SAFETY OUTCOMES IN PATIENTS (PTS) WITH RHEUMATOID ARTHRITIS (RA) TREATED WITH FILGOTINIB (FIL) IN FILOSOPHY: INTERIM RESULTS FROM A PROSPECTIVE OBSERVATIONAL STUDY

BackgroundConsideration is needed when using Janus kinase (JAK) inhibitors to treat RA in pts aged ≥65 years or those with cardiovascular (CV) risk factors. The JAK1 preferential inhibitor FIL was generally well tolerated in clinical trials[1];safety has not been determined in a real-world setting.ObjectivesTo report baseline characteristics and up to 6-month safety data from the first 480 pts treated with FIL in the FILOSOPHY study (NCT04871919), and in two mutually exclusive subgroups based on age and CV risk.MethodsFILOSOPHY is an ongoing, phase 4, non-interventional, European study of pts with RA who have been prescribed FIL for the first time and in accordance with the product label in daily practice. Baseline characteristics and the incidence of select adverse events (AEs) are assessed in pts aged ≥65 years and/or with ≥1 CV risk factor (Table 1), and in those aged <65 years with no CV risk factors.ResultsAs of the end of June 2022, 480 pts had been treated: 441 received FIL 200 mg and 39 received FIL 100 mg. Of the 480 pts, 148 (30.8%) were aged ≥65 years;332 (69.2%) were aged <65 years. In total, 86 (17.9%) were former smokers, 81 (16.9%) were current smokers and 203 (42.3%) were non-smokers (data were missing for 110 pts [22.9%]). In addition to smoking, the most frequent CV risk factors included a history of hypertension (32.3%), a history of dyslipidemia (10.2%) and a family history of myocardial infarction (8.5%;Table 1).23 pts (4.8%) discontinued treatment due to AEs. Of the 354 pts aged ≥65 years or with ≥1 CV risk factor, infections affected 64 pts (18.1%), 34 (9.6%) had COVID-19, 2 (0.6%) had herpes zoster, and cardiac disorders (angina pectoris, atrial fibrillation, palpitations and tachycardia) affected 5 pts (1.4%);no cases of malignancies were observed. In the subgroup aged <65 years and with no CV risk factors (n=126), infections occurred in 18 pts (14.3%) (9 [7.1%] had COVID-19;3 [2.4%] had herpes zoster) and malignancies (myeloproliferative neoplasm) affected 1 pt (0.8%);no pts had cardiac disorders. There were no cases of deep vein thrombosis or pulmonary embolism in either subgroup.ConclusionIn this interim analysis of FILOSOPHY, no unexpected safety signals emerged at up to 6 months. Although infections and cardiac disorders affected a numerically greater proportion of pts aged ≥65 years or with ≥1 CV risk vs those aged <65 years with no CV risk, longer follow-up on a broader cohort is necessary to further characterize the safety of FIL in different groups of pts with RA.Reference[1]Winthrop K, et al. Ann Rheum Dis 2022;81:184–92Table 1.Baseline characteristics and CV risk factorsBaseline demographics/CV risk factorsAll FIL-treated pts (N=480)≥65 years or with ≥1 CV risk factor (n=354)<65 years and no CV risk factor (n=126)*Female sex, n (%)351 (73.1)252 (71.2)99 (78.6)Age, years, mean (SD)57.6 (11.5)60.4 (10.8)49.6 (9.6)Rheumatoid factor positive, n (%)†228 (47.5)167 (47.2)61 (48.4)Anti-citrullinated protein antibody positive, n (%)‡243 (50.6)176 (49.7)67 (53. 2)Body mass index, kg/m2, mean (SD)27.6 (5.7) n=43728.0 (5.4) n=33126.3 (6.4) n=106RA disease duration, years, mean (SD)10.4 (9.4) n=47810.5 (9.5) n=35310.0 (8.8) n=125Tender joint count 28, mean (SD)8.6 (6.9) n=4578.7 (7.1) n=3408.3 (6.3) n=117Swollen joint count 28, mean (SD)5.6 (5.2) n=4525.7 (5.4) n=3365.4 (4.4) n=116Former smoker, n (%)§86 (17.9)86 (24.3)0Current smoker, n (%)§81 (16.9)81 (22.9)0Non-smoker, n (%)§203 (42.3)130 (36.7)73 (57.9)Family history of myocardial infarction, n (%)41 (8.5)41 (11.6)0Medical history of: n (%) CV disease33 (6.9)33 (9.3)0 Diabetes35 (7.3)35 (9.9)0 Dyslipidemia49 (10.2)49 (13.8)0 Hypertension155 (32.3)155 (43.8)0 Ischemic CNS  vascular disorders11 (2.3)11 (3.1)0 Peripheral vascular disease17 (3.5)17 (4.8)0*Includes 53 pts with missing smoking status data who were aged <65 years with no other CV risk factors.†Missing/unknown in 154 pts;‡Missing in 153 pts;§Smoking status data missing in 110 pts (22.9%).AcknowledgementsWe thank the physicia s and patients who participated in this study. The study was funded by Galapagos NV, Mechelen, Belgium. Publication coordination was provided by Fabien Debailleul, PhD, of Galapagos NV. Medical writing support was provided by Debbie Sherwood, BSc, CMPP (Aspire Scientific, Bollington, UK), and funded by Galapagos NV.Disclosure of InterestsPatrick Verschueren Speakers bureau: AbbVie, Eli Lilly, Galapagos, Roularta, Consultant of: Celltrion, Eli Lilly, Galapagos, Gilead, Nordic Pharma, Sidekick Health, Grant/research support from: Galapagos, Pfizer, Jérôme Avouac Speakers bureau: AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, MSD, Novartis, Pfizer, Sandoz, Sanofi, Consultant of: AbbVie, Fresenius Kabi, Galapagos, Sanofi, Grant/research support from: BMS, Fresenius Kabi, Novartis, Pfizer, Karen Bevers Grant/research support from: Galapagos, Susana Romero-Yuste Speakers bureau: AbbVie, Biogen, BMS, Lilly, Pfizer, Consultant of: Sanofi, Lilly, Grant/research support from: Lilly, MSD, Roberto Caporali Speakers bureau: AbbVie, Amgen, BMS, Celltrion, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Sandoz, UCB, Consultant of: AbbVie, Amgen, BMS, Celltrion, Eli Lilly, Fresenius Kabi, Galapagos, Janssen, MSD, Novartis, Pfizer, Roche, Sandoz, UCB, Thomas Debray Consultant of: Biogen, Galapagos, Gilead, Francesco De Leonardis Employee of: Galapagos, James Galloway Speakers bureau: AbbVie, Biogen, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Roche, UCB, Consultant of: AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Grant/research support from: AstraZeneca, Celgene, Gilead, Janssen, Medicago, Novavax, Pfizer, Monia Zignani Shareholder of: Galapagos, Employee of: Galapagos, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Amgen, BMS, Chugai, Galapagos, Lilly, Pfizer, Sanofi, Consultant of: AbbVie, Amgen, BMS, Galapagos, Lilly, Pfizer, Sanofi.

