This study aimed to demonstrate possible associations between genetic polymorphisms in Toll-like receptor 3, interferon induced with helicase C domain 1 (IFIH1) and DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 and systemic lupus erythematosus (SLE), including the phenotypes lupus nephritis and malar rash, as well as the presence of autoantibodies against nucleic acid-containing complexes. Genotyping was carried out in two Danish cohorts [Copenhagen (CPH) and Odense (ODE)] totaling 344 patients and was compared with 641 previously genotyped healthy controls. In the ODE cohort, the patients were only genotyped for the rs1990760 polymorphism of IFIH1. Single nucleotide polymorphisms (SNPs) were determined by a multiplex bead-based assay (CPH cohort) or real-time PCR (ODE cohort). Associations were investigated using the Cochran-Armitage trend test. The odds ratio (OR) for minor allele homozygotes versus major allele homozygotes suggested a protective effect of the IFIH1 rs1990760 SNP for SLE in the ODE cohort [OR 0.52, 95 % confidence intervals (95 % CI) 0.31-0.88, Pcorr. = 0.05] but not in the CPH cohort, although the OR suggested a trend in the same direction, and when combining the two patient cohorts, ORs were 0.57, 95 % CI 0.37-0.88. None of the other investigated polymorphisms showed any association with SLE. Regarding phenotypes, we found a statistically significant association between rs1990760 and malar rash in the CPH cohort, with ORs suggesting a protective effect (OR 0.28, 95 % CI 0.13-0.62 for heterozygotes and OR 0.11, 95 % CI 0.03-0.41 for homozygotes, Pcorr. = 0.0001). There were no significant associations between rs1990760 and presence of anti-dsDNA, anti-U1RNP, or anti-Smith antibodies. Our study supports previous findings of an association between the rs1990760 polymorphism of IFIH1 and SLE and indicates that this SNP may also be associated with malar rash in SLE patients although this finding needs confirmation.
In 2019 the UK Myeloma Research Alliance introduced the Myeloma Risk Profile (MRP) for prediction of outcome in patients with newly diagnosed multiple myeloma (MM), ineligible for autologous stem cell transplantation. To validate the MRP in a population-based setting we performed a study of the entire cohort of transplant ineligible MM patients above 65 years in the Danish National MM Registry. Our data confirmed the value of the MRP. In a cohort of 1,377 patients, the MRP score separated patients into three distinct risk-groups with an observed hazard ratio of 2.91 for early death in high-risk versus low-risk patients.
The prevalence of multiple myeloma (MM) is increasing in the Nordic countries and the rest of the Western World. Patients aged ≥75 years at diagnosis constitute an increasing proportion of all MM patients, but are underrepresented in randomized clinical trials. There is an urgent need for studies of the characteristics, treatment and outcome in this cohort. We present data from two nationwide population-based registries of all MM patients diagnosed in Denmark January 1st 2005 until February 18th 2020, and in Sweden from January 1st 2008 until December 31st 2019, including treatment data for patients diagnosed until 2018 (Denmark) and 2019 (Sweden). In total 4647 patients were 75 years or older at diagnosis, compared to 7378 younger patients. Patients ≥75 years, comprising approximately 40% of all MM patients, are a distinct cohort with more advanced disease at diagnosis, reflected by higher ISS (International Staging System), and a higher proportion with renal failure and anemia. We find a more gradual introduction of modern medications in the older cohort than the younger, despite simultaneous changes in guidelines. Compared to the randomized controlled trials that guide the treatment of non-transplant eligible patients, we find a higher proportion of patients ≥75 years and presenting with ISS III in real world data. Nevertheless, response rates and survival are increasing, reflecting that modern treatment regimens are effective and well tolerated, also in elderly MM patients in real-world populations.
