Citations

Abstract Objectives We investigated coronavirus disease 2019 (COVID-19) vaccine safety in pregnant and breastfeeding women with autoimmune diseases (AID) in the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. Methods Delayed-onset (>7 days) vaccine-related adverse events (AE), disease flares and AID-related treatment modifications were analysed upon diagnosis of AID vs healthy controls (HC) and the pregnancy/breastfeeding status at the time of at least one dose of vaccine. Results Among the 9201 participants to the self-administered online survey, 6787 (73.8%) were women. Forty pregnant and 52 breastfeeding patients with AID were identified, of whom the majority had received at least one dose of COVID-19 vaccine (100% and 96.2%, respectively). AE were reported significantly more frequently in pregnant than in non-pregnant patients (overall AE 45% vs 26%, P = 0.01; minor AE 40% vs 25.9%, P = 0.03; major AE 17.5% vs 4.6%, P < 0.01), but no difference was found in comparison with pregnant HC. No difference was observed between breastfeeding patients and HC with respect to AE. Post-vaccination disease flares were reported by 17.5% of pregnant and 20% of breastfeeding patients, and by 18.3% of age- and disease-matched non-pregnant and non-breastfeeding patients (n = 262). All pregnant/breastfeeding patients who experienced a disease flare were managed with glucocorticoids; 28.6% and 20% of them required initiation or change in immunosuppressants, respectively. Conclusion This study provides reassuring insights into the safety of COVID-19 vaccines administered to women with AID during the gestational and post-partum periods, helping overcome hesitant attitudes, as the benefits for the mother and for the fetus by passive immunization appear to outweigh potential risks.

Introduction Radiation therapy for head and neck squamous cell carcinoma is constrained by radiotoxicity to normal tissue. We demonstrate 100 nm theranostic nanoparticles for image-guided radiation therapy planning and enhancement in rat head and neck squamous cell carcinoma models. Methods PEG conjugated theranostic nanoparticles comprising of Au nanorods coated with Gadolinium oxide layers were tested for radiation therapy enhancement in 2D cultures of OSC-19-GFP-luc cells, and orthotopic tongue xenografts in male immunocompromised Salt sensitive or SS rats via both intratumoral and intravenous delivery. The radiation therapy enhancement mechanism was investigated. Results Theranostic nanoparticles demonstrated both X-ray/magnetic resonance contrast in a dose-dependent manner. Magnetic resonance images depicted optimal tumor-to-background uptake at 4 h post injection. Theranostic nanoparticle + Radiation treated rats experienced reduced tumor growth compared to controls, and reduction in lung metastasis. Conclusions Theranostic nanoparticles enable preprocedure radiotherapy planning, as well as enhance radiation treatment efficacy for head and neck tumors.

Abstract Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

Abstract Objectives We aimed to explore current practice and interregional differences in the treatment of idiopathic inflammatory myopathies (IIMs). We triangulated these observations considering countries' gross national income (GNI), disease subtypes, and symptoms using patient-reported information. Methods A cross-sectional ancillary analysis of the ‘COVID-19 vaccination in auto-immune disease’ (COVAD) e-survey containing demographic characteristics, IIM subtypes (DM, PM, IBM, anti-synthetase syndrome [ASSD], immune-mediated necrotizing myopathy [IMNM], overlap myopathies [OM]), current symptoms (surrogate for organ involvement) and treatments (corticosteroids [CS], immunomodulators [IM], i.e. antimalarials, immunosuppressants [IS], IVIG, biologic treatments and targeted-synthetic small molecules). Treatments were presented descriptively according to continents, GNI, IIM and organ involvement, and associated factors were analysed using multivariable binary logistic regressions. Results Of 18 851 respondents from 94 countries, 1418 with IIM were analysed (age 61 years, 62.5% females). DM (32.4%), IBM (24.5%) and OM (15.8%) were the most common subtypes. Treatment categories included IS (49.4%), CS (38.5%), IM (13.8%) and IVIG (9.4%). Notably, treatments varied across regions, GNI categories (IS mostly used in higher-middle income, IM in lower-middle income, IVIG and biologics largely limited to high-income countries), IIM subtypes (IS and CS associated with ASSD, IM with OM and DM, IVIG with IMNM, and biologic treatments with OM and ASSD) and disease manifestations (IS and CS with dyspnoea). Most inter-regional treatment disparities persisted after multivariable analysis. Conclusion We identified marked regional treatment disparities in a global cohort of IIM. These observations highlight the need for international consensus-driven management guidelines considering patient-centred care and available resources.

