhaled administration in all subjects in 50.8 and 51.5% of EBC samples, respectively. Correction of EBC concentrations for sample dilution did not explain the high variability. This high variability of EBC drug concentrations seems to preclude EBC as a matrix for pharmacokinetic analysis of tobramycin and salbutamol

Repair of joint erosions in rheumatoid arthritis: prevalence and patient characteristics in a large inception cohort

Background Joint destruction in rheumatoid arthritis (RA) was until recently seen as an irreversible state. Lately, it was found that repair of bone erosions occurs; however, little is known about its prevalence. Objective To investigate the frequency of repair and patients' characteristics associated with repair in an inception cohort. Patients and methods 250 patients with RA, included in the Leiden Early Arthritis Clinic between 1993 and 2000 and treated with conventional disease-modifying antirheumatic drugs, were studied (mean follow-up 10.1 years). Radiographs obtained annually were scored using the Sharp-van der Heijde method, initially aware of the chronology. Patients with a negative change in erosion scores on subsequent radiographs were selected and their series of radiographs were rescored with concealed time sequence by three readers. Repair was defined as agreement between two readers of a negative change in erosion scores that persisted for at least 2 years. Results Repair was identified in 32 joints in 18 patients (7.2%). Patients with repair had a greater prevalence of autoantibodies (rheumatoid arthritis, anti-citrullinated protein antibody) and a higher level of joint destruction. In the joints with repair, arthritis was absent in the 2 years preceding repair. Conclusions Repair occurred in 7.2% of the patients with RA, particularly in clinically inactive joints in patients with severe destructive disease.Pathophysiology and treatment of rheumatic disease

Eight Year Results of Disease Activity Steered Treatment in a Large Recent Rheumatoid Arthritis Cohort: Clinical and Radiological Outcomes

Pathophysiology and treatment of rheumatic disease

The association of treatment response and joint damage with ACPA-status in recent-onset RA: a subanalysis of the 8-year follow-up of the BeSt study

OBJECTIVE: Anticitrullinated protein antibodies (ACPAs) are suggested to identify different subsets of patients with rheumatoid arthritis (RA). The authors compared the clinical and radiological responses to Disease Activity Score (DAS)-steered treatment in patients with RA positive or RA negative for ACPA.METHODS: In the BehandelStrategieën (BeSt) study, 508 patients with recent-onset RA were randomised to four treatment strategies aimed at a DAS ≤2.4. Risks of damage progression and (drug-free) remission in 8 years were compared for ACPA-positive and ACPA-negative patients using logistic regression analysis. Functional ability and DAS components over time were compared using linear mixed models.RESULTS: DAS reduction was achieved similarly in ACPA-positive and ACPA-negative patients in all treatment strategy groups, with a similar need to adjust treatment because of inadequate response. Functional ability and remission rates were not different for ACPA-positive and ACPA-negative patients. ACPA-positive patients had more radiological damage progression, especially after initial monotherapy. They had a lower chance of achieving (persistent) drug-free remission.CONCLUSION: Clinical response to treatment was similar in ACPA-positive and ACPA-negative patients. However, more ACPA-positive patients, especially those treated with initial monotherapy, had significant radiological damage progression, indicating that methotrexate monotherapy and DAS- (≤2.4) steered treatment might be insufficient to adequately suppress joint damage progression in these patients

Towards personalized treatment: predictors of short-term HAQ response in recent-onset active rheumatoid arthritis are different from predictors of rapid radiological progression

Pathophysiology and treatment of rheumatic disease