Background : The UK Myeloma Research Alliance recently introduced a new clinical prediction model for outcome in newly diagnosed multiple myeloma (MM) patients not eligible for autologous hematopoietic stem-cell transplantation (ASCT) (Lancet Haematology 2019; 6: e154-66). The score or Myeloma Risk Profile, MRP, includes WHO performance status (PS), the International Staging System (ISS), age, and C-reactive protein (CRP) as prognostic variables. First a score is calculated by the formula: Score = (PS - 2) * 0.199 + (age - 74.4) * 0.0165 + (ISS - 2) * 0.212 + (log(CRP + 1) - 2.08) * 0.0315, where PS and ISS are defined as numbers between 0-4 and 1-3, respectively, and CRP is in mg/L. Next, three risk groups are defined as 1) low risk: score < -0.256, 2) medium risk: -0.256 ≤ score ≤ -0.0283, or 3) high risk: score > -0.0283. The MRP score was generated based on two prospective clinical trial cohorts, the NRCI-Myeloma XI study (ISRCTN49407852) as training set or internal validation, and the NRCI-Myeloma IX study (Blood 2011; 118, 1231-38) as test set or external validation. Both trials investigated conventional oral alkylating agents, cyclophosphamide or melphalan, in combination with thalidomide, lenalidomide, and/or bortezomib; thus including drugs typically used in treatment of elderly MM patients. Establishment of the model included 1852 patients in the training set, and 520 patients in the test set. All patients were recruited as part of clinical trials and therefore fulfilled defined inclusion and exclusion criteria. To validate the MRP score in a population-based setting we performed a study of the entire cohort of transplant ineligible MM patients in the Danish National MM Registry. Methods : The Danish MM registry started 01 January 2005. It includes registration of all diagnosed MM patients in Denmark and given first- and second-line treatment. A data validation study has been performed (J Clin Epidemiology, 2016; 8: 583-587). At 31 December 2014, 2,926 newly diagnosed treatment demanding MM patients were registered, hereof 1,803 patients were above 65 years and found ineligible for ASCT, and constituted the patient population for this study. Results: Of 1,803 transplant in-eligible but treatment demanding newly diagnosed MM patients above 65 years 426 patients had one or more missing values for calculation of the MRP score, most often this was caused by missing ISS. Thus, 1,377 patients were evaluable with a median follow-up of 40.9 months. Patients were treated according to standard of care in Denmark during the 10-years registration period which included upfront conventional alkylating agent, mostly melphalan in 37.7%, thalidomide-based in 25.6%, bortezomib-based in 26.1%, lenalidomide based in 2.7%, and only palliative, mostly steroid-based in 7.9%. The distribution of the risk groups according to MRP was as follows: low risk 28.5%, medium-risk 25.1%, and high-risk 46.4%. Ccompared to the UK datasets we had a higher proportion of high-risk patients which undoubtedly reflects that our cohort is population based. Median survivals for the 3 risk groups are presented in Table 1 and overall survival curves illustrated in Figure 1. The model performed well in separating the patients into subgroups with different survival risks. In conclusion, our real life population-based data confirm that the MRP score is a robust and valuable risk assessment tool for elderly newly diagnosed MM patients older than 65 and not eligible for ASCT. An important advantage of the MRP score is that it is calculated from simple parameters that should be part of everyday diagnostic work-up. Disclosures Vangsted: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Jansen: Honoraria. Plesner:Takeda: Consultancy; Oncopeptides: Consultancy; Genmab: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Janssen: Consultancy, Research Funding. Frederiksen:Novartis: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Abbvie: Research Funding. Abildgaard:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Research Funding.
Background:Background: Multiple Myeloma (MM) is a severe malignancy with changing treatment possibilities and generally improved survival. However, prognosis is variable, and solid prognostic models for use in the daily clinic are warranted. Several new prognostic models and frailty scores have been introduced, but it can be difficult to keep track of their performance and validation. Aims:Aims: To help clinicians prognosticate patients with newly diagnosed MM in the daily clinic, we performed a systematic review of studies validating prognostic models in general MM populations. Methods:Methods: A review was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines (PRISMA-P) and pre-registered in the International Prospective Register of Systematic Review (PROSPERO) -identification number: CRD42021230604 https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=230604 . Search strategyLouise Redder, Tine Rosenberg, and Niels Abildgaard created the search strategy in collaboration with a Health Sciences Librarian from the University of Southern Denmark. A broad search string was set up with four search blocks: the first included a validated search filter for finding prognostic and diagnostic predictions studies. The second block searched all MeSH terms for MM. The third block contained an explorative search for progression free survival (PFS) and overall survival (OS), as these were our comparative outcomes and an inclusion criterion. In the fourth block, we attempted to target MM populations as close to the real world as possible, through an explorative search for population, cohort studies, multicenter or single center, and registry.Two systematic literature searches were conducted on the 18 th of September 2020 and the 15 th of December 2021, using the electronic bibliographic databases, MEDLINE, EMBASE, and the Cochrane Library. Inclusion & exclusion criteriaStudies validating or replicating prognostic models predicting OS and/or PFS in a population-based cohort of patients with newly diagnosed MM were included. Cohorts composed by fulfilling inclusion and exclusion criteria in clinical trials were excluded. Further, we excluded cohorts based on specific ethnicities, socioeconomic status, somatic diseases or disabilities, and populations representing other plasma cell dyscrasia, such as plasma cell leukaemia or smouldering MM.A prognostic model was defined as a combination of at least two separate variables predicting patient outcome. The model had to predict OS/PFS at the time of diagnosis.The design could be cohort, nested case-control or case-cohort studies as they are recommended for prognostic model
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