Talimogene laherparepvec (T-VEC) plus ipilimumab has demonstrated greater antitumor activity versus ipilimumab alone, without additional toxicity, in patients with advanced melanoma. Here, we report the 5-year outcomes from a randomized phase II study. These data provide the longest efficacy and safety follow-up for patients with melanoma treated with a combination of an oncolytic virus and a checkpoint inhibitor. Eligible patients with unresectable stage IIIB‒IV melanoma were randomized 1:1 to receive T-VEC plus ipilimumab or ipilimumab alone. T-VEC was administered intralesionally at 10 6 plaque-forming units (PFU)/mL in week 1, followed by 10 8 PFU/mL in week 4 and every 2 weeks thereafter. Ipilimumab (3 mg/kg every 3 weeks; ≤4 doses) was administered intravenously starting at week 1 in the ipilimumab arm and week 6 in the combination arm. The primary end point was investigator-assessed objective response rate (ORR) per immune-related response criteria; key secondary end points included durable response rate (DRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 198 patients were randomized to receive the combination (n=98) or ipilimumab (n=100). The combination improved the ORR versus ipilimumab (35.7% vs 16.0%; OR 2.9; 95% CI 1.5 to 5.7; p=0.003). DRR was 33.7% and 13.0% (unadjusted OR 3.4; 95% CI 1.7 to 7.0; descriptive p=0.001), respectively. Among the objective responders, the median DOR was 69.2 months (95% CI 38.5 to not estimable) with the combination and was not reached with ipilimumab. Median PFS was 13.5 months with the combination and 6.4 months with ipilimumab (HR 0.78; 95% CI 0.55 to 1.09; descriptive p=0.14). Estimated 5-year OS was 54.7% (95% CI 43.9 to 64.2) in the combination arm and 48.4% (95% CI 37.9 to 58.1) in the ipilimumab arm. Forty-seven (48.0%) and 65 (65.0%) patients in the combination and ipilimumab arms, respectively, received subsequent therapies. No new safety signals were reported. At the 5-year follow-up, the improved response rates observed with T-VEC plus ipilimumab were durable. This is the first randomized controlled study of the combination of an oncolytic virus and a checkpoint inhibitor that meets its primary end point.Trial registration number: NCT01740297 .

Summary: Asian rhinoplasty generally requires augmentation procedures rather than reduction. Alloplastic grafts are fraught with higher complication rates. Autologous cartilage grafts are safer. However, Asian patients typically do not have adequate septal cartilages, and other autologous cartilage grafts may cause surgical site morbidities, prolonged surgical time, and complications, including warping and infection. Asian rhinoplasties were performed using fresh frozen cartilage by the senior author. Patients’ demographics and medical histories were recorded. Anthropometric measurements (nasofrontal angle, nasofacial angle, nasolabial angle, and Goode ratio) were taken on two-dimensional photographs. FACE-Q scales were used to assess patient-reported outcomes. Five Asian patients underwent rhinoplasty using the fresh frozen cartilage and were followed up for an average period of 14.2 ± 3.35 months. There was no resorption, warping, or infection. Anthropometric measurements showed no significant changes 2–4 months or 8–20 months after surgery. At the time of the 1-year follow-up, mean FACE-Q Satisfaction with Nose, and Satisfaction with Nostrils scores improved from 35.2 ± 10.06 to 60 ± 15.48 (P = 0.0002), and 42.6 ± 20.31 to 59.8 ± 38.21 (P = 0.12), respectively. Fresh frozen cadaveric cartilage is a novel option for Asian rhinoplasty. Our study demonstrated its safety and satisfying surgical outcomes.

