Reply to Viel Recknor, Christopher; Hansen, Scott G; Gaylis, Norman B ...
Clinical infectious diseases,
10/2022, Letnik:
75, Številka:
8
Journal Article
Abstract
In an exploratory trial treating “long COVID” with the CCR5-binding antibody leronlimab, we observed significantly increased blood cell surface CCR5 in treated symptomatic responders but not ...in nonresponders or placebo-treated participants. These findings suggest an unexpected mechanism of abnormal immune downmodulation in some persons that is normalized by leronlimab.
Clinical Trials Registration. NCT04678830.
Summary Background Tumour necrosis factor α (TNFα) inhibitors are frequently used to treat rheumatoid arthritis, but whether use of a different TNFα inhibitor can improve patient response is unknown. ...We assess the efficacy and safety of the TNFα inhibitor golimumab in patients with active rheumatoid arthritis who had previously received one or more TNFα inhibitors. Methods 461 patients with active rheumatoid arthritis from 82 sites in 10 countries were randomly allocated by interactive voice response system, stratified by study site and methotrexate use, to receive subcutaneous injections of placebo (n=155), 50 mg golimumab (n=153), or 100 mg golimumab (n=153) every 4 weeks between Feb 21, 2006, and Sept 26, 2007. Allocation was double-blind. Eligible patients had been treated with at least one dose of a TNFα inhibitor previously. Patients continued stable doses of methotrexate, sulfasalazine, hydroxychloroquine, oral corticosteroids, and non-steroidal anti-inflammatory drugs. The primary endpoint was achievement at week 14 of 20% or higher improvement in American College of Rheumatology criteria for assessment of rheumatoid arthritis (ACR20). At week 16, patients who had less than 20% improvement in tender and swollen joint counts were given rescue therapy and changed treatment from placebo to 50 mg golimumab, or from 50 mg to 100 mg golimumab. Drug efficacy was assessed by intention to treat and safety was assessed according to the study drug given. This study is registered with ClinicalTrials.gov , number NCT00299546. Findings Patients had discontinued previous TNFα inhibitors because of lack of effectiveness (269 58% patients) or reasons unrelated to effectiveness (246 53% patients), such as intolerance and accessibility issues. Patients had active disease, which was indicated by a median of 14·0 (IQR 9·0–22·0) swollen and 26·0 (16·0–41·0) tender joints for the whole group. 28 (18%) patients on placebo, 54 (35%) patients on 50 mg golimumab (odds ratio 2·5 95% CI 1·5–4·2, p=0·0006), and 58 (38%) patients on 100 mg golimumab (2·8 1·6–4·7, p=0·0001) achieved ACR20 at week 14. Two patients were never treated, and 57 patients did not complete the study because of adverse events, unsatisfactory treatment effect, loss to follow-up, death, or other reasons. 155 patients on placebo, 153 on 50 mg golimumab, and 153 on 100 mg golimumab were assessed for drug efficacy. For weeks 1–16, serious adverse events were recorded in 11 (7%) patients on placebo, 8 (5%) on 50 mg golimumab, and 4 (3%) on 100 mg golimumab. For weeks 1–24, after some patients were given rescue therapy, serious adverse events were recorded in 15 (10%) patients on placebo, 14 (5%) on 50 mg golimumab, and 8 (4%) on 100 mg golimumab. Interpretation Golimumab reduced the signs and symptoms of rheumatoid arthritis in patients with active disease who had previously received one or more TNFα inhibitors. Funding Centocor Research and Development and Schering-Plough Research Institute.
Long-COVID is a syndrome characterized by debilitating symptoms that persist over 3 months after infection with the SARS-CoV-2 virus. It affects 15 to 33% of COVID-19 recovered patients and has no ...dedicated treatment. First, we found that β-caryophyllene and pregnenolone have a significant synergistic effect in the resolution of LPS-induced sepsis and inflammation in mice. Then we combined these two compounds with seven others and designed a unique dietary supplement formulation to alleviate long COVID inflammatory and neurological disorders. We performed a one-arm open-labeled study at a single site with 51 eligible patients from 18 states. Each participant recorded the severity level of 12 symptoms (including fatigue, weakness, cardiac and neurological symptoms, shortness of breath, gastrointestinal disorders, ageusia or anosmia, anxiety, joint pain, rash, cough, and insomnia) at baseline, 2- and 4-week time points. On average, all the symptoms were significantly milder after 2 weeks, with further improvement after 4 weeks. Importantly, each symptom was significantly attenuated in 72 to 84% of the participants. There were no significant adverse effects. Our data indicate that the use of this nutraceutical product is a safe and significantly efficient option to reduce multiple symptoms of long COVID.
Background
Sandoz adalimumab SDZ-ADL (GP-2017) is an approved adalimumab biosimilar with similar efficacy and comparable safety and immunogenicity to reference adalimumab (ref-ADL) as confirmed by ...analytical, pharmacokinetic and confirmatory studies. ADMYRA, a phase III double-blind study, was conducted with an aim to generate efficacy, safety and immunogenicity comparability data in patients with moderate-to-severe rheumatoid arthritis (RA) having inadequate response to disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX). The study also evaluated an aspect of ‘switching’ reference product to the biosimilar in terms of efficacy, safety and immunogenicity up to Week 48.
