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Background & Aim: With larger accessibility and increased number of patients being treated with CART cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood derived (UCB) regulatory T cells (Tregs) can resolve uncontrolled inflammation and can treat acute and immune mediated lung injury in a xenogenic model as well as in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Tregs including: i) lack of plasticity when exposed to inflammatory micro-environments;ii) no requirement for HLA matching;iii) long shelf life of cryopreserved Tregs;and iv) immediate product availability for on demand treatment, makes them an attractive source for treating acute inflammatory syndromes. Therefore, we hypothesized that add-on therapy with UCB derived Tregs may resolve uncontrolled inflammation responsible for CART cell therapy associated toxicity. Methods, Results & Conclusion(s): UCB Tregs were added in 1:1 ratio to CART cells, where no interference in their ability to kill CD19+ Raji cells, was detected at different ratios : 8:1 (80.4% vs. 81.5%);4:1 (62.0% vs. 66.2%);2:1 (50.1% vs. 54.7%);1:1 (35.4% vs. 44.1%) (Fig 1A). In a xenogenic B cell lymphoma model, multiple injections of Tregs were administered after CART injection (Fig 1B), which did not impact distribution of CD8+ T effector cells (Fig 1C) or CART cells cells (Fig 1D) in different organs. No decline in the CAR T levels was observed in the Tregs recipients (Fig 1E). Specifically, no difference in tumor burden was detected between the two arms (Fig 2A). No tumor was detected in CART+Tregs in liver (Fig 2B) or bone marrow (Fig 2C). A corresponding decrease in multiple inflammatory cytokines in peripheral blood was observed in CART+Tregs when compared to CART alone (Fig 2D). Here we show "proof of concept" for add-on therapy with Tregs to mitigate hyper-inflammatory state induced by CART cells without interference in their on-target anti-tumor activity. The timing of Tregs administration after CART cells have had sufficient time for forming synapse with tumor cells allows for preservation of their anti-tumor cytotoxicity, such that the infused Tregs home to the areas of tissue damage to bind to the resident antigen presenting cells which in turn collaborate with Tregs to resolve inflammation. Such differential distribution of cells allow for a Treg "cooling blanket" and lays ground for clinical study. [Figure presented]Copyright © 2023 International Society for Cell & Gene Therapy
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mRNA is a new class of drugs that has the potential to revolutionize the treatment of brain tumors. Thanks to the COVID-19 mRNA vaccines and numerous therapy-based clinical trials, it is now clear that lipid nanoparticles (LNPs) are a clinically viable means to deliver RNA therapeutics. However, LNP-mediated mRNA delivery to brain tumors remains elusive. Over the past decade, numerous studies have shown that tumor cells communicate with each other via small extracellular vesicles, which are around 100 nm in diameter and consist of lipid bilayer membrane similar to synthetic lipidbased nanocarriers. We hypothesized that rationally designed LNPs based on extracellular vesicle mimicry would enable efficient delivery of RNA therapeutics to brain tumors without undue toxicity. We synthesized LNPs using four components similar to the formulation used in the mRNA COVID19 vaccines (Moderna and Pfizer): ionizable lipid, cholesterol, helper lipid and polyethylene glycol (PEG)-lipid. For the in vitro screen, we tested ten classes of helper lipids based on their abundance in extracellular vesicle membranes, commercial availability, and large-scale production feasibility while keeping rest of the LNP components unchanged. The transfection kinetics of GFP mRNA encapsulated in LNPs and doped with 16 mol% of helper lipids was tested using GL261, U87 and SIM-A9 cell lines. Several LNP formations resulted in stable transfection (upto 5 days) of GFP mRNA in all the cell lines tested in vitro. The successful LNP candidates (enabling >80% transfection efficacy) were then tested in vivo to deliver luciferase mRNA to brain tumors via intrathecal administration in a syngeneic glioblastoma (GBM) mouse model, which confirmed luciferase expression in brain tumors in the cortex. LNPs were then tested to deliver Cre recombinase mRNA in syngeneic GBM mouse model genetically modified to express tdTomato under LoxP marker cassette that enabled identification of LNP targeted cells. mRNA was successfully delivered to tumor cells (70-80% transfected) and a range of different cells in the tumor microenvironment, including tumor-associated macrophages (80-90% transfected), neurons (31- 40% transfected), neural stem cells (39-62% transfected), oligodendrocytes (70-80% transfected) and astrocytes (44-76% transfected). Then, LNP formulations were assessed for delivering Cas9 mRNA and CD81 sgRNA (model protein) in murine syngeneic GBM model to enable gene editing in brain tumor cells. Sanger sequencing showed that CRISPR-Cas9 editing was successful in ~94% of brain tumor cells in vivo. In conclusion, we have developed a library of safe LNPs that can transfect GBM cells in vivo with high efficacy. This technology can potentially be used to develop novel mRNA therapies for GBM by delivering single or multiple mRNAs and holds great potential as a tool to study brain tumor biology.
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Certolizumab is a Fab fragment of a humanized monoclonal antibody against tumor necrosis factor-alpha (TNF-alpha). Differing from the other TNF-alpha inhibitors due to the absence of Fc fragment and pegylation, it binds to both the soluble and transmembrane forms of TNF-alpha, creating a strong TNF-alpha blockage. Previously approved for psoriatic arthritis, certolizumab received another approval from FDA in 2018 for the treatment of moderate to severe chronic plaque psoriasis that does not respond to conventional systemic treatments or for which these treatments are contraindicated. Administered via subcutaneous injections, certolizumab also has a low-dose option for patients weighing less than 90 kg. Certolizumab is considered a safe biological drug that can be preferred during pregnancy and lactation.Copyright © 2022 by Turkish Society of Dermatology and Venereology.
