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Dermatomyositis is a chronic autoimmune disease with distinctive cutaneous eruptions and muscle weakness, and the pathophysiology is characterised by type I interferon (IFN) dysregulation. This study aims to assess the efficacy, safety, and target engagement of dazukibart, a potent, selective, humanised IgG1 neutralising monoclonal antibody directed against IFNβ, in adults with moderate-to-severe dermatomyositis. This multicentre, double-blind, randomised, placebo-controlled, phase 2 trial was conducted at 25 university-based hospitals and outpatient sites in Germany, Hungary, Poland, Spain, and the USA. Adults aged 18–80 years with skin-predominant dermatomyositis were enrolled during stages 1, 2, and 2a, and had to have a Cutaneous Dermatomyositis Disease Area and Severity Index-Activity (CDASI-A) score of 14 or more and at least one unsuccessful systemic treatment with standard of care; whereas those with muscle-predominant dermatomyositis were enrolled in stage 3 and had to have active moderate muscle involvement. Patients were randomly assigned using an interactive response technology system to dazukibart 600 mg or placebo in stage 1; dazukibart 600 mg, dazukibart 150 mg, or placebo in stage 2; dazukibart 600 mg then placebo, dazukibart 150 mg then placebo, placebo then dazukibart 600 mg, or placebo then dazukibart 150 mg in stage 2a; and dazukibart 600 mg then placebo or placebo then dazukibart 600 mg in stage 3. For stage 2a and stage 3, treatments were switched at week 12. Patients, investigators, outcome assessors, and funders were masked to the treatment assignment. Dazukibart and placebo were administered intravenously on day 1 every 4 weeks, up to and including week 8 (stages 1 and 2, and stages 2a and 3 for patients starting dazukibart), or on week 12 every 4 weeks, up to and including week 20 (stages 2a and 3 for patients who started placebo and switched to dazukibart). The primary outcome for the skin-predominant cohorts was the change from baseline in CDASI-A score at week 12 assessed in the full analysis set (FAS; stage 1) and the pooled skin FAS (stages 1, 2, and 2a), and safety in the muscle-predominant cohort. This study is registered with ClinicalTrials.gov, NCT03181893. Between Jan 23, 2018, and Feb 23, 2022, 125 adults were assessed and 50 were excluded. 75 patients were randomly assigned and treated (15 to dazukibart 150 mg, 37 to dazukibart 600 mg, and 23 to placebo). Most patients were female (53 [93%] of 57 in the skin-predominant cohort vs 13 [72%] of 18 in the muscle-predominant cohort and four [7%] vs five [28%] were male). In the FAS in stage 1 at week 12, the mean change from baseline in CDASI-A for dazukibart 600 mg was –18·8 (90% CI –21·8 to –15·8; placebo-adjusted difference –14·8 [–20·3 to –9·4]; p<0·0001). In the pooled skin FAS at week 12, the mean change from baseline in CDASI-A for the dazukibart 600 mg group was –19·2 (–21·5 to –16·8; placebo-adjusted difference –16·3 [–20·4 to –12·1]; p<0·0001), whereas the dazukibart 150 mg group was –16·6 (–19·8 to –13·4; placebo-adjusted difference –13·7 [–18·3 to –9·0]; p<0·0001). Treatment-emergent adverse events occurred in 12 (80%) of 15 patients in the dazukibart 150 mg group versus 30 (81%) of 37 in the dazukibart 600 mg group versus 18 (78%) of 23 in the placebo group, with the most common being infections and infestations (two [13%] vs 12 [32%] vs seven [30%]). Four (11%) patients in the dazukibart 150 mg group and one (4%) in the placebo group reported serious adverse events. One patient in stage 3 received dazukibart 600 mg then placebo and died during follow-up due to haemophagocytic lymphohistiocytosis and macrophage activation syndrome. Dazukibart resulted in a pronounced reduction in disease activity and was generally well tolerated, supporting IFNβ inhibition as a highly promising therapeutic strategy in adults with dermatomyositis. Pfizer.

In two trials involving patients with relapsing multiple sclerosis, the anti-CD20+ monoclonal antibody ocrelizumab was associated with lower annualized relapse rates, lower risk of disability progression, and better MRI features than interferon beta-1a. Despite the availability of several disease-modifying treatments for relapsing forms of multiple sclerosis, patients often continue to have clinical and subclinical disease activity, and neurologic disability continues to accrue. Thus, there is a need for more effective treatments with acceptable safety profiles. 1 – 3 B cells are thought to influence the underlying pathogenesis of multiple sclerosis by means of antigen presentation, 4 autoantibody production, 5 , 6 cytokine regulation, 4 and the formation of ectopic lymphoid aggregates in the meninges, which possibly contribute to cortical demyelination and neurodegeneration. 7 , 8 Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20, a cell-surface antigen that is expressed . . .