Abstract Background/Aims Flares following COVID-19 vaccination are an emerging concern among patients with rare rheumatic disease like idiopathic inflammatory myositis (IIMs), whereas data and understanding of this is rather limited. We aimed to study the prevalence, characteristics and determinants of IIM flares following COVID-19 vaccination. Methods CoVAD (COVID-19 Vaccination In Autoimmune Diseases) surveys are global patient self-reported e-surveys from 109 countries conducted in 2021 and 2022. Flares of IIM were defined by 4 definitions; a. patient self-reported, b. physician and immunosuppression (IS) denoted, c. sign directed (new erythematous rash, or worsening myositis or arthritis), d. MCID worsening of PROMISPF10a score between the patients who had taken both surveys. Descriptive statistics and multivariate regression were used to describe the predictors of flare. Cox-regression analysis was used to differentiate flares by IIM subtypes. Results Among the 1,278 IIM patients, aged 63 (50-71) years, 276 (21.5%) were dermatomyositis, 237 (18.5%) IBM, 899 (70.3%) were female and most were Caucasian (80.8%). Flares of IIM were seen in 123/1278 (9.6%), 163/1278 (12.7%), 112/1278 (8.7%), and 16/96 (19.6%) by definitions a-d respectively with median time to flare being 71.5 (10.7-235) days. Muscle weakness (69.1%), and fatigue (56.9%) were the most common symptoms of flare. The predictors of self-reported flare were: inactive/disease in remission prior to first dose of vaccine (OR = 4.3, 95%CI=2.4-7.6), and anxiety disorder (OR = 2.2, 95%CI=1.1-4.7). Rituximab use (OR = 0.3, 95%CI=0.1-0.7) and IBM (OR = 0.3, 95%CI=0.1-0.7) were protective. Physician defined flares were seen more often in females, mixed ethnicity, and those with asthma, ILD, and anxiety disorder (OR ranging 1.6-7.0, all p < 0.05). Notably, overlap myositis (OM) had higher HR for flare compared to polymyositis (HR = 2.3, 95%CI=1.2-4.4, p = 0.010). Conclusion Nearly one in ten individuals with IIM develop flares after vaccination, more so among women, those with overlap myositis, and inactive disease prior to vaccination. Formal definition of flares in IIM is needed. Disclosure L. Gupta: None. N. R: None. Z. Griger: None. V. Agarwal: None. P. Sen: None. M. Joshi: None. S. Saha: None. K. Jagtap: None. O. Distler: Honoraria; Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos, Glenmark, GSK, Horizon (Curzion), Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Mitsubishi Tanabe, Novartis, Roche, Roivant, Sanofi, Serodapharm, Topadur and UCB. E. Nikiphorou: Honoraria; Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, and Lilly. Grants/research support; Pfizer and Lilly. A. Tan: Honoraria; Abbvie, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB. S. Shinjo: None. N. Ziade: Honoraria; Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, and Pierre Fabre. M. Milchert: None. I. Parodis: Honoraria; Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis and F. Hoffmann-La Roche AG. M. Kuwana: None. A. Makol: None. J. Pauling: None. C. Wincup: None. J. Lilleker: Honoraria; Sanofi Genzyme, Roche, and Biogen. A. Nune: None. J. Day: Grants/research support; CSL Limited. H. Chinoy: Consultancies; Novartis, Eli Lilly, Orphazyme, Astra Zeneca. Honoraria; UCB, and Biogen. Grants/research support; Eli Lilly and UCB. V. Agarwal: None. R. Aggarwal: Consultancies; Bristol Myers-Squibb, Pfizer, Genentech, Octapharma, CSL Behring, Mallinckrodt, AstraZeneca, Corbus, Kezar, Abbvie, Janssen, Alexion, Argenx, Q32, EMD-Serono, Boehringer Ingelheim, and Roivant.

