A novel sustained-release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers.

The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharmacokinetics, safety and tolerability of a new sustained-release cysteamine dosage form, PO-001, in healthy volunteers. This was a randomized, investigator-blinded, three-way cross-over study to compare single doses (600 mg) of PO-001 with Cystagon® (immediate-release) and Procysbi® (delayed-release). Collected blood samples were analyzed for plasma cysteamine concentrations and pharmacokinetic parameters were estimated by noncompartmental analysis. In addition, plasma cysteamine concentrations were analyzed using a population pharmacokinetic approach using NONMEM® . Pharmacokinetics showed clear sustained-release characteristics of PO-001 over time with a lower Cmax and longer Tmax compared to Cystagon® and Procysbi® . All treatment-emergent adverse events were of mild severity, with the exception of two subjects who reported moderate severity gastrointestinal problems including vomiting and diarrhea, which were related to Cystagon® intake. Population PK simulations showed a favourable PK profile based on Cmax and Ctrough concentrations at steady state. In conclusion, a single dose of 600 mg PO-001 was well tolerated with no findings of clinical concern. This new cysteamine bitartrate formulation showed pharmacokinetics of a sustained-release formulation, which may be beneficial for the treatment of cystinosis patients. This study supports advancing this type of sustained-release formulation into a subsequent study to confirm reduced dosing frequency with efficient control of white blood cells (WBCs) cystine levels. Netherlands Trial Registry (NTR) (NL67638.056.18).

Sustained drug-free remission in rheumatoid arthritis after DAS-driven or non-DAS-driven therapy: a comparison of two cohort studies.

OBJECTIVES: To compare the prevalence of and predictors for sustained drug-free remission in two cohorts of patients with recent-onset RA treated with DAS-driven therapy or non-DAS-driven therapy. METHODS: Sustained drug-free remission was assessed after 5 years of follow-up in 508 patients treated with DAS-driven therapy (DAS ≤ 2.4) in a randomized treatment cohort, and in 424 patients who received non-DAS-driven therapy in a prospective inception cohort. The design of the DAS-driven cohort required systematic joint assessments with DAS-driven restart of therapy. Predictors for remission were identified by univariable and multivariable logistic regression in each cohort separately and in a combined multivariate logistic regression analysis corrected for propensity scores, including a sensitivity analysis on patients receiving initial monotherapy. RESULTS: Patients in the DAS-driven cohort had more active disease at baseline, but the prevalence of sustained drug-free remission was similar after DAS-driven (9.8%) and non-DAS-driven therapy (10.6%). Among patients with ACPA, drug-free remission was more frequently achieved after DAS-driven than after non-DAS-driven therapy (5.4 vs. 2.1%, OR = 2.68, 95% CI 0.97, 7.43). Absence of ACPA and short symptom duration were independent predictors for sustained drug-free remission in both cohorts. Initial treatment choice and inclusion period were not predictive. The sensitivity analysis yielded comparable results. CONCLUSION: Retrospectively comparing a DAS-driven to a non-DAS-driven therapy cohort, the occurrence and predictors of sustained drug-free remission were similar. The DAS-driven cohort had a more unfavourable prognosis. DAS-driven therapy may improve the chance of sustained drug-free remission in ACPA-positive patients with recent-onset RA.

The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study.

OBJECTIVE: To compare clinical and radiological outcomes of four dynamic treatment strategies in recent-onset rheumatoid arthritis (RA) after 5 years follow-up. METHODS: 508 patients with recent-onset RA were randomly assigned into four treatment strategies: sequential monotherapy; step-up combination therapy; initial combination with prednisone; initial combination with infliximab. Treatment adjustments were made based on 3-monthly disease activity score (DAS) measurements (if DAS >2.4 next treatment step; if DAS ≤ 2.4 during ≥ 6 months taper to maintenance dose; if DAS <1.6 during ≥ 6 months stop antirheumatic treatment). Primary and secondary outcomes were functional ability, joint damage progression, health-related quality of life and (drug-free) remission percentages. RESULTS: After 5 years, 48% of patients were in clinical remission (DAS <1.6) and 14% in drug-free remission, irrespective of initial treatment. After an earlier improvement in functional ability and quality of life with initial combination therapy, from 1 year onwards clinical outcomes were comparable across the groups and stable during 5 years. The initial combination groups showed less joint damage in year 1. In years 2-5 annual progression was comparable across the groups. After 5 years, initial combination therapy resulted in significantly less joint damage progression, reflecting the earlier clinical response. CONCLUSION: Irrespective of initial treatment, an impressive improvement in clinical and radiological outcomes of RA patients can be achieved with dynamic treatment aimed at reducing disease activity, leading to 48% remission, 14% drug-free remission and sustained functional improvement. Starting with combination therapy resulted in earlier clinical improvement and less joint damage without more toxicity.

Blood pressure changes in patients with recent-onset rheumatoid arthritis treated with four different treatment strategies: a post hoc analysis from the BeSt trial.

OBJECTIVE: To evaluate the effect of disease activity and antirheumatic treatment on blood pressure (BP) in patients with recent-onset rheumatoid arthritis (RA). METHODS: 508 patients with RA were randomised to receive (1) sequential monotherapy, (2) step-up combination therapy, (3) initial combination with prednisone or (4) with infliximab. Systolic and diastolic BP (SBP, DBP), disease activity score (DAS) and body mass index (BMI) were evaluated every 3 months. A linear mixed model was used to model SBP and DBP in each treatment group during year 1, adjusting for baseline BP, changes in BMI, DAS and cardiovascular medication. RESULTS: In all groups, mean SBP and DBP were lower for patients with DAS < or =2.4 than for patients with DAS >2.4. In addition, patients initially treated with infliximab (group 4) had a larger decrease in SBP and DBP over time than patients in groups 1-3. The decrease in BP was also observed in patients treated with infliximab after failure on conventional disease-modifying antirheumatic drugs in groups 1-3. The decrease in BP associated with treatment with infliximab occurred irrespective of the DAS response. CONCLUSION: A lower DAS is associated with lower BP. An additional decrease in BP was observed in patients treated with infliximab. Further research is needed to confirm the effect of infliximab on BP.

The BeSt story: on strategy trials in rheumatoid arthritis.

PURPOSE OF REVIEW: To give an overview of recent strategy trials for the treatment of rheumatoid arthritis. RECENT FINDINGS: Strategy studies showed a clear benefit of dynamic result-driven treatment towards tight control of disease activity compared with 'usual care' in rheumatoid arthritis patients. In addition, treatment given after short symptom duration gives better outcomes than later initiation of treatment. In many trials, combination therapies, especially combinations with prednisolone or biologicals, were superior to monotherapies. Moreover, combination therapies were more effective if given early in the disease as compared with a delayed introduction, giving support to the window of opportunity hypothesis. In the BeSt study, initial combination therapy could be successfully discontinued in half of the patients, emphasizing that 'initial' would mean 'temporary'. Less evidence is available about initial combination in comparison with combination therapy with a shorter delay. Larger tight-controlled, goal-steered, dynamic strategy trials comparing initial combination therapy with a short-delay combination therapy will help to translate the use of initial (temporary) combination therapy into normal daily practice. SUMMARY: Treatment strategy trials have demonstrated that in the majority of patients with rheumatoid arthritis, the following approach is the most beneficial: goal-steered, dynamic treatment towards tight control of disease activity, including early introduction of (an) effective disease-modifying antirheumatic drug(s) in combination with prednisone or antitumor necrosis factor, which includes tapering of the medication if remission or low disease activity is achieved.