EFFICACY AND SAFETY OF DAZODALIBEP (VIB4920/HZN4920) IN SUBJECTS WITH SJÖGREN'S SYNDROME: A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PROOF OF CONCEPT STUDY

BackgroundSjögren's syndrome (SS) is a chronic, systemic autoimmune disease affecting exocrine glands, primarily the salivary and tear glands, with potentially severe manifestations in multiple organs. No approved disease-modifying therapies exist. Dazodalibep (DAZ) is a biologic antagonist of CD40L.ObjectivesThe objective of this study was to evaluate the efficacy and safety of DAZ therapy in adult SS subjects with moderate-to-high systemic disease activity (NCT04129164).MethodsWe conducted a randomized, double-blind, placebo-controlled, crossover study to evaluate DAZ therapy in adult SS subjects with moderate-to-high systemic disease activity, as defined by a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score ≥ 5. Eligible subjects were randomized 1:1 to receive intravenous DAZ 1500 mg or placebo (PBO) Q2W x 3 doses, then Q4W x 4 additional doses. Starting on Day 169, subjects initially randomized to DAZ received PBO Q4W x 5 doses and subjects randomized to PBO received DAZ Q4W x 5 doses and were then followed for 12 weeks. The primary endpoint was the change from Baseline in ESSDAI at Day 169. Safety assessments included the incidence of adverse (AEs), serious AEs (SAEs), and AEs of special interest (AESIs).ResultsThe 74 randomized subjects all received ≥1 dose of study medication (DAZ, N=36;PBO, N=38). The baseline demographics and disease characteristics were balanced between the two groups. The change from Baseline to Day 169 in ESSDAI score (LS mean ± SE), was -6.3 ± 0.6 in DAZ-treated subjects compared to -4.1 ± 0.6 in the PBO group, a difference of -2.2 (p = 0.0167). Compared to the PBO group, the DAZ group showed positive trends in the EULAR Sjögren's Syndrome Patient Reported Index score, and Functional Assessment of Chronic Illness Therapy-Fatigue score at Day 169. A post-hoc responder analysis of subjects achieving high levels (5 and 6 points) of improvement on ESSDAI favored DAZ (61.1% and 60.0%) over PBO (35.1% and 34.3%).The reported AEs were generally mild through Day 169 and similar in frequency between treatment groups. The most frequently reported AEs occurring in ≥5% of DAZ-treated subjects and >PBO were COVID-19, diarrhea, dizziness, ligament sprain, upper respiratory tract infection, contusion, device allergy, fatigue, hypertension, and oropharyngeal pain. Two SAEs were reported in a single DAZ-treated subject: this subject was a 59-year-old female who experienced a grade 3 SAE of COVID-19 infection and later died of unknown cause 46 days after last administration of DAZ (12 days after COVID-19 diagnosis). There was a single AESI of herpes zoster in a DAZ-treated subject.ConclusionDAZ is a potential new therapy for the treatment of systemic disease activity in patients with SS. SS subjects with moderate-to-high systemic disease receiving DAZ experienced a statistically significant reduction in disease activity relative to PBO as measured by the improvement in ESSDAI score. Except for a case of severe COVID-19 infection, DAZ therapy in SS subjects appeared to be well tolerated. Larger controlled trials of DAZ therapy for SS are warranted to further explore its safety profile and confirm its clinical efficacy.Table 1.Efficacy and Safety DataPBO N=38DAZ 1500 mg N=36EfficacyΔESSDAI, LS mean (SE) †-4.1 (0.6)-6.3 (0.6)*ΔESSPRI, LS mean (SE) †-1.12 (0.29)-1.80 (0.31)ΔFACIT-Fatigue, LS mean (SE) †5.8 (1.6)8.1 (1.6)AE Summary, n (%)≥1 AE23 (60.5)28 (77.8)≥1 related AE8 (21)10 (27.8)≥1 SAE01 (2.8)≥1 related SAE00≥1 AE leading to discontinuation00≥1 AESI01 (2.8)≥1 Death01 (2.8)Efficacy endpoints as of Day 169;† Analyzed using MMRM;Comparisons vs PBO;*p<0.05;AE summaries based on AEs that occurred through Day 169;AE, adverse event;AESI, adverse event of special interest;ESSDAI, EULAR Sjögren's Syndrome Disease Activity Index;ESSPRI, EULAR Sjögren's Syndrome Patient Reported Index;FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-Fatigue;PBO, placebo;SAE, serious adverse eventFigure 1.AcknowledgementsFunded by Horizon herapeutics. Medical writing support provided by B Lujan, PhD, an employee of Horizon Therapeutics.Disclosure of InterestsE. William St. Clair Consultant of: Horizon Therapeutics, Bristol Myers Squibb, CSL Behring, Resolve Therapeutics, Sonoma Biotherapeutics. Royalties: UpToDate, Liangwei Wang Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Ilias Alevizos Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, William Rees Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Alan Baer Consultant of: Bristol Myers Squibb, Wan Fai Ng Consultant of: Novartis, GlaxoSmithKline, Abbvie, BMS, Sanofi, MedImmune, Janssen and UCB, Ghaith Noaiseh Consultant of: Novartis, Chiara Baldini Consultant of: GSK, and Sanofi.