In patients presenting with a first clinical demyelinating event that is suggestive of multiple sclerosis (MS), treatment with interferon beta can delay the occurrence of further attacks and the onset of MS. We investigated the effects of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event. We undertook a multicentre phase 3 study (REbif FLEXible dosing in early MS [REFLEX]) that included patients (aged 18–50 years) with a single clinical event suggestive of MS, and at least two clinically silent T2 lesions on brain MRI. Participants were randomly assigned in a 1:1:1 ratio by use of a centralised interactive voice response system to receive the serum-free formulation of subcutaneous interferon beta-1a 44 μg three times a week or once a week (plus placebo twice a week for masking), or placebo three times a week for up to 24 months. Patients and physicians were masked to group allocation. The primary endpoint was time to a diagnosis of MS as defined by the 2005 McDonald criteria and the main secondary endpoint was time to clinically definite MS (CDMS) as defined by the Poser criteria. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00404352. 517 patients were randomly assigned (171 to subcutaneous interferon beta-1a three times a week, 175 to subcutaneous interferon beta-1a once a week, and 171 to placebo) and 515 were treated. The 2-year cumulative probability of McDonald MS was significantly lower in patients treated with subcutaneous interferon beta-1a (three times a week 62·5%, p<0·0001, hazard ratio [HR] 0·49 [95% CI 0·38–0·64]; once a week 75·5%, p=0·008, HR 0·69 [0·54–0·87]) versus placebo (85·8%). 2-year rates of conversion to CDMS were lower for both interferon beta-1a dosing regimens (three times a week 20·6%, p=0·0004, HR 0·48 [0·31–0·73]; once a week 21·6%, p=0·0023, HR 0·53 [0·35–0·79]) than for placebo (37·5%). Adverse events were within the established profile for subcutaneous interferon beta-1a. Both regimens of subcutaneous interferon beta-1a delayed clinical relapses and subclinical disease activity. The potential differences between the regimens warrant longer-term study. Merck Serono SA, Geneva, Switzerland.

Type I interferons (IFN-I) were first discovered as an antiviral factor by Isaacs and Lindenmann in 1957, but they are now known to also modulate innate and adaptive immunity and suppress proliferation of cancer cells. While much has been revealed about IFN-I, it remains a mystery as to why there are 16 different IFN-I gene products, including IFNβ, IFNω, and 12 subtypes of IFNα. Here, we discuss shared and unique aspects of these IFN-I in the context of their evolution, expression patterns, and signaling through their shared heterodimeric receptor. We propose that rather than investigating responses to individual IFN-I, these contexts can serve as an alternative approach toward investigating roles for IFNα subtypes. Finally, we review uses of IFNα and IFNβ as therapeutic agents to suppress chronic viral infections or to treat multiple sclerosis.

The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial. In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18–50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348. 187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32–0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40–1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma. Alemtuzumab's consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here. Genzyme (Sanofi) and Bayer Schering Pharma.

Despite early reports to the contrary, there is increasing evidence that patients with severe COVID-19 have a robust type I interferon response, which contrasts with the delayed, possibly suppressed, interferon response seen early in infection. A robust type I interferon response could exacerbate hyperinflammation in the progression to severe COVID-19 through diverse mechanisms. Further understanding of the roles of type I interferon at different stages of infection and in patients with mild versus severe COVID-19 will provide insights for the therapeutic use of interferon administration or JAK inhibitors in patients with COVID-19.In this Comment, Jeong Seok Lee and Eui-Cheol Shin discuss contradictory results regarding the downregulation or upregulation of type I interferon responses in patients with COVID-19 and the implications for therapies that target this pathway.

In this trial, daclizumab high-yield process (a monoclonal antibody that binds to CD25 and modulates interleukin-2 signaling) was more effective than interferon beta-1a in patients with relapsing–remitting multiple sclerosis. Infection and rash were more common with daclizumab. Daclizumab is a humanized monoclonal antibody that binds to the alpha subunit (CD25) of the high-affinity interleukin-2 receptor. 1 , 2 Daclizumab treatment prevents signaling through the high-affinity interleukin-2 receptor and increases the availability of interleukin-2 to signal at its intermediate-affinity receptor. 1 , 2 The use of daclizumab in patients with multiple sclerosis was based initially on the hypothesis that it directly antagonizes activated CD25+ effector T cells, which have long been implicated as key mediators of the pathogenic effects of multiple sclerosis. 1 , 3 Notably, effector T-cell numbers and recall responses appear to be largely unaffected by daclizumab in vivo. 3 Other clinically important . . .