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A new coronavirus infection caused by the SARS-CoV-2 virus is characterized by a systemic hyperinflammatory response with a pronounced increase in the content of pro-inflammatory cytokines. Materials and methods. The study was conducted on the basis of the Samara Regional Children's Infectious Diseases Hospital from 2021 to 2022. 40 patients with moderate (n = 20, group I) and severe forms (n = 20, group II) COVID-19 were studied, the comparison group consisted of patients with viral pneumonia of another etiology (n = 35, group III). Results. The infectious agent SARS-CoV-2 induces high levels of cytokines IL-6 (p < 0.005), IL-8 (p < 0.05) and a slight increase in TNF-alpha (p < 0.05). IL-8 was significantly associated with disease duration (p < 0.01). We assume that the value of this interleukin will increase in the post-COVID period. Conclusions. Changes in IL-6 and IL-8 levels in patients with COVID-19, along with clinical features, are important biomarkers for predicting the severity and duration of the disease.Copyright © Children Infections.All rights reserved
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BackgroundUpadacitinib (UPA) is an oral JAK inhibitor (JAKi) approved for the treatment of RA. JAKi have been associated with an elevated risk of herpes zoster (HZ) in patients (pts) with RA. The adjuvanted recombinant zoster vaccine (RZV, Shingrix) was shown to be well-tolerated and effective in preventing HZ in adults aged ≥ 50 years.[1] The efficacy and safety of RZV have not been studied in pts with RA while on UPA in combination with MTX.ObjectivesTo assess the immunogenicity of RZV in pts with RA receiving UPA 15 mg once daily (QD) with background MTX.MethodsEligible adults aged ≥ 50 years with RA enrolled in the ongoing SELECT-COMPARE phase 3 trial (NCT02629159) received two RZV doses, administered at the baseline and week (wk) 12 visits. Pts should have been on stable doses of UPA 15 mg QD and background MTX for ≥ 8 wks before the first vaccination and ≥ 4 wks after the second vaccination. Antibody titers were collected pre-vaccination (baseline), 4 wks post-dose 1 vaccination (wk 4), and 4 wks post-dose 2 vaccination (wk 16). The primary endpoint was the proportion of pts with a humoral response to RZV defined as ≥ 4-fold increase in pre-vaccination concentration of anti-glycoprotein E [gE] titer levels at wk 16. Secondary endpoints included humoral response to RZV at wk 4 and the geometric mean fold rise (GMFR) in anti-gE antibody levels at wks 4 and 16. Cell-mediated immunogenicity to RZV was an exploratory endpoint evaluated by the frequencies of gE-specific CD4+ [2+] T cells (CD4+ T cells expressing ≥ 2 of 4 activation markers: IFN-γ, IL-2, TNF-α, and CD40 ligand) measured by flow cytometry at wks 4 and 16 in a sub-cohort of pts.ResultsOf the 95 pts who received ≥ 1 RZV dose, 93 (98%) received both RZV doses. Pts had a mean (standard deviation) age of 62.4 (7.5) years. The median (range) disease duration was 11.7 (4.9–41.6) years and duration of UPA exposure was 3.9 (2.9–5.8) years. At baseline, all but 2 pts were receiving concomitant MTX and half (50%) were taking an oral corticosteroid (CS) at a median daily dose of 5.0 mg. One pt discontinued UPA by wk 16. Blood samples were available from 90/93 pts. Satisfactory humoral responses to RZV occurred in 64% (95% confidence interval [CI]: 55–74) of pts at wk 4 and 88% (81–95) at wk 16 (Figure 1). Age (50–< 65 years: 85% [95% CI: 75–94];≥ 65 years: 94% [85–100]) and concomitant CS (yes: 87% [77–97];no: 89% [80–98]) use at baseline did not affect humoral responses at wk 16. GMFR in anti-gE antibody levels compared with baseline values were observed at wks 4 (10.2 [95% CI: 7.3–14.3]) and 16 (22.6 [15.9–32.2]). Among the sub-cohort of pts, nearly two-thirds achieved a cell-mediated immune response to RZV (wk 4: n = 21/34, 62% [95% CI: 45–78];wk 16: n = 25/38;66% [51–81]). Within 30 days post-vaccination of either RZV dose, no serious adverse events (AEs) (Table 1) or HZ were reported. AEs that were possibly related to RZV were reported in 17% of pts. One death occurred more than 30 days after wk 16 due to COVID-19 pneumonia.ConclusionMore than three-quarters (88%) of pts with RA receiving UPA 15 mg QD on background MTX achieved a satisfactory humoral response to RZV at wk 16. In a subgroup of pts, two-thirds (66%) achieved a cell-mediated immune response to RZV at wk 16. Age and concomitant CS use did not negatively affect RZV response.Reference[1]Syed YY. Drugs Aging. 2018;35:1031–40.Table 1. Safety Results Through 30-Days Post-RZV Vaccination in UPA-Treated PatientsEvent, n (%)UPA 15 mg QD (N = 95)Any AE38 (40%)AE with reasonable possibility of being related to UPAa13 (14%)AE with reasonable possibility of being related to RZVa16 (17%)Severe AEb1 (1%)Serious AE0AE leading to discontinuation of UPA0Death0AE, adverse event;QD, once daily;RZV, adjuvanted recombinant zoster vaccine;UPA, upadacitinib.aAs assessed by the investigator.bHypersensitivity.AcknowledgementsAbbVie funded this study and participated in the study design, research, 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 InterestsKevin Winthrop Consultant of: AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, Gilead, GSK, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Grant/research support from: AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, Gilead, GSK, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Justin Klaff Shareholder of: AbbVie, Employee of: AbbVie, Yanxi Liu Shareholder of: AbbVie, Employee of: AbbVie, CONRADO GARCIA GARCIA: None declared, Eduardo Mysler Speakers bureau: AbbVie, Amgen, AstraZeneca, BMS, Eli Lilly, GlaxoSmithKline, Pfizer, Roche, and Sandoz, Consultant of: AbbVie, Amgen, AstraZeneca, BMS, Eli Lilly, GlaxoSmithKline, Pfizer, Roche, and Sandoz, Alvin F. Wells Consultant of: AbbVie, Amgen, BMS, Eli Lilly, Novartis, Pfizer, and Sanofi, Xianwei Bu Shareholder of: AbbVie, Employee of: AbbVie, Nasser Khan Shareholder of: AbbVie, Employee of: AbbVie, Michael Chen Shareholder of: AbbVie, Employee of: AbbVie, Heidi Camp Shareholder of: AbbVie, Employee of: AbbVie, Anthony Cunningham Consultant of: GSK, Merck Sharp & Dohme, and BioCSL/Sequirus.