PLACEBO-CONTROLLED EFFICACY AND SAFETY OF UPADACITINIB THROUGH ONE YEAR IN PATIENTS WITH NON-RADIOGRAPHIC AXIAL SPONDYLOARTHRITIS

BackgroundUpadacitinib (UPA), a Janus kinase inhibitor, was effective and well tolerated in patients (pts) with non-radiographic axial spondyloarthritis (nr-axSpA) through 14 weeks (wks) of treatment.[1]ObjectivesThis analysis assessed the efficacy and safety of UPA vs placebo (PBO) through 1 year.MethodsThe SELECT-AXIS 2 nr-axSpA study included a 52-wk randomized, double-blind, PBO-controlled period. Enrolled adults had a clinical diagnosis of active nr-axSpA fulfilling the 2009 ASAS classification criteria, objective signs of inflammation based on MRI sacroiliitis and/or elevated C-reactive protein, and an inadequate response to NSAIDs. One-third of pts had an inadequate response to biologic DMARDs. Pts were randomized 1:1 to UPA 15 mg once daily or PBO. Concomitant medications, including NSAIDs, had to be kept stable through wk 52. The study protocol outlined that pts who did not achieve ASAS20 at any two consecutive study visits between wks 24 to 52 should receive rescue therapy with NSAIDs, corticosteroids, conventional synthetic/biologic DMARDs, or analgesics. Cochran-Mantel-Haenszel (CMH) test with non-responder imputation incorporating multiple imputation (NRI-MI) was used to handle missing data and intercurrent events for binary efficacy endpoints. Mixed-effect model repeated measures (MMRM) was used to assess continuous efficacy endpoints. NRI was used for binary endpoints after rescue and as observed analysis excluding data after rescue for continuous endpoints. Treatment-emergent adverse events (TEAEs) are reported through wk 52.ResultsOf the 314 pts randomized, 259 (82%;UPA, n=130;PBO, n=129) completed wk 52 on study drug. More pts achieved an ASAS40 response with UPA vs PBO from wks 14 to 52 with a 20% treatment difference at wk 52 (63% vs 43%;nominal P <.001;Figure 1). The proportion of pts achieving ASDAS inactive disease with UPA remained higher than PBO at wk 52 (33% vs 11%;nominal P <.0001;Figure 1). Consistent improvements and maintenance of efficacy were also seen across other disease activity measures. Between wks 24 and 52, fewer pts on UPA (9%) than PBO (17%) received rescue therapy. A similar proportion of pts in each treatment group had a TEAE (Table 1). Infections were the most common TEAE;the rates of serious infections and herpes zoster were higher with UPA vs PBO, although no new serious infections were reported from wks 14 to 52. COVID-19 events were balanced between treatment groups. No opportunistic infections, malignancy excluding non-melanoma skin cancer, adjudicated major adverse cardiovascular events, inflammatory bowel disease, or deaths were reported. Two pts (1.3%) on PBO had adjudicated venous thromboembolic events.ConclusionUPA showed consistent improvement and maintenance of efficacy vs PBO through 1 year across multiple disease activity measures. No new safety risks were identified with longer-term UPA exposure. These results continue to support the benefit of UPA in pts with active nr-axSpA.Reference[1]Deodhar A, et al. Lancet. 2022;400(10349):369–379.Table 1.Safety through week 52Event, n (%)PBO (n = 157)UPA 15 mg QD (n = 156)Any AE103 (66%)107 (69%)Serious AE6 (3.8%)6 (3.8%)AE leading to D/C4 (2.5%)6 (3.8%)COVID-19-related AE22 (14%)24 (15%)Deaths00Infection60 (38%)68 (44%) Serious infection1 (0.6%)2 (1.3%) Herpes zoster1 (0.6%)5 (3.2%)Malignancy other than NMSC00NMSC1 (0.6%)0Hepatic disorder7 (4.5%)6 (3.8%)Neutropenia1 (0.6%)8 (5.1%)MACE (adjudicated)00VTE (adjudicated)2 (1.3%)a0Uveitisb3 (1.9%)2 (1.3%)Inflammatory bowel disease00aBoth patients had non-serious events of deep vein thrombosis in the lower limb with risk factors including obesity and prior deep vein thrombosis in one patient and concomitant COVID-19 infection in the other patient.bThree events of uveitis occurred in each treatment group (among n = 3 patients in the PBO group and n = 2 patients in the UPA group);two events in the PBO group and one in the UPA group occurred in patients with a history of uveitis.AcknowledgementsAbbVie funded this study and participated in the study design, res arch, analysis, data collection, interpretation of data, review, and approval of the . All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Julia Zolotarjova, MSc, MWC, of AbbVie.Disclosure of InterestsFilip van den Bosch Speakers bureau: AbbVie, Amgen, Galapagos, Janssen, Lilly, Merck, MoonLake, Novartis, Pfizer, and UCB., Consultant of: AbbVie, Amgen, Galapagos, Janssen, Lilly, Merck, MoonLake, Novartis, Pfizer, and UCB., Atul Deodhar Consultant of: AbbVie, Amgen, Aurinia, BMS, Celgene, GSK, Janssen, Lilly, MoonLake, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Bristol Myers Squibb, Celgene, GSK, Lilly, Novartis, Pfizer, and UCB, Denis Poddubnyy Speakers bureau: AbbVie, Biocad, BMS, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, MSD, Medscape, MoonLake, Novartis, Peervoice, Pfizer, Roche, Samsung Bioepis, and UCB, Consultant of: AbbVie, Biocad, BMS, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, MSD, Medscape, MoonLake, Novartis, Peervoice, Pfizer, Roche, Samsung Bioepis, and UCB, Grant/research support from: AbbVie, Lilly, MSD, Novartis, and Pfizer., Walter P Maksymowych Consultant of: AbbVie, BMS, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Novartis, Pfizer, and UCB, Employee of: Chief Medical Officer of CARE Arthritis Limited, Désirée van der Heijde Consultant of: AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, and UCB, Employee of: Director of Imaging Rheumatology BV, Tae-Hwan Kim Speakers bureau: AbbVie, Celltrion, Kirin, Lilly, and Novartis., Mitsumasa Kishimoto Consultant of: AbbVie, Amgen, Asahi-Kasei Pharma, Astellas, Ayumi Pharma, BMS, Chugai, Daiichi Sankyo, Eisai, Gilead, Janssen, Lilly, Novartis, Ono Pharma, Pfizer, Tanabe-Mitsubishi, and UCB., Xenofon Baraliakos Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, and UCB, Consultant of: AbbVie, BMS, Chugai, MSD, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie and Novartis, Yuanyuan Duan Shareholder of: AbbVie, Employee of: AbbVie, Kristin D'Silva Shareholder of: AbbVie, Employee of: AbbVie, Peter Wung Shareholder of: AbbVie, Employee of: AbbVie, In-Ho Song Shareholder of: AbbVie, Employee of: AbbVie.