Several controlled studies provide evidence that treatment with interferon beta in patients with a first event suggestive of multiple sclerosis (MS) delays conversion to clinically definite MS (CDMS). Our aim was to determine whether early initiation of treatment with interferon beta prevents development of confirmed disability in MS. In the initial placebo-controlled phase of the double-blinded BENEFIT study, patients with a first event suggestive of MS and a minimum of two clinically silent lesions in MRI were randomised to receive either interferon beta-1b 250 μg (n=292) or placebo (n=176) subcutaneously every other day for 2 years, or until diagnosis of CDMS. Patients were then eligible to enter the follow-up phase with open-label interferon beta-1b. In the current prospectively planned analysis 3 years after randomisation, the effects of early interferon beta-1b treatment were compared with those of delayed treatment initiated after diagnosis of CDMS or after 2 years on the study. The primary outcomes of this ITT analysis were time to diagnosis of CDMS, time to confirmed expanded disability status scale (EDSS) progression, and score on a patient-reported functional assessment scale (FAMS-TOI). This trial is registered with ClinicalTrials.gov, number NCT00185211. Of the 468 patients originally randomised, 418 (89%) entered the follow-up phase; 392 (84%) completed 3 years' post-randomisation follow-up. After 3 years, 99 (37%) patients in the early group developed CDMS compared with 85 (51%) patients in the delayed treatment group. Early treatment reduced the risk of CDMS by 41% (hazard ratio 0·59, 95% CI 0·44–0·80; p=0·0011; absolute risk reduction 14%) compared with delayed treatment. Over 3 years, 42 (16%) patients in the early group and 40 (24%) in the delayed group had confirmed EDSS progression; early treatment reduced the risk for progression of disability by 40% compared with delayed treatment (0·60, 0·39–0·92; p=0·022; absolute risk reduction 8%). The FAMS-TOI score was high and stable in both groups over the 3-year period (p=0·31). Our data suggest that early initiation of treatment with interferon beta-1b prevents the development of confirmed disability, supporting its use after the first manifestation of relapsing-remitting MS.

The pandemic of COVID-19 has posed an unprecedented threat to global public health. However, the interplay between the viral pathogen of COVID-19, SARS-CoV-2, and host innate immunity is poorly understood. Here we show that SARS-CoV-2 induces overt but delayed type-I interferon (IFN) responses. By screening 23 viral proteins, we find that SARS-CoV-2 NSP1, NSP3, NSP12, NSP13, NSP14, ORF3, ORF6 and M protein inhibit Sendai virus-induced IFN-β promoter activation, whereas NSP2 and S protein exert opposite effects. Further analyses suggest that ORF6 inhibits both type I IFN production and downstream signaling, and that the C-terminus region of ORF6 is critical for its antagonistic effect. Finally, we find that IFN-β treatment effectively blocks SARS-CoV-2 replication. In summary, our study shows that SARS-CoV-2 perturbs host innate immune response via both its structural and nonstructural proteins, and thus provides insights into the pathogenesis of SARS-CoV-2. The pandemic of SARS-CoV-2 post a significant threat to public health. Here the authors show, by screening 23 viral proteins, that both structural and non-structural SARS-CoV-2 proteins are capable of modulating host innate immunity and type interferon responses, with this information serves to warrant further studies on SARS-CoV-2 pathogenesis.

Objective: To evaluate the efficacy and safety of subcutaneous peginterferon beta-1a over 2 years in patients with relapsing–remitting multiple sclerosis in the ADVANCE study. Methods: Patients were randomized to placebo or 125 µg peginterferon beta-1a every 2 or 4 weeks. For Year 2 (Y2), patients originally randomized to placebo were re-randomized to peginterferon beta-1a every 2 weeks or every 4 weeks. Patients randomized to peginterferon beta-1a in Year 1 (Y1) remained on the same dosing regimen in Y2. Results: Compared with Y1, annualized relapse rate (ARR) was further reduced in Y2 with every 2 week dosing (Y1: 0.230 [95% CI 0.183–0.291], Y2: 0.178 [0.136–0.233]) and maintained with every 4 week dosing (Y1: 0.286 [0.231–0.355], Y2: 0.291 [0.231–0.368]). Patients starting peginterferon beta-1a from Y1 displayed improved efficacy versus patients initially assigned placebo, with reductions in ARR (every 2 weeks: 37%, p<0.0001; every 4 weeks: 17%, p=0.0906), risk of relapse (every 2 weeks: 39%, p<0.0001; every 4 weeks: 19%, p=0.0465), 12-week disability progression (every 2 weeks: 33%, p=0.0257; every 4 weeks: 25%, p=0.0960), and 24-week disability progression (every 2 weeks: 41%, p=0.0137; every 4 weeks: 9%, p=0.6243). Over 2 years, greater reductions were observed with every 2 week versus every 4 week dosing for all endpoints and peginterferon beta-1a was well tolerated. Conclusions: Peginterferon beta-1a efficacy is maintained beyond 1 year, with greater effects observed with every 2 week versus every 4 week dosing, and a similar safety profile to Y1. Clinicaltrials.gov Registration Number: NCT00906399.