Oral lesions in patients with severe COVID-19 in the National Institute of Respiratory Diseases in Mexico: Case series

Introduction SARS-CoV-2 is a neurotropic, mucotropic, and sialotropic virus that can affect the salivary glands' function, taste sensations, smell, and oral mucosa integrity.1 The oral cavity is a perfect habitat for SARS-CoV-2 invasion due to the special affinity the virus has for cells with angiotensinconverting enzyme (ACE2) receptors, such as those from the respiratory tract, oral mucosa, tongue, and salivary glands. Aphthous lesions with necrosis and hemorrhagic crusts have been described to manifest more regularly in older adults with immunosuppression and severe COVID-19 infection;one hypothesis for the development of aphthous lesions and/or ulcers is given due to the ACE2 receptor and the SARS-CoV-2 interaction, which could alter the epithelial lining of salivary glands and keratinocytes, causing lesions in the oral cavity.4 At the same time, different etiological factors such as infections, immune system alterations, and direct trauma to the oral mucosa or epithelium,5 may be related to the stress of a prolonged hospital stay.6 Including pressure in the oral cavity conditioned by the prone position, malposition of the endotracheal tube (mainly in the corners of the lips),7 medication-related nutritional deficiencies8 such as lopinavir, and ritonavir, oseltamivir, hydroxychloroquine, among others.9-12 Thrombotic vasculopathy secondary to COVID-19 has also been described, induced by system mediators in the microvascular walls, which impairs endothelial cells, and activates coagulation factors13 and a possible hypersensitivity reaction of the mucosa to the presence of SARS-CoV-2 in the epithelium14,15;there is also the hypothesis that it could be associated with an exanthem pattern induced by the inflammatory action of the SARSCoV-2 virus,16 presented as increased levels of cytokines (including interleukin-1, tumor necrosis facto-a), and arachidonic acid metabolites (prostaglandins) secondary to the stem cell factor production and the basic fibroblast growth factor of keratinocytes from the basal layer, in relation to post-inflammatory pigmentations that could appear in areas previously affected by trauma or chronic inflammation.17 Oral manifestations in COVID-19 patients appear, on many occasions, even before respiratory symptoms, although exanthematic lesions observed in COVID-19 patients can also be observed in other viral processes. Physical examination revealed a patient in a supine position with orotracheal intubation and orogastric tube, with aphthous-type ulcers, some of them had blood crusts of different sizes on the lower lip (both skin and mucosa), dorsum, and lateral edge of the tongue, gum, and vestibular fornix (Figure 3). Initial physical examination shows the patient in a supine position supported by high-flow nasal prongs, upper and lower lips edema and ulcer-like lesions with hematic crusts on both lips (Figure 4), topical management with steroids and GELCLAIRE® Oral Gel (glycyrrhetinic acid and polyvinylpyrrolidone) is observed.