Abstract Background/Aims Post COVID-19 syndrome (PCS) is an emerging cause of morbidity and poor quality of life in COVID-19 survivors. We aimed to assess the prevalence, risk factors, outcomes, and association with disease flares of PCS in patients with autoimmune rheumatic diseases (AIRDs) and non-rheumatic autoimmune diseases (nrAIDs), both vulnerable groups understudied in the current literature using data from the 2nd COVID-19 Vaccination in Autoimmune Diseases (COVAD) global multicentre patient self-reported e-survey. Methods The survey was circulated from February to July 2022 by the international COVAD Study Group (157 collaborators from 106 countries), and demographics, comorbidities, AIRD/nrAID status, COVID-19 history, vaccination details, and PROMIS physical and mental function were recorded. PCS was defined as symptom resolution time >90 days following acute COVID-19. Predictors of PCS were analysed using regression models for the different groups. Results 7666 total respondents completed the survey. Of these, 2650 respondents with complete responses had positive COVID-19 infection, and 1677 (45.0% AIRDs, 12.5% nrAIDs, 42.5% HCs) completed the survey >90 days post acute COVID-19. Of these, 136 (8.1%) had PCS. Prevalence of PCS was higher in AIRDs (10.8%) than healthy controls HCs (5.3%) (OR: 2.1; 95%CI: 1.4-3.1, p = 0.002). Across the entire cohort, a higher risk of PCS was seen in women (OR: 2.9; 95%CI: 1.1-7.7, p = 0.037), patients with long duration of AIRDs/nrAIDs (OR 1.01; 95%CI: 1.0-1.02, p = 0.016), those with comorbidities (OR: 2.8; 95%CI: 1.4-5.7, p = 0.005), and patients requiring oxygen supplementation for severe acute COVID-19 (OR: 3.8; 95%CI: 1.1-13.6, p = 0.039). Among patients with AIRDs, comorbidities (OR 2.0; 95%CI: 1.08-3.6, p = 0.026), and advanced treatment (OR: 1.9; 95%CI: 1.08-3.3, p = 0.024), or intensive care (OR: 3.8; 95%CI: 1.01-14.4, p = 0.047) for severe COVID-19 were risk factors for PCS. Notably, patients who developed PCS had poorer PROMIS global physical [15 (12-17) vs 12 (9-15)] and mental health [14 (11-16) vs 11 (8-14)] scores than those without PCS. Conclusion Individuals with AIRDs have a greater risk of PCS than HCs. Associated comorbid conditions, and advanced treatment or intensive care unit admission for severe COVID-19 confer a higher risk of PCS. It is imperative to identify risk factors for PCS for immediate multidisciplinary management in anticipation of poor physical and mental health. Disclosure L. Gupta: None. P. Sen: None. N. R: None. M. Joshi: None. S. Saha: None. K. Jagtap: None. V. Agarwal: None. O. Distler: Consultancies; Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos, Glenmark, GSK, Horizon (Curzion), Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Mitsubishi Tanabe, Novartis, Roche, Roivant, Sanofi, Serodapharm, Topadur and UCB. E. Nikiphorou: Honoraria; Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, and Lilly. Grants/research support; Pfizer and Lilly. A. Tan: Honoraria; Abbvie, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB. S. Shinjo: None. N. Ziade: Honoraria; Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, and Pierre Fabre. M. Milchert: None. I. Parodis: Honoraria; Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis and F. Hoffmann-La Roche AG. M. Kuwana: None. A. Makol: None. J.D. Pauling: None. C. Wincup: None. J. Lilleker: Honoraria; Sanofi Genzyme, Roche, and Biogen. A. Nune: None. J. Day: Grants/research support; CSL Limited. H. Chinoy: Consultancies; Novartis, Eli Lilly, Orphazyme, Astra Zeneca. Honoraria; UCB, and Biogen. Grants/research support; Eli Lilly and UCB. V. Agarwal: None. R. Aggarwal: Consultancies; Bristol Myers-Squibb, Pfizer, Genentech, Octapharma, CSL Behring, Mallinckrodt, AstraZeneca, Corbus, Kezar, Abbvie, Janssen, Alexion, Argenx, Q32, EMD-Serono, Boehringer Ingelheim, and Roivant.