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BackgroundThe COVID-19 pandemic triggered serious challenges in the treatment of chronic diseases due to the lack of access to medical attention. Patients with rheumatic diseases (RD) must have adequate treatment compliance in order to reach and maintain remission or low activity of their diseases. Treatment suspension because of non-medical reasons might lead to disease activation and organ damage.ObjectivesIdentify the frequency of biologic treatment (bDMARD) suspension in patients with RD during the COVID-19 pandemic and determine the associated factors for suspension.MethodsIn this study we included all patients registered in the Mexican Biologics Adverse Events Registry (BIOBADAMEX), that started bDMARD before March 2019 and suspended treatment during the COVID-19 pandemic. We used descriptive statistic to analyze baseline characteristics and main treatment suspension causes. We used Chi[2] and Kruskal Wallis tests to analyze differences between groups.ResultsA total of 832 patients patients registered in BIOBADAMEX were included in this study, 143 (17%) suspended bDMARD during the COVID-19 pandemic. The main causes of suspension were inefficacy in 54 (38%) patients, followed by other motives in 49 (34%) patients from which 7 (5%) was loss of medical coverage. Adverse events and loss of patients to follow up were the motive in 16 (11%) and 15 (11%) patients respectively.When we compared the group that suspended bDMARD with the non-suspenders (Table 1), we found statistical differences in patient gender, with 125 (87%) female patients that suspended bDMARD, with a median age of 52 (42-60) years, and a treatment duration of 3.8 years.ConclusionIn our study we found that 17% of patients with RD suspended bDMARD treatment during the COVID-19 pandemic and that non-medical motives such as lack of patients follow up and loss of medical coverage due to unemployment were important motives. These results are related to the effect of the pandemic on other chronic diseases.Table 1.Patients baseline characteristicsPatients that did not suspended bDMARD during pandemic (n = 689)Patients that suspended bDMARD during pandemic (n = 143)pFemale gender, n(%)549 (79.7)125 (87.4)0.02Age, median (IQR)55 (45 – 63)52 (42 – 60)0.04Body mass index, median (IQR)26.4 (23 – 30.4)27.23 (24.2 – 30.46)0.13Social security, n(%)589 (85.5)128 (89.5)0.2Diagnosis0.7- Rheumatoid arthritis444 (64.4)97 (67.8)- Juvenil idiopathic athritis29 (4.2)2 (1.4)- Ankyosing sponylitis93 (13.5)19 (13.3)- Psoriasic arthritis43 (6.2)6 (4.2)- Systemic lupus erithematosus32 (4.6)9 (6.3)- Others48 (6.9)10 (6.9)Disease duration, median (IQR)11 (7 – 19.5)12 (6 - 18)0.95Comorbidities, n(%)305 (44.3)73 (51)0.08Previos biologic, n(%)249 (36.1)60 (42)0.1Treatment at pandemic iniciation, n(%)0.8 - Etanercept a34 (4.9)5 (3.5)- Infliximab a24 (3.5)5 (3.5)- Adalimumab130 (18.9)22 (15.4)- Rituximab a61 (8.9)25 (17.5)- Abatacept76 (11)20 (14)- Tocilizumab82 (11.9)18 (12.6)- Certolizumab92 (13.4)28 (19.6)- Rituximab b7 (1)0- Golimumab36 (5.2)5 (3.5)- Tofacitinib14 (2)1 (0.7)- Infliximab b4 (0.5)2 (1.4)- Etanercept b31 (4.5)6 (4.2)- Baricitinib12 (1.7)1 (0.7)- Belimumab5 (0.7)1 (0.7)- Secukinumb8 (1.2)3 (2.1)Steroids use, n(%):254 (36.9)57 (39.9)0.2Steroids dose (mg), median (IQR)6 (5 – 10)6 (5 – 10)0.47DMARD use, n(%):538 (78.1)118 (82.5)0.1Treatment duration, median (IQR)5.06 (4.04 – 5.78)3.82 (3.35 – 4.95)0.001Suspension motive, n(%)NA- Inefficacy-54 (37.8)- Adverse event-16 (11.2)- Pregnancy-2 (1.4)- Loss of patient-15 (10.5)- Remission-7 (4.9)- Others-49 (34.2)Adverse events, n(%):102 (14.8)24 (16.8)0.3- Severe, n(%)13 (1.9)5 (3.5)0.4a original, b biosimilarREFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsVijaya Rivera Teran: None declared, Daniel Xavier Xibille Friedmann: None declared, David Vega-Morales: None declared, Sandra Sicsik: None declared, Angel Castillo Ortiz: None declared, Fedra Irazoque-Palazuelos: None declared, Dafhne Miranda: None declared, Iris Jazmin Colunga-Pedraza: None declared, Julio Cesar Casasola: None declared, Omar Elo Muñoz-Monroy: None declared, Sandra Carrilo: None declared, Angélica Peña: None declared, Sergio Duran Barragan: None declared, Luis Francisco Valdés Corona: None declared, Estefanía Torres Valdéz: None declared, Azucena Ramos: None declared, Aleni Paz: None declared, ERICK ADRIAN ZAMORA-TEHOZOL: None declared, Deshire Alpizar-Rodriguez Employee of: Scientific Advisor in GSK México.
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Introduction: Adjuvant anti-cancer systemic therapy (SACT) following lung resection improves overall survival in stage II/II non-small cell lung cancer (NSCLC). The Getting It Right First Time (GIRFT) National Specialty Report for Lung Cancer recommends centres publish adjuvant SACT rates for National benchmarking and proposes a target of >40% of eligible patients undergo SACT. We report a regional audit into the uptake of adjuvant SACT in Greater Manchester (GM). Method(s): A retrospective case review of all patients undergoing curative-intent NSCLC surgery with a pathological stage of II/III from 01/01/21 to 30/04/21. Data collected included patient demographics, uptake of adjuvant SACT, reasons for no adjuvant SACT and tolerance and complications of SACT. Result(s): 58 patients underwent surgical resection within the audit period and were eligible for adjuvant SACT. Median age was 70 years (range 45 - 81) and 60% were female. 47% (27/58) commenced adjuvant SACT;41% (24/58) were treated with chemotherapy and 7% (4/58) were treated with tyrosine kinase inhibitors. 58% (14/24) of patients that commenced adjuvant chemotherapy completed 4 cycles. Carboplatin/Vinorelbine was the commonest regimen (82%, 18/22). There were no grade III-V complications and no chemotherapy-related deaths. Dose reduction due to toxicity was required in 14% (3/22). The reasons adjuvant systemic therapy was not given were patient choice in 32% (10/31), poor physical health such that risks outweighed benefits in 42% (13/31), and other reasons (e.g. need to treat synchronous primary tumours) in 26% (8/31). COVID-19 was not recorded as a cause for adjuvant omission/ dose reduction. Conclusion(s): This data provides national benchmarking information for adjuvant SACT in NSCLC and suggests the target of >40% is achievable and appropriate. Interventions that improve patient fitness pre- and post-operatively might increase adjuvant SACT uptake. This regional audit will be extended to review all eligible patients in 2021 and further data will be presented. Disclosure: No significant relationships.Copyright © 2023 Elsevier B.V.