To study the pathophysiology, clinical features, diagnosis and management of coronovirus: A review study

In the current scenario, amongst the various other diseases, covid-19 is one of the deadliest one. Its outbreak began in China but soon the disease spread worldwide. It's a highly contagious disease, being airborne therefore, dentists and other health professionals must be well informed about the symptoms of this disease and the precautionary methods to protect themselves and the general population from it. The objective of this paper is to raise awareness of the above review of PPE, its findings and their relevance to dentistry.In this article, we have tried to mention few of the precautionary methods that can be followed by the dental and other medical professionals to protect themselves from this disease.

Research in brief

The authors reported no adverse reactions to phage therapy, regardless of type of bacterial infection, type of phages used, or method of treatment. 11 patients displayed some measure of symptom improvement or reduced bacterial presence;four exhibited no response to treatment. T-helper cells key to malaria vaccine Scientists studying why immunity against Plasmodium falciparum lasts only a short time after immunisation found that T-helper cells reacted exclusively to the protein sequence of the vaccine strain and showed hardly any cross-reactivity with naturally occurring variants. For more on cancer drug and SARS-CoV-2 see ACS Infect Dis 2022;published online June 29. https://doi.org/10.1021/acsinfecdis.2c00008 For more on COVID-19 in pregnancy in sub-Saharan Africa see Clin Infect Dis 2022;published online June 8. https://doi.org/10.1093/cid/ciac294 For more on the spread of enteric viruses through saliva see Nature 2022;published online June 29. https://doi.org/10.1038/s41586-022-04895-8 For more on influenza vaccination and Alzheimer's disease see J Alzheimers Dis 2022;published online June 13. https://doi.org/10.3233/jad-220361 For more on extensively drug-resistant Neisseria gonorrhoeae see Euro Surveill 2022;27: 2200455 For more on bacteriophage therapy case series see Clin Infect Dis 2022;published online June 9. https://doi.org/10.1093/cid/ciac453 For more on T-helper cells and malaria vaccine see Sci Immunol 2022;7: eabm9644

ORAL MANIFESTATIONS ASSOCIATED WITH COVID‑19 PATIENTS IN SAUDI ARABIA

COVID-19 was recognized by the World Health Organization (WHO) as a pandemic disease since most of the countries reported significant numbers of deaths and infected people starting with December 2019 (WHO, 2020). The diversity of COVID-19 manifestations can be attributed to the sites where the SARS-Cov-2 receptors Angiotensin-converting Enzymes 2 (ACE2) were found, which include, but were not limited to, lung, kidney, salivary glands and gastrointestinal tract [1,12-14]. Dealing with COVID-19 had shown that many oral manifestations could be in direct relation to the infection itself. [...]another study [15] reported that at least one oral manifestation concerning the oral cavity and salivary gland was found on 67.2% of the 58 observed patients, in whom a dry mouth had the highest prevalence and gingival bleeding - the lowest. A P-value < 0.05 was considered significant. 3.RESULTS The link was distributed to a total of 515 patients tested positive with COVID-19, 512 of them having responded to the questionnaire (a response rate of 99%).

Highlights from this issue

Economic, clinical and social impact of simple limbal epithelial transplantation for limbal stem cell deficiency (see page 923) A comprehensive literature survey, questionnaire-based survey and economic analysis indicates that simple limbal epithelial transplantation is a better alternative to cultivated limbal epithelial transplantation in terms of anatomical success, cost and accessibility. Association between body mass index and diabetic retinopathy in Asians: the Asian eye epidemiology Consortium (AEEC) study (see page 980) In a pooled analysis including 10 010 Asian adults with diabetes from 12 cross-sectional studies across six Asian countries, obesity was inversely associated with both any diabetic retinopathy and vision-threatening diabetic retinopathy, independent of potential risk factors. Efficacy of a novel personalised aflibercept monotherapy regimen based on polypoidal lesion closure in participants with polypoidal choroidal vasculopathy (see page 987) We report the results of a novel personalised anti-vascular endothelial growth factor monotherapy regimen for the management of polypoidal choroidal vasculopathy which achieves comparable outcomes to a fixed 8-weekly regimen and high polypoidal lesion closure rate.