CLINICAL SIGNIFICANCE OF SERUM FERRITIN IN PATIENTS WITH SYSTEMIC SCLEROSIS

BackgroundThe main systemic sclerosis (SSc) manifestations are skin thickening, microangiopathy and ischemic changes in tissues, fibrotic damage to the lungs, heart, kidneys, and digestive system, arthritis, and myopathy. Acute phase reactants (APR) like erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) reflect inflammation activity in various inflammatory conditions. Ferritin is a protein bound to iron;low serum ferritin indicates iron deficiency and/or anemia. Instead, high ferritin levels are associated with inflammatory and non-inflammatory conditions such as dermatomyositis, pulmonary fibrosis, lupus, systemic COVID-19, vasculitis, tissue damage, thromboembolic complications, and metastatic cancer. The possible role of ferritin in SSc as APR is unclear.ObjectivesWe aimed to assess whether ferritin levels can reflect the severity of SSc and predict the outcome.Methods241 files of SSc patients with information on serum ferritin level (ferritin over 300 mg/dL is considered elevated) who visited the Rambam Rheumatology Institute in the years 2004-2021were used for retrospective analysis. Patients' demographic, clinical, laboratory, imaging, and respiratory function data were collected from electronic hospital files. Statistics included Student's T-test, Pearson's chi-squared test, and Kaplan-Meier curve;statistical significance was determined as p<0.05.Results36 patients (FerEl-SSc) had elevated ferritin values;the rest (n=205) represented the second group (FerNor-SSc). Significant differences were seen in gender (male 44.4% - 15.6%), disease duration (4.56 - 7.7 years), modified Rodnan skin score (12.3 - 6.9), as well as in incidence of lung (65.7% - 38.7%), heart (51.4% - 21.1%), and renal (28.6% - 5.9%) involvement. Increased ferritin correlated with elevated ESR, CRP, creatinine, creatine kinase, troponin, and reduced hemoglobin, impaired pulmonary function tests and reduced left ventricular ejection fraction on echocardiography. Patients with elevated ferritin had a significant increase in mortality rates (52.8% and 35.1%) and non-significant reduction in survival.ConclusionOur study demonstrated that ferritin has a potential as a sensitive marker for SSc severity in term of skin thickening, vital organ complications, and mortality. The ferritin test is simple and inexpensive, it can add to the complex SSc assessment and contribute to treatment decision-making in complicated SSc.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

TYPE I INTERFERON SCORE IS ASSOCIATED WITH THE SEVERITY AND POOR PROGNOSIS IN ANTI-MDA5 ANTIBODY-POSITIVE DERMATOMYOSITIS PATIENTS