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BackgroundIn rheumatoid arthritis (RA) and spondyloarthritis (Spa), persistent pain remains challenging. In active disease, diffuse noxious inhibitory controls (assessed through conditioned pain modulation (CPM)) are impaired [1]. Little is known regarding impairment of pain pathways in patients under bMDARD.ObjectivesThe main objective of the RAPID (Rheumatism Pain Inhibitory Descending pathways) study, was to assess descending pain modulation (through CPM paradigm) in patients with active RA or Spa, after introduction of first bDMARD with anti-TNF.MethodsWe included 50 RA and 50 Spa patients with active disease, naïve of bDMARD. We assessed clinical disease variables for patients, together with responses to various psychological questionnaires. All participants underwent QST with the determination of heat and cold pain thresholds (HPT-CPT) on dominant forearm and CPM. CPM paradigm require a conditioning stimulus, here applied to the non-dominant foot (cold circulating bath at 8°C during 1min). Descending pain control was assessed as the change in HPT (in °C) following the conditioning stimulus: the higher the CPM effect, the more efficient the inhibitory control. Patients were followed at 3 and 6 months after TNF inhibitor initiation. At both follow-up visits, clinical monitoring of the rheumatism and repeated thermal QST and CPM.ResultsOne hundred patients were included, 59 women, mean age 45.8 (± 14.6) and mean disease duration 7.93 (± 7.96) years. Due to COVID surge 87 patients initiated an anti-TNF, 74 patients completed the follow-up. At 6 months, 40 patients achieved a good therapeutic response (good EULAR response or ASDAS major improvement), 19 patients had a moderate therapeutic response (moderate EULAR response or clinically important improvement) and 15 patients had no therapeutic response. At the end of follow-up, 51 patients were in remission or low disease activity and 47 patients had a pain intensity <4/10. Thermal pain thresholds did not significantly change during follow-up. Mean HPT was at beaseline 42.35°C (+/- 3.68) and at 6 months 42.17°C (+/- 3.67). Mean CPT was at baseline 13.11°C (+/- 10.04) and at 6 months 12.86°C (+/- 9.45). Conditioned pain modulation was significantly changed during follow-up. Mean CPM effect was at baseline 0.25°C (±2.57), 2.64°C (±2.12) at 3 months and 2.96°C (±2.50) at 6 months. At the end of the 6 months follow-up, mean CPM effect was significantly higher in patients with residual mean pain intensity <4/10 compared to patients with persisting pain ≥ 4/10: 3,25°C (± 2,68) vs 2,47 (± 2,11) (p=0.04).ConclusionAfter TNF inhibitor initiation in active RA or SpA, impaired diffuse noxious inhibitory controls are significantly improved. Apart from their articular efficacy, TNF inhibitor have an action on the central nervous system and pain modulation pathways. In patients with persisting pain under bDMARD, diffuse noxious inhibitory controls are not as efficient as patient without residual pain.Reference[1]Trouvin AP, Simunek A, Coste J, Medkour T, Carvès S, Bouhassira D, Perrot S. Mechanisms of chronic pain in inflammatory rheumatism: the role of descending modulation. Pain. 2022 Aug 3. doi: 10.1097/j.pain.0000000000002745.Figure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Background/Objectives: Li-Fraumeni Syndrome (LFS) is a rare hereditary cancer predisposition syndrome characterized by high lifetime risks for multiple primary malignancies. Although most individuals with LFS inherit a pathogenic TP53 variant from a parent, approximately 20% have de novo variants with no suggestive family cancer history. This may result in an LFS experience distinct from individuals with affected relatives. This multi-case study report examines the unique psychosocial experiences of three young adults with de novo TP53 variants. Method(s): The National Cancer Institute's LFS study (NCT01443468) recruited adolescents and young adults (AYAs;aged 15-39 years) with LFS for qualitative interviews. Three participants had a de novo TP53 variant and a personal cancer history. An interprofessional team analyzed interview data using extended case study and narrative methods. Result(s): De novo participants lacked familiarity with LFS to situate a cancer diagnosis, interpret genetic test results, or adjust to chronic cancer risk. Communicating with and receiving support from family was challenged by their lack of common experience. De novo participants experienced socioemotional isolation, which was amplified during the COVID-19 pandemic. To cope, they sought support in online rare disease communities or through mental health providers. Conclusion(s): Individuals with de novo variants may lack familial guides and familiar providers to address disease management and uncertainty. Specialty health and mental health providers may support de novo patients across hereditary cancer syndromes by validating their uncertainties and connecting them with diseasespecific patient advocacy groups that support adjustment to chronic cancer risk.
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Lung cancer is the leading cause of cancer related deaths worldwide, with a relatively low 5-year survival rate. Although there are some therapies against lung cancer, new effective treatment options are urgently required. Recently during the COVID-19 pandemic, we have seen that SARSCoV-2 binds to its receptor angiotensin-converting enzyme 2 (ACE2) via spike S1 to enter the cells. This study underlines the importance of SARS-CoV-2 spike S1 in inducing death in human lung cancer cells. Interestingly, we have seen that recombinant spike S1 treatment at very low doses led to death of human A549 lung cancer cells. On the other hand, boiled recombinant SARS-CoV-2 spike S1 remained unable to induce death, suggesting that the induction of cell death in A549 cells was due to native SARS-CoV-2 spike S1 protein. SARS-CoV-2 spike S1-induced A549 cell death was also inhibited by neutralizing antibodies against spike S1 and ACE2. Moreover, our newly designed wild type ACE2-interacting domain of SARS-CoV-2 (wtAIDS), but not mAIDS, peptide also attenuated SARS-CoV-2 spike S1-induced cell death, suggesting that SARS-CoV-2 spike S1- induced death in lung cancer cells depends on its interaction with ACE2 receptor. Similarly, recombinant spike S1 treatment also led to death of H1299 and H358 human lung cancer cells. Finally, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) intoxication led to the formation tumors in lungs of A/J mice and alternate day intranasal treatment with low dose of recombinant SARS-CoV-2 spike S1 from 22-weeks of NNK insult (late stage) led to induced apoptosis and tumor regression in the lungs. These studies indicate that recombinant SARS-CoV-2 Spike S1 protein may have implications in the treatment of lung cancer.
