Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir–ritonavir, and ...ribavirin for treating patients with COVID-19.
This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT04276688.
Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3–7). The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days IQR 5–11) than the control group (12 days 8–15; hazard ratio 4·37 95% CI 1·86–10·24, p=0·0010). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir–ritonavir because of biochemical hepatitis. No patients died during the study.
Early triple antiviral therapy was safe and superior to lopinavir–ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted.
The Shaw-Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine.
Treating to low disease activity is routine in rheumatoid arthritis, but no comparable goal has been defined for systemic lupus erythematosus (SLE). We sought to define and validate a Lupus Low ...Disease Activity State (LLDAS).
A consensus definition of LLDAS was generated using Delphi and nominal group techniques. Criterion validity was determined by measuring the ability of LLDAS attainment, in a single-centre SLE cohort, to predict non-accrual of irreversible organ damage, measured using the Systemic Lupus International Collaborating Clinics Damage Index (SDI).
Consensus methodology led to the following definition of LLDAS: (1) SLE Disease Activity Index (SLEDAI)-2K ≤4, with no activity in major organ systems (renal, central nervous system (CNS), cardiopulmonary, vasculitis, fever) and no haemolytic anaemia or gastrointestinal activity; (2) no new lupus disease activity compared with the previous assessment; (3) a Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment (scale 0-3) ≤1; (4) a current prednisolone (or equivalent) dose ≤7.5 mg daily; and (5) well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents. Achievement of LLDAS was determined in 191 patients followed for a mean of 3.9 years. Patients who spent greater than 50% of their observed time in LLDAS had significantly reduced organ damage accrual compared with patients who spent less than 50% of their time in LLDAS (p=0.0007) and were significantly less likely to have an increase in SDI of ≥1 (relative risk 0.47, 95% CI 0.28 to 0.79, p=0.005).
A definition of LLDAS has been generated, and preliminary validation demonstrates its attainment to be associated with improved outcomes in SLE.
T-follicular helper (Tfh) cells are a specialized subset of T cells that provide help to B cells and promote the formation of germinal centers (GCs). Tfh cells transmit important signals to B cells ...that drive class switch recombination, somatic hyper-mutation, the generation of high-affinity antibodies, immunological memory and their differentiation into plasma cells or memory B cells in the GCs. Tfh-cell differentiation is regulated by the coordinated functions of distinct cytokines, including interleukin (IL)-6, IL-21, IL-12, IL-23, IL-2, IL-7 and transforming growth factor-β (TGF-β), as well as transcription factors, including B-cell lymphoma 6 protein (Bcl-6), Signal transducers and activators of transcription (STAT)1, STAT3, STAT4, B-cell activating transcription factor (Batf), interferon regulatory factor 4 (IRF4), v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (C-Maf), T-cell-specific transcription factor 1 (TCF-1) and Achaete-scute homolog 2 (Acl2), which have been shown to form a complex transcriptional network. In addition, increasing evidence indicates that epigenetic regulations, such as DNA methylation, histone modifications and non-coding RNA regulations, also coordinately control the differentiation and function of Tfh cells along with transcription factors. Furthermore, abnormalities in the regulation of Tfh cells have been associated with several autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS) and rheumatoid arthritis (RA). Herein, this review aims to summarize the coordinate regulation and interaction of transcription factors, cytokines and epigenetic modifications that control Tfh-cell differentiation as well as the mechanism of dysregulation of Tfh cells in pathogenesis of autoimmune diseases, which highlight potential therapeutic targets.
Objective
To determine the effectiveness of nurse‐led consultations in patients with stable rheumatoid arthritis (RA) in Hong Kong.
Methods
The present work was a single‐center, randomized, ...open‐label, noninferiority trial. Patients who had rheumatoid arthritis (RA) with low disease activity (LDA) were randomized at a 1:1 ratio to attend a nurse‐led consultation or rheumatologist follow‐up visit for 2 years. The primary end point was the proportion of patients whose RA remained at LDA. Secondary end points included the proportion of patients with RA in disease remission and the scores recorded on the Leeds Satisfaction Questionnaire at 2 years, changes from baseline on the Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP), modified Sharp/van der Heijde score (SHS), Health Assessment Questionnaire disability index (HAQ DI), Short Form 36 (SF‐36) physical component score, and 19‐item Compliance Questionnaire for Rheumatology (CQR‐19) score.
Results
Among 280 patients who were randomized equally to either attend nurse‐led consultations or rheumatologist follow‐up visits, 267 patients completed the study. In the nurse‐led consultation and rheumatologist follow‐up groups, 92.1% and 91.4% patients, respectively, remained at LDA at 2 years. The 95% confidence intervals (95% CIs) of the adjusted treatment difference were within the predefined noninferiority margin in both the intention‐to‐treat analysis (95% CI 5.75, 7.15) and the per‐protocol analysis (95% CI 1.67, 7.47). Although the changes in DAS28‐CRP score over 2 years were significantly different between the 2 treatment groups (P < 0.001), there were no significant changes from baseline in SHS, HAQ DI, SF‐36 physical component scores, and CQR‐19 scores. At the end of the study, more patients expressed satisfaction with nurse‐led consultations.
Conclusion
Nurse‐led consultations were not inferior to rheumatologist follow‐up visits in patients with stable RA.
Objective
Human complement C4 is complex, with multiple layers of diversity. The aims of this study were to elucidate the copy number variations (CNVs) of C4A and C4B in relation to disease risk in ...systemic lupus erythematosus (SLE), and to compare the basis of race‐specific C4A deficiency between East Asians and individuals of European descent.