BackgroundAnti-MDA5 antibody-positive dermatomyositis (anti-MDA5+DM) is a rare autoimmune disease associated with a high mortality rate due to rapid-progressive interstitial lung disease (RP-ILD), particularly in East Asia[1]. MDA5, acts as a cytoplasmic sensor of viral RNA, thus activating antiviral responses including the type I interferon (IFN) signaling pathway[2]. The involvement of type 1 IFN in the pathogenesis of MDA5+DM has been proposed based on the significantly elevated expression of its downstream stimulated genes(ISG) in muscle, skin, lung, and peripheral blood[3;4]. Janus kinase inhibitor, which targets the IFN pathway, combined with glucocorticoid could improve the survival of early-stage MDA5+DM-ILD patients[5]. In clinical practice, there is still an urgent demand for sensitive biomarkers to facilitate clinical risk assessment and precise treatment.ObjectivesThis study aimed to investigate the clinical significance of interferon score, especially IFN-I score, in patients with anti-MDA5+DM.MethodsDifferent subtypes of idiopathic inflammatory myopathy, including anti-MDA5+DM(n=61), anti-MDA5-DM(n=20), antisynthetase syndrome(ASS,n=22),polymyositis(PM,n=6) and immune-mediated necrotizing myopathy(IMNM,n=9), and 58 healthy controls were enrolled.. A multiplex quantitative real-time PCR(RT-qPCR) assay using four TaqMan probes was utilized to evaluate two type I ISGs (IFI44, MX1, which are used for IFN-I score), one type II ISG (IRF1), and one housekeeping gene (HRPT1). Clinical features and disease activity index were compared between high and low IFN-I score groups in 61 anti-MDA5+DM patients. The association between laboratory findings and the predictive value of baseline IFN-I score level for mortality was analyzed.ResultsThe IFN scores were significantly higher in patients with anti-MDA5+DM than in HC (Figure 1A). The IFN-I score correlated positively with serum IFN α(r = 0.335, P =0.008), ferritin (r = 0.302, P = 0.018), and Myositis Disease Activity Assessment Visual Analogue Scale (MYOACT) score(r=0.426, P=0.001). Compared with patients with low IFN-I scores, patients with high IFN-I scores showed increased MYOACT score, CRP, AST, ferritin, and the percentages of plasma cells (PC%) but decreased lymphocyte count, natural killer cell count, and monocyte count. The 3-month survival rate was significantly lower in patients with IFN-I score > 4.9 than in those with IFN-I score ≤ 4.9(72.9% vs. 100%, P=0.044)(Figure 1B).ConclusionIFN score, especially IFN-I score, detected by multiplex RT-qPCR, can be a valuable biomarker for monitoring disease activity and predicting mortality in anti-MDA5+DM patients.References[1]I.E. Lundberg, M. Fujimoto, J. Vencovsky, R. Aggarwal, M. Holmqvist, L. Christopher-Stine, A.L. Mammen, and F.W. Miller, Idiopathic inflammatory myopathies. Nat Rev Dis Primers 7 (2021) 86.[2]G. Liu, J.H. Lee, Z.M. Parker, D. Acharya, J.J. Chiang, M. van Gent, W. Riedl, M.E. Davis-Gardner, E. Wies, C. Chiang, and M.U. Gack, ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS-CoV-2 papain-like protease to evade host innate immunity. Nat Microbiol 6 (2021) 467-478.[3]G.M. Moneta, D. Pires Marafon, E. Marasco, S. Rosina, M. Verardo, C. Fiorillo, C. Minetti, L. Bracci-Laudiero, A. Ravelli, F. De Benedetti, and R. Nicolai, Muscle Expression of Type I and Type II Interferons Is Increased in Juvenile Dermatomyositis and Related to Clinical and Histologic Features. Arthritis Rheumatol 71 (2019) 1011-1021.[4]Y. Ye, Z. Chen, S. Jiang, F. Jia, T. Li, X. Lu, J. Xue, X. Lian, J. Ma, P. Hao, L. Lu, S. Ye, N. Shen, C. Bao, Q. Fu, and X. Zhang, Single-cell profiling reveals distinct adaptive immune hallmarks in MDA5+ dermatomyositis with therapeutic implications. Nat Commun 13 (2022) 6458.[5]Z. Chen, X. Wang, and S. Ye, Tofacitinib in Amyopathic Dermatomyositis–Associated Interstitial Lung Disease. New England Journal of Medicine 381 (2019) 291-293.AcknowledgementsThis work was supported by the National Natural Science Foundation of China [81974251], and Shanghai Hospital Develop ent Center, Joint Research of New Advanced Technology Project [SHDC12018106]Disclosure of InterestsNone Declared.

Analysis of the COVID-19 Lockdown Impact on Biological Parameters and Physical Performance in Football Players

The COVID-19 pandemic has caused significant changes in global sustainability, but specifically, this study analyses the impact of lockdown on health and behavior in the game of football. The 2020/2021 Italian football competitive season (indicated as "post-COVID”), taking place following an obliged lockdown and longer than the normal summery season break, was characterized by very short recovery times and was compared to the 2018–2019 "pre-COVID” season, which had a regular course. The comparisons were about anthropometric and hormonal responses, muscle damage, and the physical performance of players in the major league (Serie A), and were made considering two extreme points of the competitive seasons: before the preparatory period (T0) and at the end of the season (T1). Turning to the results, it is significant to note the following: (1) body fat percentage was lower at the start (T0) of the post-COVID season than at the start of the pre-COVID season. During both seasons, serum CK and LDH increased in T1 and were significantly higher in both T0 and T1 of the post-COVID season. (2) Cortisol and testosterone concentrations increased in both seasons from T0 to T1;however, in the post-COVID season, concentrations of both were higher than in the previous season. The testosterone to cortisol ratio increased at the end of the pre-COVID season, whilst strongly decreasing at T1 of the post-COVID season. (3) Blood lactate concentrations significantly decreased during the pre-COVID season but remained unchanged during the post-COVID season. We may conclude that the enforced suspension period and the consequent rapid resumption of all activities influenced the physical and physiological state of professional footballers.