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The TG6002.03 trial is a dose-escalation phase 1 clinical trial of TG6002 infusion via the hepatic artery in patients with liver-dominant colorectal cancer metastases. TG6002 is an engineered Copenhagen strain oncolytic Vaccinia virus, deleted of thymidine kinase and ribonucleotide reductase to enhance tumor selective viral replication and expressing FCU1, an enzyme converting the non-cytotoxic prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). In this trial, patients with advanced unresectable liver-dominant metastatic colorectal cancer who had failed previous oxaliplatin and irinotecan-based chemotherapy were treated with up to 2 cycles of TG6002 infusion 6 weeks apart via the hepatic artery on day 1 combined with oral 5-FC on days 5 to 14 (where day 1 = TG6002 infusion). TG6002 infusion was performed over 30 minutes via selective catheterization of the hepatic artery proper. 5-FC oral dosing was 50mg/kg x4 daily. Blood was sampled for TG6002 pharmacokinetics and 5-FC and 5-FU measurements. Sampling of liver metastases was performed at screening and on day 4 or day 8 for virus detection and 5-FC and 5-FU quantification. In total, 15 patients (median age 61 years, range 37-78) were treated in 1 UK centre and 2 centres in France and received a dose of TG6002 of 1 x 106 (n=3), 1 x 107 (n=3), 1 x 108 (n=3), or 1 x 109 pfu (n=6). Fourteen of the 15 patients received a single cycle of treatment, including one patient who did not received 5-FC, and one patient received two cycles. TG6002 was transiently detected in plasma following administration, suggesting a strong tissue selectivity for viral replication. In the highest dose cohort, a virus rebound was observed on day 8, concordant with replication time of the virus. In serum samples, 5-FU was present on day 8 in all patients with a high variability ranging from 0.8 to 1072 ng/mL and was measurable over several days after initiation of therapy. Seven of the 9 patients evaluable showed the biodistribution of the virus in liver lesions by PCR testing on day 4 or day 8. Translational blood samples showed evidence for T-cell activation and immune checkpoint receptor-ligand expression. At 1 x 109 pfu, there was evidence for T-cell proliferation and activation against tumour-associated antigens by ELISpot and for immunogenic cell death. In terms of safety, a total of 34 TG6002-related adverse events were reported, of which 32 were grade 1-2 and 2 were grade 3. The maximum tolerated dose was not reached, and a single dose-limiting toxicity was observed consisting of a myocardial infarction in a context of recent Covid-19 infection in a 78-year-old patient. These results indicate that TG6002 infused via the hepatic artery in combination with oral 5-FC was well tolerated, effectively localized and replicated in the tumor tissues, expressed its therapeutic payload and showed anti-tumoral immunological activity.
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Background: Older patients with cancer are at a higher risk of invasive infections. Vaccination is an effective approach to decrease the mortality and morbidity associated with infections. Objective(s): Our primary objective was to evaluate the proportion of older patients with cancer who had received routine vaccinations against pneumococcal, influenza, and coronavirus disease 2019 (COVID-19). Our secondary objective was to identify the factors associated with vaccine uptake such as age, sex, education, marital status, comorbidities, and place of residence. Material(s) and Method(s): This cross-sectional observational study was conducted in the geriatric oncology outpatient clinic of the Department of Medical Oncology at the Tata Memorial Hospital, a tertiary care cancer hospital in Mumbai, India, from February 2020 to January 2023. We included all patients aged >=60 years who were evaluated in the geriatric oncology clinic during the study period and for whom the immunization details were available. The uptake of COVID-19 vaccine was calculated from March 2021 onwards, which was when the COVID-19 vaccine became available to patients aged >=60 years in India. Result(s): We enrolled 1762 patients;1342 (76.2%) were male. The mean age was 68.4 (SD, 5.8) years;795 (45%) patients were from the west zone of India. Only 12 (0.68%) patients had received the pneumococcal vaccine, and 13 (0.7%) had received the influenza vaccine. At least one dose of the COVID-19 vaccine had been taken by 1302 of 1562 patients (83.3%). On univariate logistic regression, education, marital status, geographic zone of residence, and primary tumor site were correlated with the uptake of COVID-19 vaccine. Factors associated with a greater COVID-19 vaccine uptake included education (up to Std 10 and higher vs. less than Std 10: Odds Ratio [OR], 1.46;95% confidence interval [CI], 1.07-1.99;P = 0.018, and illiterate vs. less than Std 10: OR, 0.70;95% CI, 0.50-0.99;P = 0.041), marital status (unmarried vs. married: OR, 0.27;95% CI, 0.08-1.08;P = 0.046, and widow/widower vs. married: OR, 0.67;95% CI, 0.48-0.94;P = 0.017), lung and gastrointestinal vs. head-and-neck primary tumors (lung cancer vs. head-and-neck cancer: OR, 1.60;95% CI, 1.02-2.47;P = 0.038, and gastrointestinal vs.head-and-neck cancer: OR, 2.18;95% CI, 1.37-3.42;P < 0.001), and place of residence (west zone vs. central India: OR, 0.34;95% CI, 0.13-0.75;P = 0.015). Conclusion(s): Fewer than 1 in 100 older Indian patients with cancer receive routine immunization with influenza and pneumococcal vaccines. Hearteningly, the uptake of COVID-19 vaccination in older Indian patients with cancer is over 80%, possibly due to the global recognition of its importance during the pandemic. Similar measures as those used to increase the uptake of COVID-19 vaccines during the pandemic may be beneficial to increase the uptake of routine vaccinations.Copyright © 2023 Cancer Research, Statistics, and Treatment.