Methods
Eligible patients (
N
= 353) were randomized 1:1 to receive subcutaneous (sc) SDZ-ADL 40 mg (
n
= 177) or ref-ADL (
n
= 176) every other week from Week 0 to Week 24. At Week 24, all patients with at least a moderate response by Disease Activity Score-28 including high-sensitivity C-reactive protein (DAS28-CRP) in the SDZ-ADL group continued SDZ-ADL (
n
= 159), and in the ref-ADL group were switched to SDZ-ADL (
n
= 166), treated for up to 46 weeks. The primary endpoint was change in DAS28-CRP from baseline at Week 12. Other efficacy endpoints included proportion of patients with European League Against Rheumatism (EULAR) response, EULAR remission, Boolean remission, safety and immunogenicity.
Results
The DAS28-CRP score changes from baseline at Week 12 were similar between SDZ-ADL (− 2.16) and ref-ADL (− 2.18) with a mean difference (95% CI) of 0.02 (− 0.24 to 0.27), which was within the pre-specified equivalence margin of ± 0.6. After switching treatment from ref-ADL to SDZ-ADL, the mean DAS28-CRP change was similar between the SDZ-ADL and ‘ref-ADL/switched SDZ-ADL’ group (− 3.09 vs − 3.05). The proportion of patients with good/moderate EULAR response was 69.2%/29.0% in the SDZ-ADL group and 68.0%/29.6% in the ‘ref-ADL/switched SDZ-ADL’ group. The proportion of patients in EULAR remission was 51.4% and 54.4% and in Boolean remission was 16.8% and 21.6% for SDZ-ADL and ‘ref-ADL/switched SDZ-ADL’ groups, respectively. The secondary endpoints were similar across the treatment groups. The incidence of adverse events (AEs) and injection-site reactions were low and similar between SDZ-ADL and ‘ref-ADL/switched SDZ-ADL’ groups (AEs 70.6% vs 68.8%, injection-site reactions 4.0% vs 6.3%), and most of these patients experienced AEs of mild or moderate severity. Antidrug antibodies were detected in 24.2% and 25.6% of patients treated with SDZ-ADL and ‘ref-ADL/switched SDZ-ADL’, respectively, from baseline to Week 48, of which 72.5% in SDZ-ADL and 79.1% in ‘ref-ADL/switched SDZ-ADL’ groups were neutralizing.
Conclusions
In patients with moderate-to-severe RA who had an inadequate response to DMARDs, SDZ-ADL demonstrated a similar efficacy and a comparable safety and immunogenicity profile to ref-ADL. Efficacy was sustained after switching from ref-ADL to SDZ-ADL with no impact on safety (NCT02744755).
Reiter's syndrome is an acute inflammatory arthritis with no standard treatment options for patients unresponsive to nonsteroidal antiinflammatory drugs (NSAID). In patients positive for human ...immunodeficiency virus (HIV), HIV-RNA levels have been correlated with elevated tumor necrosis factor-alpha (TNF-alpha) levels. We investigated the safety and activity of infliximab, an anti-TNF-alpha chimeric monoclonal antibody, in the treatment of an HIV positive patient with Reiter's refractory to NSAID therapy. A 41-year-old HIV positive man with Reiter's syndrome was treated with infliximab 300 mg intravenously at Weeks 0, 2, and 6 and then every 6 to 7 weeks thereafter. He presented with severe fatigue, pain, muscle wasting, synovitis of the elbows, wrists and knees, a scaly rash in the groin area, burning during urination, and severe onycholysis on all digits. Laboratory assessment revealed hemoglobin 7.8 g/dl, erythrocyte sedimentation rate (ESR) 152 mm/h, white blood cell count 5700 cells/mm3, and C-reactive protein (CRP) 65.7 mg/dl. HIV viral load on presentation was 1600 quantitative:ultrasensitive (Qn:US) copies/ml, decreased from a maximum of 428,000 Qn:US copies/ml at the start of antiretroviral therapy. After 6 months taking infliximab, all complaints resolved, nails regrew, and the rash cleared. CRP decreased to 0.8 mg/dl and ESR to 22 mm/h. During this 6 month period antiretroviral therapy remained unchanged, and the viral titer remained below 400 Qn:US copies/ml.
To assess the efficacy and safety of 1 versus 2 courses of rituximab over 48 weeks in patients with rheumatoid arthritis (RA).
Adult patients taking methotrexate with a previous inadequate response ...to > or = 1 tumor necrosis factor inhibitor received 1 course of open-label rituximab (2 x 1000 mg IV) at baseline. From Week 24, patients were randomized to receive an additional course of retreatment with rituximab or placebo. Efficacy responses at Week 48 relative to baseline were assessed.
Of 559 patients who received the open-label first course of rituximab, 475 patients were randomized to a second course (rituximab retreatment: n = 318, placebo retreatment: n = 157). Relative to baseline, patients who took rituximab during retreatment had significantly improved efficacy at Week 48 compared to patients who took a placebo during retreatment American College of Rheumatology (ACR20) criteria, 54% vs 45%, p = 0.02; change in Disease Activity Score-28 mean -1.9 vs -1.5, p = 0.006. Differences in efficacy between groups were first observed following Weeks 28-32. Worsening of most components of the ACR core set occurred in the placebo-retreated patients with relative maintenance of these measures in rituximab-retreated patients. Randomized patients who had achieved week 24 ACR responses following the first course had greater odds of losing response if retreated with placebo (odds ratios for ACR20, ACR50, ACR70: 2.09, 2.03, and 4.09, respectively). Following retreatment, the proportion of patients experiencing any adverse events (AE), serious AE, infections, and serious infections were comparable between the rituximab and placebo retreatment groups.
Two courses of rituximab about 6 months apart resulted in improved and sustained efficacy at 1 year, compared with 1 course, with a similar safety profile.
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