US drug approvals rise in 2020 over previous year

Several medicines were approved as first treatments, including Gilead Sciences' Veklury (remdesivir) for patients with COVID-19 who require hospitalization (4);Amivas' artesunate for injection for severe malaria (5);Horizon Therapeutics Ireland DAC's Tepezza (teprotumumab-trbw), an antibody drug conjugate (ADC) for treating thyroid eye disease (6);and Ultragenyx Pharmaceutical's Dojolvi (triheptanoin) and Alnylam Pharmaceuticals' Oxlumo (lumasiran), both first treatments for metabolic disorders-Dojolvi for treating paediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders (7) and Oxlumo (lumasiran) for treating the rare genetic disorder, primary hyperoxaluria type 1 (8). Blueprint Medicines Corporation) for treating unresectable or metastatic gastrointestinal stromal tumours harboring a platelet-derived growth factor receptor alpha exon 18 mutation (9);Koselugo (selumetinib, AstraZeneca Pharmaceuticals), for neurofibromatosis type 1 (10);Pemazyre (pemigatinib, Incyte Corporation), for certain types of previously treated, advanced bile duct cancer (cholangiocarcinoma) (11);Tabrecta (capmatinib, Novartis) for non-small cell lung cancer that has spread to other parts of the body and whose tumours have mutations that lead to MET exon 14 skipping (12);and Retevmo (selpercatinib, Loxo Oncology, a subsidiary of Eli Lilly and Company) for treating three types of tumours with alterations of the "rearranged during transfection" gene (13). Gilead, "U.S. FDA Approves Kite's Tecartus, the First and Only CAR T Treatment for Relapsed or Refractory Mantle Cell Lymphoma," Press Release, 24 July 2020.

DERMATO-NEURO SYNDROME PRECIPITATED BY COVID-19 INFECTION IN THE SETTING OF SCLEROMYXEDEMA

BackgroundA black female in her 40s presented with a nonpruritic rash for 10 months consisting of bumps on the face, hands, forearms, and thighs. She had no prior treatment. Past medical history was significant for pulmonary embolism (PE) 6 years prior. She had no personal or family history of autoimmune disease. Physical exam revealed numerous smooth 2-3 mm skin-colored papules over the bilateral forearm dorsa, hands, anterior thighs, and face. Serum protein electrophoresis revealed monoclonal IgG lambda gammopathy. Skin biopsy of her left elbow showed dermal fibroplasia with mucin deposition. IgG was less than 1.5 grams/deciliter;bloodwork was otherwise stable. The diagnosis of scleromyxedema was rendered.ObjectivesThe objective of this clinical case was to evaluate a neurologic sequela of COVID-19 infection in a patient with scleromyxedema.MethodsOne month following diagnosis of scleromyxedema, our patient was diagnosed with COVID-19 five days before admission to the emergency department with altered mental status and aphasia. Rheumatology was consulted due to malignant hypertension and acute kidney injury with question of scleroderma-like renal crisis in the setting of recently diagnosed COVID-19 infection, although she had no other features of systemic sclerosis. The infectious disease team was consulted due to COVID-19-induced inflammatory reaction.ResultsThe patient's creatinine kinase and brain natriuretic peptide were elevated. Creatinine and potassium trended upwards. She developed seizures and became hemodynamically unstable with rapidly declining clinical status. She was transferred to the intensive care unit, where she developed respiratory arrest, shock, hyperkalemia, and acidemia. She received escalating doses of pressors but experienced frequent arrhythmic disturbances and developed asystole. Resuscitation efforts were unsuccessful;she expired within 24 hours of consultation.ConclusionDermato-neuro syndrome (DNS) is a potential complication of scleromyxedema associated with confusion, dysarthria, seizures, and coma. The patient's clinical presentation is consistent with DNS in the setting of scleromyxedema likely precipitated by COVID-19. Intravenous immunoglobulins are first-line treatment for scleromyxedema;however, it is associated with risk of venous thromboembolism. The patient was considered for treatment as an outpatient but deferred due to history of PE. She was reevaluated for treatment upon presentation to the hospital, but given the severity and rapidity of her condition, it was already too late. This is the second reported case of COVID-19 induced DNS in a patient with scleromyxedema. Given the severity, we recommend early initiation of treatment in patients with scleromyxedema and aggressive treatment for those contracting COVID-19.References[1] Haber R, Bachour J, El Gemayel M. Scleromyxedema treatment: a systematic review and update. Int J Dermatol. 2020;59:1191-1201.[2] Flannery MT, Humphrey D. Deep Venous Thrombosis with Pulmonary Embolism Related to IVIg Treatment: A Case Report and Literature Review. Case Rep Med. 2015;971321.[3] Lee YH, Sahu J, O'Brien MS, D'Agati VD, Jimenez SA. Scleroderma Renal Crisis-Like Acute Renal Failure Associated With Mucopolysaccharide Accumulation in Renal Vessels in a Patient With Scleromyxedema. J Clin Rheumatol. 2011;17:318-322.[4] Hoffman-Vold AM, Distler O, Bruni C, et al. Systemic sclerosis in the time of COVID-19. Lancet Rheumatol. 2022;4:e566-575.[5] Fritz M, Tinker D, Wessel AW, et al. SARS-CoV-2: A potential trigger of dermato-neuro syndrome in a patient with scleromyxedema. JAAD Case Rep. 2021;18:99-102.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

A call for an integrated biology

The Song of the Cell tells the story of how we came to understand ourselves and other complex living organisms as mosaics of these atoms of life. There is the "dividing cell”, which takes us to the 2001 Nobel Prize in Physiology or Medicine that Nurse won, alongside Leland Hartwell and Tim Hunt, for elucidating the roles of cyclin and cyclin-dependent kinase proteins in regulating the cell cycle, and to the invention of reproductive in-vitro fertilisation by Patrick Steptoe and Robert Edwards during the 1970s. Quite what the "new human” of the subtitle refers to is never fully clear, but the ability to reprogramme cell states, as for example, in the method devised by stem-cell researcher Shinya Yamanaka to induce mature somatic cells back to pluripotency, might have the potential to grow organs in vitro, to regenerate tissues in vivo, and even to create synthetic embryo-like structures without the involvement of fertilisation. Mukherjee rightly admits that this view goes too far, but it might at least be understood as suggesting that trying to attack cancer at the genetic level is like hoping to stop traffic jams by fixing the faulty brakes of the car that caused the last one.