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BackgroundRheumatoid Arthritis (RA) patients are effectively treated with anti-TNF-α therapy. However, pharmacological non-adherence limits the achievement of the therapeutic objective. This is a multifactorial behavior where factors such as the route of administration, frequency, tolerance, perception of improvement, polypharmacy and social factors are involved [1,2].ObjectivesTo explore the factors associated with non-adherence to anti TNF-α in RA patients during the COVID-19 pandemic.MethodsThis is a cohort of RA patients treated with anti TNF-α in Medicarte SAS, a Colombian center for Immune-Mediated Diseases, between January to December 2021. The program implements strategies such as pharmacotherapeutic support, informed dispensing, phone calls, text messages and home care services to increase adherence. Adherence was defined as dispensing at least 10/12 (>0.80) prescribed monthly doses for 1 year. Sociodemographic characteristics, time in the program, DAS28-CRP, HAQ and treatment were included as exposure variables. For continuous variables, median and interquartile range (IQR) were calculated. Adjusted Odds Ratio (AOR) with logistic regression were calculated, and a p-value <0.05 was considered as statistically significant.Results565 patients were included, 85.8% (n=485) were women, median age 56 years (IQR: 49-65), disease evolution time 13.7 years (IQR: 7.7-20.8), 51% (n=288) had been in the program for more than 3 years, the median time in treatment with anti TNF-α was 3 years (IQR: 1-3) and DAS-28-CRP 2.4 (IQR: 1.6-3.4). The most frequently anti TNF-α prescribed was etanercept 46.0% (n=260), followed by adalimumab 23% (n=130), subcutaneous golimumab 13.3% (n=75), certolizumab 11.0% (n=62) and intravenous golimumab 6.7% (n=38). At the admission, 18.2% (n=103) of the patients had high activity, 38.6% (n=218) mild activity, 9.2% (n=52) low activity and 34% (n=192) were in remission. At the end of follow-up, 6.4% (n=36) of patients had high activity, 18.2% (n=103) mild activity, 14.3% (n= 81) low activity and 61.1% (n= 345) were in remission. The 51.5% (n=291) did not have pharmacological adherence. The use of etanercept (AOR 0.36 CI95% 0.23- 0.58, p < 0.001) and adequate functionality measured through HAQ (AOR 0.64 CI95% 0.42- 0.97, p < 0.04) were associated with a lower risk of non-adherence. Higher DAS28-CRP at the end of follow up was associated with non-adherence (AOR 1.29 CI95% 1.12 - 1.48, p < 0.001).ConclusionDuring COVID-19 pandemic, the implementation of strategies in the home care patient program guaranteed adherence close to 50% in our cohort. Higher values of DAS28-CRP were associated with non-adherence, whilst etanercept use and a normal HAQ value were associated with a higher probability of adherence.References[1]Marengo MF, Suarez-Almazor ME. Improving treatment adherence in patients with rheumatoid arthritis: what are the options? Int J Clin Rheumtol. 2015 Oct 1;10(5):345-356.[2]Smolen JS, Gladman D, McNeil HP, Mease PJ, Sieper J, Hojnik M, et al. Predicting adherence to therapy in rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis: a large cross-sectional study. RMD Open. 2019 Jan 11;5(1):e000585.Acknowledgements:NIL.Disclosure of InterestsWilmer Gerardo Rojas Zuleta Speakers bureau: Pfizer, Jannsen Cilag, Bristol Myers Squibb, Amgen, Eli lilly, Mario Barbosa: None declared, Oscar Jair Felipe Díaz Speakers bureau: Pfizer, Jannsen Cilag, Bristol Myers Squibb, Amgen, Eli lilly, Adelis Enrique Pantoja Marquez: None declared, Jeixa Canizales: None declared, Carolina Becerra-Arias: None declared, Jorge Hernando Donado Gómez: None declared, Natalia Duque Zapata: None declared.
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BackgroundAlthough studies have quantified adherence to medications among patients with rheumatic diseases (RD) during the COVID-19, lack of direct pre-pandemic comparison precludes understanding of impact of the pandemic.ObjectivesOur objective was to evaluate the effect of the COVID-19 pandemic on adherence to disease modifying drugs (DMARDs) including conventional synthetic (csDMARDs) and targeted synthetic (tsDMARDs).MethodsWe linked population-based health data on all physician visits, hospital admissions, and all dispensed medications, regardless of payer in British Columbia from 01/01/1996 to 3/31/2021. We identified prescriptions for csDMARDs (including methotrexate, hydroxychloroquine) and tsDMARDs, namely anti-TNFs (including infliximab, etanercept, adalimumab) and rituximab using drug identification numbers among indicated individuals with RD. We defined March 11, 2020, as the ‘index date' which corresponded to the date that mitigation measures for the COVID-19 pandemic were first introduced. We assessed adherence as proportion days covered (PDC), calculated monthly in the 12 months before and 12 months after the index date. We used interrupted time-series models, namely segmented regression to estimate changes and trends in adherence before and after the index date.ResultsOur analysis showed that the mean PDCs for all included DMARDs stayed relatively steady in the 12 months before and after mitigation measures were introduced (see Table 1). Adherence was highest among anti-TNFs, methotrexate, and azathioprine. Anti-TNFs were on a downward trajectory 12 months prior to the index date. Interrupted time-series modeling demonstrated statistically significant differences in the trends in PDCs post- vs. pre-mitigation measures for all anti-TNFS (slope [∂]: 1.38, standard error [SE]: 0.23), infliximab (∂: 1.35, SE: 0.23), adalimumab (∂: 0.82, SE: 0.25), and etanercept (∂: 1.07, SE: 0.25) (see Figure 1a). Conversely, the csDMARDs were on a flatter trajectory, and methotrexate (∂: -0.53, SE: 0.16), leflunomide (∂: 0.43, SE: 0.08), mycophenolate (∂: -1.26, SE: 0.48), cyclophosphamide (∂: 0.29, SE: 0.05), minocycline (∂: 0.04, SE: 0.02), chloroquine (∂: 0.02, SE: 0.00) showed statistically significant changes in estimated PDC trajectory after mitigation measures were introduced (see Figure 1b).ConclusionThis population-based study demonstrates that messaging and pandemic mitigation measures did not affect adherence to DMARDs.Table 1.Mean PDC 1 year before and after mitigation measures for the COVID-19 pandemic were introduced.MedicationMean PDC (%) 12 months before index dateMean PDC (%) 12 months after index datecsDMARDsmethotrexate28.926.8azathioprine21.819.5sulfasalazine16.214.9leflunomide14.313.0cyclosporine13.711.5hydroxychloroquine10.59.6mycophenolate4.52.9antimalarials4.43.9penicillamine3.53.4cyclophosphamide1.50.7chlorambucil1.20.4minocycline1.10.9gold0.50.2chloroquine0.10.0tsDMARDsanti-TNFs52.149.2infliximab41.838.3adalimumab40.336.8etanercept31.828.9rituximab3.42.9REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Background: Several pro- and anti-inflammatory cytokines involved in COVID-19 and it is reasonable to speculate that