On August 24, 1998, Remicade ® (infliximab), the first tumor necrosis factor-α (TNF) inhibitor, received its initial marketing approval from the US Food and Drug Administration for the treatment of Crohn’s disease. Subsequently, Remicade was approved in another five adult and two pediatric indications both in the USA and across the globe. In the 20 years since this first approval, Remicade has made several important contributions to the advancement of science and medicine: 1) clinical trials with Remicade established the proof of concept that targeted therapy can be effective in immune-mediated inflammatory diseases; 2) as the first monoclonal antibody approved for use in a chronic condition, Remicade helped in identifying methods of administering large, foreign proteins repeatedly while limiting the body’s immune response to them; 3) the need to establish Remicade’s safety profile required developing new methods and setting new standards for postmarketing safety studies, specifically in the real-world setting, in terms of approach, size, and duration of follow-up; 4) the study of Remicade has improved our understanding of TNF’s role in the immune system, as well as our understanding of the pathophysiology of a range of diseases characterized by chronic inflammation; and 5) Remicade and other TNF inhibitors have transformed treatment practices in these chronic inflammatory diseases: remission has become a realistic goal of therapy and long-term disability resulting from structural damage can be prevented. This paper reviews how, over the course of its development and 20 years of use in clinical practice, Remicade was able to make these contributions.
ObjectiveTo evaluate the efficacy of ustekinumab by prior treatment exposure and disease duration in tumour necrosis factor inhibitor (TNF)-naïve patients with psoriatic arthritis (PsA) in the PSUMMIT 1 and PSUMMIT 2 studies.MethodsIn the phase 3, randomised, placebo-controlled PSUMMIT 1 and PSUMMIT 2 studies, adults with active PsA for ≥6 months despite conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and/or non-steroidal anti-inflammatory drugs (NSAIDs) (PSUMMIT 1) or csDMARDs, NSAIDs and/or anti-TNF agents (PSUMMIT 2) were enrolled. Patients were randomised to subcutaneous injections of placebo, ustekinumab 45 mg or ustekinumab 90 mg at weeks 0 and 4 and every 12 weeks. Efficacy was assessed at week 24 using the American College of Rheumatology criteria and 28-joint count disease activity score using C reactive protein (DAS28-CRP); radiographical progression, enthesitis, and dactylitis were also assessed in this post hoc analysis.ResultsA total of 747 patients were included; all 747 were TNF-naïve, of which, 179 were methotrexate-naïve and TNF-naïve, and 146 were all csDMARD-naïve and TNF-naïve. At week 24, greater proportions of ustekinumab-treated patients had ≥20%/50%/70% improvement in American College of Rheumatology criteria (ACR20/ACR50/ACR70) responses, DAS28-CRP response and DAS28-CRP remission versus placebo in all three prior-treatment populations, with similar differences between treatment groups. Greater proportions of ustekinumab-treated patients also had complete resolution of enthesitis and dactylitis at week 24 across the three prior-treatment populations. Mean changes from baseline in total van der Heijde-Sharp Score at week 24 were generally smaller for ustekinumab-treated patients versus placebo but were statistically significant only in the full TNF-naïve population. Response rates for ACR20/ACR50/ACR70 were similar for TNF-naïve patients with PsA durations of <1 year, ≥1 to <3 years, and ≥3 years.ConclusionUstekinumab-treated patients demonstrated greater clinical response at week 24 compared with placebo regardless of prior treatment exposure and PsA disease duration.