Serine-arginine protein kinases and their targets in viral infection and their inhibition.

Accumulating evidence has consolidated the interaction between viral infection and host alternative splicing. Serine-arginine (SR) proteins are a class of highly conserved splicing factors critical for the spliceosome maturation, alternative splicing and RNA metabolism. Serine-arginine protein kinases (SRPKs) are important kinases that specifically phosphorylate SR proteins to regulate their distribution and activities in the central pre-mRNA splicing and other cellular processes. In addition to the predominant SR proteins, other cytoplasmic proteins containing a serine-arginine repeat domain, including viral proteins, have been identified as substrates of SRPKs. Viral infection triggers a myriad of cellular events in the host and it is therefore not surprising that viruses explore SRPKs-mediated phosphorylation as an important regulatory node in virus-host interactions. In this review, we briefly summarize the regulation and biological function of SRPKs, highlighting their involvement in the infection process of several viruses, such as viral replication, transcription and capsid assembly. In addition, we review the structure-function relationships of currently available inhibitors of SRPKs and discuss their putative use as antivirals against well-characterized viruses or newly emerging viruses. We also highlight the viral proteins and cellular substrates targeted by SRPKs as potential antiviral therapeutic candidates.

Metabolic risks and prognosis of COVID-19: are dietary patterns important?

PurposeThis study aims to identify the dietary patterns of two groups of subjects (with and without COVID-19), and to assess the relationship of findings with the prognosis of COVID-19 and metabolic risk parameters.Design/methodology/approachThis study included 100 individuals in the age range of 19–65 years. The medical history, and data on biochemical, hematological and inflammatory indicators were retrieved from the files. A questionnaire for the 24-h food record and the food intake frequency was administered in face-to-face interviews, and dietary patterns of subjects were assessed.FindingsIn individuals with COVID-19, the hip circumference, the waist-hip ratio and the body fat percentage were significantly higher (p < 0.05), and the muscle mass percentage was significantly lower (p < 0.05). Mediterranean diet adherence screener (MEDAS), dietary approaches to stop hypertension (DASH) and healthy eating ındex-2015 (HEI-2015) scores were low in the two groups. A linear correlation of DASH scores was found with the muscle mass percentage (p = 0.046) and a significant inverse correlation of with the body fat percentage (p = 0.006). HEI-2015 scores were significantly and negatively correlated with body weight, body mass index, waist circumference, hip circumference and neck circumference (p < 0.05). Every one-unit increase in MEDAS, DASH and HEI-2015 scores caused reductions in C-reactive protein levels at different magnitudes. Troponin-I was significantly and negatively correlated with fruit intake (p = 0.044), a component of a Mediterranean diet and with HEI-2015 total scores (p = 0.032).Research limitations/implicationsThe limitation of this study includes the small sample size and the lack of dietary interventions. Another limitation is the use of the food recall method for the assessment of dietary patterns. This way assessments were performed based on participants' memory and statements.Practical implicationsFollowing a healthy diet pattern can help reduce the metabolic risks of COVÍD-19 disease.Originality/valueDespite these limitations, this study is valuable because, to the best of the authors' knowledge, it is the first study demonstrating the association of dietary patterns with disease prognosis and metabolic risks concerning COVID-19. This study suggests that dietary patterns during the COVID-19 process may be associated with several metabolic risks and inflammatory biomarkers.

Chewing the fat: How lipidomics is changing our understanding of human health and disease in 2022

Lipids are biological molecules that play vital roles in all living organisms. They perform many cellular functions, such as 1) forming cellular and subcellular membranes, 2) storing and using energy, and 3) serving as chemical messengers during intra- and inter-cellular signal transduction. The large-scale study of the pathways and networks of cellular lipids in biological systems is called "lipidomics” and is one of the fastest-growing omics technologies of the last two decades. With state-of-the-art mass spectrometry instrumentation and sophisticated data handling, clinical studies show how human lipid composition changes in health and disease, thereby making it a valuable medium to collect for clinical applications, such as disease diagnostics, therapeutic decision-making, and drug development. This review gives a comprehensive overview of current workflows used in clinical research, from sample collection and preparation to data and clinical interpretations. This is followed by an appraisal of applications in 2022 and a perspective on the exciting future of clinical lipidomics.

Role and mechanistic actions of protein kinase inhibitors as an effective drug target for cancer and COVID.