their removal from blood might limit organ damage. Hemoperfusion with CytoSorb is a technique developed to adsorb molecules in the middle molecular weight range (up to 55 kDa). Studies in vitro and in vivo have shown that HP is highly effective in clearing blood from a number of cytokines. Method(s): We report a case series of 9 consecutive COVID-patients admitted to our COVID Intensive Care Unit (ICU). Five of them were treated with HP using CytoSorb (T), due to the heavy emergency overload it was impossible to deliver blood purification in the other 4 patients (C), who were also considered as potential candidates by the attending medical team. All patients had pneumonia and respiratory failure requiring continuous positive airway pressure. Different antibacterial prophylaxes, antiviral, and anti-inflammatory therapies including steroids were delivered. Result(s): Our results show a better clinical course of T compared to control patients (C), in fact all T except 1 survived, and only 2 of them were intubated, while all C required intubation and died. CRP decreased in both groups, but to a greater extent after HP. Lymphocytopenia worsened in control patient but not in treated patient after HP. Procalcitonin increased in 2 of the not treated patients. In all survived patients (n = 4) HP reduced pro-inflammatory cytokines, as IL-6, TNF-alpha, and IL-8. Notably, a striking effect was observed on IL-6 levels that at the end of the second session were decreased by a 40% than before the first treatment. Serum levels of IL-8 and TNF-alpha were lowered within normal range. In all patients the treatment was safe and there were no complications. Conclusion(s): Our study suggests a potential efficacy of HP in an early phase of viral infection not only for improving survival in the treated patients but also by the remodeling treatment-associated cytokine levels.
ABSTRACT
Introduction: Croatian National Cancer Registry of Croatian Institute for Public Health reported that in year 2020 lung cancer was the second most common cancer site diagnosed in men with 16% and the third most common in women with 10% incidence among all cancer sites. Unfortunatelly lung cancer has the highest mortality in both men and women. Haematological malignancies had 7% share in all malignancies in both male and female cances cases. In 2020 190 newly diagnosed cases of lymphatic leukemia in men and 128 cases in women were reporeted, meaning 1.5 and 1.2% of all malignancies, respectively. Chronic lymphatic leukemia (CLL) is an advanced age disease and incidence increases with age. Impaired immunity, T and B cell dysfunction in CLL, chromosomal aberations, long-term immunosuppressive therapy and genetic factors can all cause secondary malignancies. Co- occurence of solid tumors and CLL is very rare. Although patiens with CLL have an increased risk of developing second primary malignancies including lung carcinoma, the data about their clinical outcomes are lacking. Parekh et al. retrospectively analyzed patients with simultaneous CLL and lung carcinoma over a 20-year period, and they found that ~2% of patients with CLL actually developed lung carcinoma. The authors claimed that up to 38% of patients will also develop a third neoplasm more likely of the skin (melanoma and basal cell carcinoma), larynx (laryngeal carcinoma) or colon. Currently there are no specific guidelines for concurrent CLL and non-small cell lung carcinoma (NSCLC) treatment. Usually, when the tumors are diagnosed simultaneously, treatment is based to target the most aggressive malignancy, as the clinical outcomes depend on the response of the tumor with the poorest prognosis. For this reason, a multidisciplinary approach is mandatory. Case report: A patient with history of coronary heart disease, myocardial infarction and paroxysmal atrial fibrillation was diagnosed in 2019 (at the age of 71) with B chronic lymphocytic leukemia with bulky tumor (inguinal lymph nodes 8x5 cm), stage B according to Binet, intermediate risk. He was treated with 6 cycles of chemoimmunotherapy (rituximab/cyclofosfamid/fludarabine). In 10/2019 remission was confirmed, but MSCT described tumor in the posterior segment of upper right lung lobe measuring 20x17 mm and bilateral metastases up to 11 mm. Bronchoscopy and biopsy were performed, and EGFR neg, ALK neg, ROS 1 neg, PD-L1>50% adenocarcinoma was confirmed. He was referred to Clinical Hospital Center Osijek where monotherapy with pembrolizumab in a standard dose of 200 mg intravenously was started in 01/2020. Partial remission was confirmed in October 2020. Immunotherapy was discontinued due to development of pneumonitis, dysphagia and severe weight loss (20kg), but without radiologically confirmed disease progression. At that time he was referred to our hospital for further treatment. Gastroscopy has shown erosive gastritis with active duodenal ulcus, Forrest III. Supportive therapy and proton pump inhibitor were introduced. After complete regression of pneumonitis, improvement of general condition and resolution of dysphagia, no signs of lung cancer progression were found and pembrolizumab was reintroduced in 12/2021. Hypothyroidism was diagnosed in 01/2021 and levothyroxine replacement ther apy was started. In 03/2021 he underwent surgical removal of basal cell carcinoma of skin on the right temporal region with lobe reconstruction. From 02/2021, when pembrolizumab was reintroduced, regression in tumor size was continously confirmed with complete recovery of general condition. He was hospitalized for COVID 19 infection in 09/2021, and due to complications pembrolizumab was discontinued till 11/2021. Lung cancer immunotherapy proceeded till 11/2022, when Multidisciplinary team decided to finish pembrolizumab because of CLL relapse. CLL was in remission till August 2022 when due to B symptoms, lymphcytosis, anemia and generalized lymphadenopathy, hematological workup including biopsy of cervical lymph node was performed and CLL/SLL relapse was confirmed. Initially chlorambucil was introduced, but disease was refractory. Based on cytogenetic test results (IGHV unmutated, negative TP53) and due to cardiovascular comorbidity (contraindication for BTK inhibitors) venetoclax and rituximab were started in 01/2023. After just 1 cycle of treatment normal blood count as well as regression of B symptoms and peripheral lymphadenopathy occured, indicating the probability of complete disease remission. In our patient with metastatic lung adenocarcinoma excellent disease control is achieved during 41 month of treatment in first line setting. Furthermore, relapsed/refractory CLL/SLL is currently in confirmed remission. Conclusion(s): Successful treatment of patients with multiple primary malignancies is based on multidisciplinarity, early recognition and management of side effects, treatment of comorbidities with the aim of prolonging life, controlling symptoms of disease and preserving quality of life.