SUMMARYThe objective of this paper is to evaluate the safety and effectiveness of using doxazosin standard formulation in elderly hypertensive patients who were either uncontrolled or newly diagnosed, and replacing standard doxazosin with doxazosin in the gastrointestinal therapeutic system (GITS) formulation. We designed a postmarketing surveillance, open‐label non‐comparative, multicentre, clinical study covering primary care patients aged 65 years or older diagnosed with essential uncontrolled arterial hypertension. The study covered a period of 6–9 months, divided into two phases. Phase I involved a minimum of three and maximum of six months in treatment with standard doxazosin; phase II began with the changeover from standard doxazosin to the GITS formulation and lasted 12 weeks. Of the 1705 patients initially enrolled, 1292 (75.8%) completed the study. Reduction in systolic blood pressure was 22.3 mmHg (13.7%) in phase I, and 3.9 mmHg (2.77%) in phase II; reduction in diastolic blood pressure was 12.4 mmHg (13.2%) in phase I, and 2.4 mmHg (2.9%) in phase II. The percentage of controlled patients was 40.5% (691/1705) by the end of phase I and 45.3% (776/1705) by the end of phase II. A total of 154 patients suffered adverse events (AE), 127 during phase I and 27 in phase II. We conclude that doxazosin in its two formulations is effective and safe for the purpose of lowering blood pressure in elderly patients.
BackgroundPSUMMIT 1 and PSUMMIT 2 were Phase 3 trials of ustekinumab (UST) in adults with PsA.ObjectivesEvaluate the efficacy of UST by prior treatment exposure and disease duration in PsA patients (pts) in PSUMMIT 1 and 2.MethodsPts had active PsA (≥5 swollen, ≥5 tender joints, CRP ≥3.0mg/dL,) for ≥6 mos despite treatment with DMARDs and/or NSAIDs (PSUMMIT 1) or DMARDs, NSAIDs, and/or anti-tumor necrosis factor (TNF) agents (PSUMMIT 2). In both studies, pts were randomized to SC injections of placebo (PBO) or UST 45mg or 90mg at wks 0, 4 and every 12 wks. PBO pts crossed over to UST 45mg at wk 24. At wk 16, early escape (PBO –> UST45mg; UST45mg –> UST90mg; UST90mg –> UST90mg) was possible. Stable doses of MTX were allowed. Pooled data from both PSUMMIT 1 and 2 were analyzed. Efficacy assessments included ACR response, DAS28-CRP response, DAS28-CRP remission (score <2.6), changes in enthesitis (modified MASES index) and dactylitis scores, and total van der Heijde-Sharp (vdH-S) score for radiographic progression. Pts who were anti-TNF-naïve, MTX- and anti-TNF-naïve, all DMARD- and anti-TNF-naïve were evaluated. ACR response at wks 4 and 16 to assess for early efficacy was also evaluated for anti-TNF-naïve pts with PsA duration <1 year, ≥1 to <3 years, and ≥3 years.ResultsIn the pooled data, 747 pts were anti-TNF-naïve (53.8% were male; mean age=47 years); 179 pts were MTX- and anti-TNF-naïve (63.7% were male; mean age =47 years); 146 pts were all DMARD- and anti-TNF-naïve (61.0% male; mean age=46 years). In all three prior treatment populations significantly greater proportions of pts in the combined UST group vs PBO achieved an ACR20, ACR50, or ACR70 at wk 24. (Table). Similarly, greater proportions of pts in the combined UST group had DAS28-CRP response or remission vs PBO across all three prior treatment populations. In anti-TNF-naïve pts, improvements in enthesitis and dactylitis were significantly greater in the combined UST group vs PBO, and mean change in total vdH-S score was significantly greater for pts in the PBO group than the combined UST group; comparable trends were observed for the MTX- and anti-TNF-naïve pts and all DMARD- and anti-TNF-naïve pts, but did not reach statistical significance due to the smaller sample sizes in both subgroups. Among anti-TNF-naïve pts treated with UST, ACR20/50/70 response rates were similar across different PsA disease duration groups at early time-points (either wk4 or wk16).ConclusionsUST-treated patients had greater improvements in signs and symptoms of PsA regardless of prior treatment exposure and disease duration.Disclosure of InterestI. McInnes Consultant for: Janssen Research & Development, LLC, S. Chakravarty Employee of: Janssen Scientific Affairs, LLC, G. Morgan Employee of: Janssen Scientific Affairs, LLC, I. Apaolaza Employee of: Janssen Biologics, BV, S. Kafka Employee of: Janssen Scientific Affairs, LLC, E. Hsia Employee of: Janssen Research & Development, LLC, M. Song Employee of: Janssen Research & Development, LLC, Y. You Employee of: Janssen Research...
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