Kinases can be grouped into 20 families which play a vital role as a regulator of neoplasia, metastasis, and cytokine suppression. Human genome sequencing has discovered more than 500 kinases. Mutations of the kinase itself or the pathway regulated by kinases leads to the progression of diseases such as Alzheimer's, viral infections, and cancers. Cancer chemotherapy has made significant leaps in recent years. The utilization of chemotherapeutic agents for treating cancers has become difficult due to their unpredictable nature and their toxicity toward the host cells. Therefore, targeted therapy as a therapeutic option against cancer-specific cells and toward the signaling pathways is a valuable avenue of research. SARS-CoV-2 is a member of the Betacoronavirus genus that is responsible for causing the COVID pandemic. Kinase family provides a valuable source of biological targets against cancers and for recent COVID infections. Kinases such as tyrosine kinases, Rho kinase, Bruton tyrosine kinase, ABL kinases, and NAK kinases play an important role in the modulation of signaling pathways involved in both cancers and viral infections such as COVID. These kinase inhibitors consist of multiple protein targets such as the viral replication machinery and specific molecules targeting signaling pathways for cancer. Thus, kinase inhibitors can be used for their anti-inflammatory, anti-fibrotic activity along with cytokine suppression in cases of COVID. The main goal of this review is to focus on the pharmacology of kinase inhibitors for cancer and COVID, as well as ideas for future development.

The regulation of host cytoskeleton during SARS-CoV-2 infection in the nervous system

The global economy and public health are currently under enormous pressure since the outbreak of COVID-19. Apart from respiratory discomfort, a subpopulation of COVID-19 patients exhibits neurological symptoms such as headache, myalgia, and loss of smell. Some have even shown encephalitis and necrotizing hemorrhagic encephalopathy. The cytoskeleton of nerve cells changes drastically in these pathologies, indicating that the cytoskeleton and its related proteins are closely related to the pathogenesis of nervous system diseases. In this review, we present the up-to-date association between host cytoskeleton and coronavirus infection in the context of the nervous system. We systematically summarize cytoskeleton-related pathogen-host interactions in both the peripheral and central nervous systems, hoping to contribute to the development of clinical treatment in COVID-19 patients.

Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases.

Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly acting antiviral (DAA) drugs, which interfere with viral proteins and confer great selectivity towards their viral targets but suffer from resistance and limited spectrum. Nowadays, host-targeted antivirals (HTAs) are on the rise, in the drug discovery and development pipelines, in academia and in the pharmaceutical industry. These drugs target host proteins involved in the virus life cycle and are considered promising alternatives to DAAs due to their broader spectrum and lower potential for resistance. Herein, we discuss an important class of HTAs that modulate signal transduction pathways by targeting host kinases. Kinases are considered key enzymes that control virus-host interactions. We also provide a synopsis of the antiviral drug discovery and development pipeline detailing antiviral kinase targets, drug types, therapeutic classes for repurposed drugs, and top developing organizations. Furthermore, we detail the drug design and repurposing considerations, as well as the limitations and challenges, for kinase-targeted antivirals, including the choice of the binding sites, physicochemical properties, and drug combinations.

Study on the effect of Xuanfei Jiere Granules in the treatment of COVID-19 by network pharmacology and molecular docking

Objective: To explore the effect and mechanism of Xuanfei Jiere Granules in the treatment of corona virus disease 2019 (COVID-19) complicated with fever. Methods: The effective components of Xuanfei Jiere Granules were screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and the potential target genes were predicted. The disease targets of COVID-19 complicated with fever were searched by GeneCards and CTD databases, and the common targets were obtained, and then introduced into Cytoscape to construct the "component-target-disease" network. The above 2 common targets were input into the online database of STRING protein interaction, and the results were imported into Cytoscape software to obtain Protein-Protein Interaction(PPI) network;R language was used to analyze the common targets with Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis. Results: 84 active components and 82 targets were obtained. The pathway enrichment analysis showed that Xuanfei Jiere Granules mainly acted on protein kinase B(AKT1), tumor protein P53(TP53), interleukin-6(IL6) and other key targets in the treatment of COVID-19 complicated with fever. KEGG pathway enrichment analysis showed that the action was mainly related to the influence of fluid shear stress and atherosclerosis, human cytomegalovirus infection, and AGE-RAGE in diabetic complications and other signal pathways. The results of molecular docking showed that the core target had strong affinity with beta-sitosterol, formononetin, N-trans ferulyl tyramine and so on. Conclusion: This study preliminarily verified that Xuanfei Jiere Granules can play a role in the treatment of COVID-19 complicated with fever through multi-components, multi-targets and multi-pathways.

SARS-CoV-2 infection and smoking: What is the association? A brief review.

Susceptibility to severe illness from COVID-19 is anticipated to be associated with cigarette smoking as it aggravates the risk of cardiovascular and respiratory illness, including infections. This is particularly important with the advent of a new strain of coronaviruses, the severe acute respiratory syndrome coronavirus (SARS-CoV-2) that has led to the present pandemic, coronavirus disease 2019 (COVID-19). Although, the effects of smoking on COVID-19 are less described and controversial, we presume a link between smoking and COVID-19. Smoking has been shown to enhance the expression of the angiotensin-converting enzyme-2 (ACE-2) and transmembrane serine protease 2 (TMPRSS2) key entry genes utilized by SARS-CoV-2 to infect cells and induce a 'cytokine storm', which further increases the severity of COVID-19 clinical course. Nevertheless, the impact of smoking on ACE-2 and TMPRSS2 receptors expression remains paradoxical. Thus, further research is necessary to unravel the association between smoking and COVID-19 and to pursue the development of potential novel therapies that are able to constrain the morbidity and mortality provoked by this infectious disease. Herein we present a brief overview of the current knowledge on the correlation between smoking and the expression of SARS-CoV-2 key entry genes, clinical manifestations, and disease progression.

Cytokines and microRNAs in SARS-CoV-2: What do we know?