Methods
The East Asian study population included 999 SLE patients and 1,347 healthy subjects. Variations in gene copy numbers (GCNs) of total C4, C4A, and C4B, as well as C4‐Long and C4‐Short genes, were determined and validated using independent genotyping technologies. Genomic regions with C4B96 were investigated to determine the basis of the most basic C4B protein occurring concurrently with C4A deficiency.
Results
In East Asians, high GCNs of total C4 and C4A were strongly protective against SLE, whereas low and medium GCNs of total C4 and C4A, and the absence of C4‐Short genes, were risk factors for SLE. Homozygous C4A deficiency was infrequent in East Asian subjects, but had an odds ratio (OR) of 12.4 (P = 0.0015) for SLE disease susceptibility. Low serum complement levels were strongly associated with low GCNs of total C4 (OR 3.19, P = 7.3 × 10−7) and C4B (OR 2.53, P = 2.5 × 10−5). Patients with low serum complement levels had high frequencies of anti–double‐stranded DNA antibodies (OR 4.96, P = 9.7 × 10−17), hemolytic anemia (OR 3.89, P = 3.6 × 10−10), and renal disease (OR 2.18, P = 8.5 × 10−6). The monomodular‐Short haplotype found to be prevalent in European Americans with C4A deficiency, which was in linkage disequilibrium with HLA–DRB1*0301, was scarce in East Asians. Instead, most East Asian subjects with C4A deficiency were found to have a recombinant haplotype with bimodular C4‐Long and C4‐Short genes, encoding C4B1 and C4B96, which was linked to HLA–DRB1*1501. DNA sequencing revealed an E920K polymorphism in C4B96.
Conclusion
C4 CNVs and deficiency of C4A both play an important role in the risk and manifestations of SLE in East Asian and European populations.
Combating COVID-19: East meets West Li, Donald; Lau, Chak-Sing
British journal of general practice,
07/2020, Letnik:
70, Številka:
696
Journal Article
Recenzirano
Odprti dostop
Community engagement is the first line of defence in the battle against infectious diseases. Yet there are international differences in the actions, response, and empowerment of the population in ...building a firewall against the deadly COVID-19 virus.
Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous ...genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.
Summary Background Persistent use of glucocorticoid drugs is associated with bone loss and increased fracture risk. Concurrent oral bisphosphonates increase bone mineral density and reduce frequency ...of vertebral fractures, but are associated with poor compliance and adherence. We aimed to assess whether one intravenous infusion of zoledronic acid was non-inferior to daily oral risedronate for prevention and treatment of glucocorticoid-induced osteoporosis. Methods This 1-year randomised, double-blind, double-dummy, non-inferiority study of 54 centres in 12 European countries, Australia, Hong Kong, Israel, and the USA, tested the effectiveness of 5 mg intravenous infusion of zoledronic acid versus 5 mg oral risedronate for prevention and treatment of glucocorticoid-induced osteoporosis. 833 patients were randomised 1:1 to receive zoledronic acid (n=416) or risedronate (n=417). Patients were stratified by sex, and allocated to prevention or treatment subgroups dependent on duration of glucocorticoid use immediately preceding the study. The treatment subgroup consisted of those treated for more than 3 months (272 patients on zoledronic acid and 273 on risedronate), and the prevention subgroup of those treated for less than 3 months (144 patients on each drug). 62 patients did not complete the study because of adverse events, withdrawal of consent, loss to follow-up, death, misrandomisation, or protocol deviation. The primary endpoint was percentage change from baseline in lumbar spine bone mineral density. Drug efficacy was assessed on a modified intention-to-treat basis and safety was assessed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov , number NCT00100620. Findings Zoledronic acid was non-inferior and superior to risedronate for increase of lumbar spine bone mineral density in both the treatment (least-squares mean 4·06% SE 0·28 vs 2·71% SE 0·28, mean difference 1·36% 95% CI 0·67–2·05, p=0·0001) and prevention (2·60% 0·45 vs 0·64% 0·46, 1·96% 1·04–2·88, p<0·0001) subgroups at 12 months. Adverse events were more frequent in patients given zoledronic acid than in those on risedronate, largely as a result of transient symptoms during the first 3 days after infusion. Serious adverse events were worsening rheumatoid arthritis for the treatment subgroup and pyrexia for the prevention subgroup. Interpretation A single 5 mg intravenous infusion of zoledronic acid is non-inferior, possibly more effective, and more acceptable to patients than is 5 mg of oral risedronate daily for prevention and treatment of bone loss that is associated with glucocorticoid use. Funding Novartis Pharma.
The tissue-resident memory T (TRM) cells constitute a newly identified subset of memory T cells which are non-circulating and they persist for long-term in epithelial barrier tissues, including skin, ...lung, gastrointestinal tract and reproductive tract, and in non-barrier tissues, including brain, kidney, pancreas and joint. These cells provide rapid on-site immune protection against previous exposed pathogens in peripheral tissues. There cells are transcriptionally, functionally and phenotypically distinguished from circulating effector memory T cells. In addition to their protective functions, increasing evidence reveals that autoreactive and/or aberrantly activated TRM cells may be involved in the pathogenesis of autoimmune disorders such as psoriasis and, as recently reported, may contribute to vitiligo, autoimmune hepatitis and rheumatoid arthritis. Therefore, this review aims to summarize the current progress in the biology of TRM cells, such as the newly identified TRM markers, upstream regulators, and the functions of TRM cells. We also discuss the contributions of TRM cells to the development of autoimmunity to broaden our understanding of autoimmune diseases and to provide novel potential therapeutic strategies for these diseases.
PDF