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The diagnosis of acromegaly is still a difficult task, as the disease has a slow onset and progression, and some of its symptoms may resemble those of other common conditions. Delays in diagnosis are common. Moreover, due to the continuous requirement for mask-wearing in many healthcare settings to prevent the spread of COVID-19, it is crucial to conduct a comprehensive examination of each patient without a face mask.Copyright © The Author(s). 2022.
ABSTRACT
BackgroundSafety and efficacy of updated bivalent vaccines, containing both the original vaccine variant of SARS-CoV-2 Spike and either Omicron variants BA.1 or BA.4/5, are of particular interest in arthritis patients on immunosuppressive therapies. With the continuous emergence of new viral variants, it is important to evaluate whether updated vaccines induce more adverse events in this patient group.ObjectivesTo examine if a second booster dose with updated bivalent vaccine increases the risk of adverse events, compared to the first booster dose with monovalent vaccines.MethodsThe prospective Nor-vaC study investigates vaccine responses in patients with immune mediated inflammatory diseases using immunosuppressive therapies (1). The present analyses included arthritis patients who received two booster doses. Patients received available vaccines according to the Norwegian vaccination program. The current recommendation in the Norwegian arthritis population is a three-dose primary vaccination series followed by two booster doses. Adverse events following vaccines doses were self-reported through questionnaires. Adverse events following the first (monovalent) and second (bivalent) booster were compared with McNemar's test.ResultsBetween 7th of July 2021 and 6th of December 2022 a total of 243 arthritis patients (127 rheumatoid arthritis, 65 psoriatic arthritis, 51 spondyloarthritis) on immunosuppressive therapies (Table 1) received a first, monovalent (BNT162b2, mRNA-1273) and a second, bivalent booster dose (BNT162b2 (WT/OMI BA.1), mRNA-1273.214, BNT162b2 (WT/OMI BA.4/BA.5)). Adverse events were recorded within 2 weeks in all patients (Figure 1). In total, 45 vs 49 (19% vs 20 %) patients reported any adverse event after a second, bivalent booster dose, compared to the first, monovalent booster, respectively. There was no significant difference in adverse events overall (p= 0.57). The most common adverse events after the second booster were pain at injection site (12 %), flu-like symptoms (9 %) and headache (6 %). No new safety signals emerged. A total of 15 (6 %) patients reported a disease flare after receiving the second, bivalent booster, compared to 21 (8 %) after the first, monovalent booster.ConclusionThere was no difference in adverse events between the monovalent, first booster, and the bivalent, second booster, indicating that bivalent vaccines are safe in this patient group.Reference[1]Syversen S.W. et al Arthritis Rheumatol 2022Table 1.Demographic characteristics and immunosuppressive medication in patients receiving a 1st monovalent and a 2nd bivalent booster dose.CharacteristicsPatients, n (%)Total243Age (years), median (IQR)61 (52-67)Female152 (63)Immunosuppressive medicationTNFi monoa75 (31)TNFi comboa+b72 (30)Methotrexate62 (26)Rituximab9 (4)IL-inhibitorsc6 (2)JAK-inhibitorsd11 (5)Othere8 (3)1st boosterBNT162b2106 (44)mRNA-1273137 (56)2nd boosterBNT162b2 (WT/OMI BA.1)65 (25)BNT162b2 (WT/OMI BA.4/BA.5)120 (47)mRNA-1273.214 (WT/OMI BA.1)58 (23)Results in n (%) unless otherwise specified.aTumor necrosis factor inhibitors: infliximab, etanercept, adalimumab, golimumab, certolizumab pegol.bCombination therapy: methotrexate, sulfasalazine, leflunomide, azathioprine.cInterleukin inhibitors: tocilizumab, secukinumab.dJanus kinase inhibitors: filgotinib, baricitinib, upadacitinib, tofacitinib.eOther: abatacept, sulfasalazine, leflunomide, azathioprine.Figure 1.Adverse events after bivalent vaccine as a 2nd booster dose compared to a monovalent vaccine as a 1st booster dose.[Figure omitted. See PDF]AcknowledgementsWe thank the patients and health-care workers who have participated in the Norwegian study of vaccine response to COVID-19. We thank the patient representatives in the study group, Kristin Isabella Kirkengen Espe and Roger Thoresen. We thank all study personnel, laboratory personnel, and other staff involved at the clinical departments involved, particularly Synnøve Aure, Margareth Sveinsson, May Britt Solem, Elisabeth Røssum-Haaland, and Kjetil Bergsmark.Disclosure of InterestsHilde Ørbo: None declared, Ingrid Jyssum: None declared, Anne Therese Tveter: None declared, Ingrid E. Christensen: None declared, Joseph Sexton: None declared, Kristin Hammersbøen Bjørlykke Speakers bureau: Janssen-Cilag, Grete B. Kro: None declared, Tore K. Kvien Speakers bureau: Amgen, Celltrion, Egis, Evapharma, Ewopharma, Hikma, Oktal, Sandoz, Sanofi, Consultant of: AbbVie, Biogen, Celltrion, Eli Lilly, Gilead, Mylan, Novartis, Pfizer, Sandoz, Sanofi, Grant/research support from: AbbVie, Amgen, BMS MSD, Novartis, Pfizer, UCB, Ludvig A. Munthe Speakers bureau: Novartis, Cellgene, Gunnveig Grodeland Speakers bureau: Bayer, Sanofi, ThermoFisher, Consultant of: AstraZeneca, Siri Mjaaland: None declared, John Torgils Vaage: None declared, Espen A Haavardsholm Speakers bureau: Pfizer, UCB, Consultant of: AbbVie, Boehringer-Ingelheim, Eli Lilly, Gilead, Kristin Kaasen Jørgensen Speakers bureau: Bristol-Myers Squibb, Roche, Sella Aarrestad Provan: None declared, Silje Watterdal Syversen: None declared, Guro Løvik Goll Speakers bureau: AbbVie/Abbott, Galapagos, Pfizer, UCB, Consultant of: AbbVie/Abbott, Galapagos, Pfizer, UCB.