The coronavirus disease 2019 (COVID-19) pandemic constitutes a global health emergency. Currently, there are no completely effective therapeutic medications for the management of this outbreak. The cytokine storm is a hyperinflammatory medical condition due to excessive and uncontrolled release of pro-inflammatory cytokines in patients suffering from severe COVID-19, leading to the development of acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS) and even mortality. Understanding the pathophysiology of COVID-19 can be helpful for the treatment of patients. Evidence suggests that the levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1 and IL-6 are dramatically different between mild and severe patients, so they may be important contributors to the cytokine storm. Several serum markers can be predictors for the cytokine storm. This review discusses the cytokines involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, focusing on interferons (IFNs) and ILs, and whether they can be used in COVID-19 treatment. Moreover, we highlight several microRNAs that are involved in these cytokines and their role in the cytokine storm caused by COVID-19.

Inhibitors of One or More Cellular Aurora Kinases Impair the Replication of Herpes Simplex Virus 1 and Other DNA and RNA Viruses with Diverse Genomes and Life Cycles.

We utilized a high-throughput cell-based assay to screen several chemical libraries for inhibitors of herpes simplex virus 1 (HSV-1) gene expression. From this screen, four aurora kinase inhibitors were identified that potently reduced gene expression during HSV-1 lytic infection. HSV-1 is known to interact with cellular kinases to regulate gene expression by modulating the phosphorylation and/or activities of viral and cellular proteins. To date, the role of aurora kinases in HSV-1 lytic infection has not been reported. We demonstrated that three aurora kinase inhibitors strongly reduced the transcript levels of immediate-early (IE) genes ICP0, ICP4, and ICP27 and impaired HSV-1 protein expression from all classes of HSV-1, including ICP0, ICP4, ICP8, and gC. These restrictions caused by the aurora kinase inhibitors led to potent reductions in HSV-1 viral replication. The compounds TAK 901, JNJ 7706621, and PF 03814735 decreased HSV-1 titers by 4,500-, 13,200-, and 8,400-fold, respectively, when present in a low micromolar range. The antiviral activity of these compounds correlated with an apparent decrease in histone H3 phosphorylation at serine 10 (H3S10ph) during viral infection, suggesting that the phosphorylation status of H3 influences HSV-1 gene expression. Furthermore, we demonstrated that the aurora kinase inhibitors also impaired the replication of other RNA and DNA viruses. These inhibitors significantly reduced yields of vaccinia virus (a poxvirus, double-stranded DNA, cytoplasmic replication) and mouse hepatitis virus (a coronavirus, positive-sense single-strand RNA [ssRNA]), whereas vesicular stomatitis virus (rhabdovirus, negative-sense ssRNA) yields were unaffected. These results indicated that the activities of aurora kinases play pivotal roles in the life cycles of diverse viruses. IMPORTANCE We have demonstrated that aurora kinases play a role during HSV-1 lytic infection. Three aurora kinase inhibitors significantly impaired HSV-1 immediate-early gene expression. This led to a potent reduction in HSV-1 protein expression and viral replication. Together, our results illustrate a novel role for aurora kinases in the HSV-1 lytic cycle and demonstrate that aurora kinase inhibitors can restrict HSV-1 replication. Furthermore, these aurora kinase inhibitors also reduced the replication of murine coronavirus and vaccinia virus, suggesting that multiple viral families utilize the aurora kinases for their own replication.

Nintedanib: a review of the properties, function, and usefulness to minimize COVID-19-induced lung injury.

INTRODUCTION: In severe COVID-19 patients, acute respiratory distress syndrome (ARDS)-induced lung injury regularly causes a pulmonary fibrotic phase. There is no approved therapy for the COVID-19-induced pulmonary fibrosis. However, administration of an anti-fibrotic agent, in the early acute phase of the severe COVID-19 with ARDS, may improve the infection outcomes. AREAS COVERED: In this review, the main characteristics of nintedanib and its usefulness to treat COVID-19-induced fibrosis were studied. In July 2022, a literature search was performed from PubMed, Google Scholar, and the WHO databases for studies focusing on the properties, function, efficacy, and safety of nintedanib against different lung injuries. EXPERT OPINION: Nintedanib interferes with lung fibrosis and tumor angiogenesis by targeting multiple receptor tyrosine kinases (RTKs). Loss of RTKs activity leads to blocking downstream signaling cascades and inhibiting the proliferation and migration of lung fibroblasts. Targeting RTKs may be useful in the treatment of COVID-19 lung fibrosis. Nintedanib may be a superior agent compared to pirfenidone for the treatment of COVID-19 ARDS-related pulmonary fibrosis. Investigation of the efficacy and safety of nintedanib in the early stages of COVID-19-induced ARDS is critical since it may decrease the oxygen dependency and degree of lung fibrosis after the hospital discharge.

Azithromycin in COVID‑19 Patients: Pharmacological Mechanism, Clinical Evidence and Prescribing Guidelines: An International Journal of Medical Toxicology and Drug Experience

The global COVID-19 pandemic has led to a race to find medications that can improve the prognosis of the disease. Azithromycin, in association with hydroxychloroquine or chloroquine, has been proposed as one such medication. The aim of this review is to describe the pharmacological mechanism, clinical evidence and prescribing guidelines concerning azithromycin in COVID-19 patients. There is weak evidence on the antiviral and immunomodulating effects of azithromycin, which in addition is not based on results from COVID-19 patients specifically. Therefore, this antibacterial should be considered only as empirical treatment of community-acquired pneumonia (CAP), although not all current treatment guidelines are in agreement. After the initial expectations raised by a small trial, more recent evidence has raised serious safety concerns on the use of hydroxychloroquine or chloroquine with azithromycin to treat COVID-19 patients, as all these drugs have arrhythmogenic potential. The World Health Organization has not made recommendations suggesting the use of azithromycin with hydroxychloroquine or chloroquine as treatment for COVID-19, but some national organisations have taken a different position, recommending this as first-line treatment. Several scientific societies, including the American College of Cardiology, have cautioned about the risks of this treatment in view of the lack of evidence concerning its benefits.