Primary adrenal insufficiency is a life-threatening endocrine disease unless properly treated. However, few studies on the prevalence, concomitances of the disease, and prescribing of drugs have been ...published. The goal of the study was to establish the prevalence of primary adrenal insufficiency in Iceland and additionally, to study the most common concomitant diseases in patients with primary adrenal insufficiency, as well as the mode of glucocorticoid replacement therapies.
To achieve this, the medical records of all patients in Iceland who had received the International Classification of Diseases and Related Health Problems, 10th Revision, diagnosis code E27, were evaluated for true primary adrenal insufficiency. Additionally, these records were evaluated for concomitant diseases, as well as the mode of glucocorticoid replacement therapy. The study covered the whole population of Iceland over 18 years of age. It was thus a nationwide study. The records were retrieved from large hospitals and clinics and every practicing specialist in endocrinology.
Primary adrenal insufficiency was found in 53 individuals, 26 women and 27 men, yielding a prevalence of 22.1 per 100,000 population. Hypothyroidism was by far the most common concomitant disease. Most patients had their glucocorticoid deficiency replaced with short-acting glucocorticoids.
The prevalence of primary adrenal insufficiency in Iceland is higher than in earlier reports, with comorbidities being in line with recent studies. Treatment is according to the latest protocols.
There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with higher prevalence or increased ...progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore present a target population for MGUS screening. This two-part study is the first study to evaluate the relationship of MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio (OR)= 1.10; 95% confidence interval (CI): 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer associated with the progression of MGUS, except for myeloid malignancies which were associated with lower risk of progression (hazard ratio (HR)=0.37; 95%CI: 0.16-0.89; p=0.028). Our findings indicate that a prior cancer are not a significant aetiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer.
Abstract
Serum free light chain (FLC) concentration is greatly affected by kidney function. Using a large prospective population-based cohort, we aimed to establish a reference interval for FLCs in ...persons with chronic kidney disease (CKD). A total of 75422 participants of the iStopMM study were screened with serum FLC, serum protein electrophoresis and immunofixation. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine. Central 99% reference intervals were determined, and 95% confidence intervals calculated. Included were 6461 (12%) participants with measured FLCs, eGFR < 60 mL/min/1.73 m
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, not receiving renal replacement therapy, and without evidence of monoclonality. Using current reference intervals, 60% and 21% had kappa and lambda FLC values outside the normal range. The FLC ratio was outside standard reference interval (0.26–1.65) in 9% of participants and outside current kidney reference interval (0.37–3.10) in 0.7%. New reference intervals for FLC and FLC ratio were established. New reference intervals for the FLC ratio were 0.46–2.62, 0.48–3.38, and 0.54–3.30 for eGFR 45–59, 30–44, and < 30 mL/min/1.73 m
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groups, respectively. The crude prevalence of LC-MGUS in CKD patients was 0.5%. We conclude that current reference intervals for FLC and FLC ratio are inaccurate in CKD patients and propose new eGFR based reference intervals to be implemented.
Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Population-based screening for MGUS could identify candidates for early treatment in MM. Here we describe the ...Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), the first population-based screening study for MGUS including a randomized trial of follow-up strategies. Icelandic residents born before 1976 were offered participation. Blood samples are collected alongside blood sampling in the Icelandic healthcare system. Participants with MGUS are randomized to three study arms. Arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. Participants who progress are offered early treatment. Samples are collected longitudinally from arms 2 and 3 for the study biobank. All participants repeatedly answer questionnaires on various exposures and outcomes including quality of life and psychiatric health. National registries on health are cross-linked to all participants. Of the 148,704 individuals in the target population, 80 759 (54.3%) provided informed consent for participation. With a very high participation rate, the data from the iStopMM study will answer important questions on MGUS, including potentials harms and benefits of screening. The study can lead to a paradigm shift in MM therapy towards screening and early therapy.
Multiple myeloma (MM) patients have increased risk of severe coronavirus disease 2019 (COVID-19) when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Monoclonal gammopathy ...of undetermined significance (MGUS), the precursor of MM has been associated with immune dysfunction which may lead to severe COVID-19. No systematic data have been published on COVID-19 in individuals with MGUS. We conducted a large population-based cohort study evaluating the risk of SARS-CoV-2 infection and severe COVID-19 among individuals with MGUS. We included 75,422 Icelanders born before 1976, who had been screened for MGUS in the Iceland Screens Treats or Prevents Multiple Myeloma study (iStopMM). Data on SARS-CoV-2 testing and COVID-19 severity were acquired from the Icelandic COVID-19 Study Group. Using a test-negative study design, we included 32,047 iStopMM participants who had been tested for SARS-CoV-2, of whom 1754 had MGUS. Among these participants, 1100 participants, tested positive, 65 of whom had MGUS. Severe COVID-19 developed in 230 participants, including 16 with MGUS. MGUS was not associated with SARS-CoV-2 infection (Odds ratio (OR): 1.05; 95% confidence interval (CI): 0.81-1.36; p = 0.72) or severe COVID-19 (OR: 0.99; 95%CI: 0.52-1.91; p = 0.99). These findings indicate that MGUS does not affect the susceptibility to SARS-CoV-2 or the severity of COVID-19.
Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor condition that precedes multiple myeloma and related disorders but has also been associated with other medical ...conditions. Since systematic screening is not recommended, MGUS is typically diagnosed due to underlying diseases and most cases are not diagnosed. Most previous studies on MGUS disease associations have been based on clinical cohorts, possibly resulting in selection bias. Here we estimate this selection bias by comparing clinically diagnosed and screened individuals with MGUS with regards to demographics, laboratory features, and comorbidities. A total of 75,422 participants in the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study were screened for MGUS by serum protein electrophoresis, immunofixation and free light chain assay (clinicaltrials gov. Identifier: NCT03327597). We identified 3,352 individuals with MGUS, whereof 240 had previously been clinically diagnosed (clinical MGUS), and crosslinked our data with large, nationwide registries for information on comorbidities. Those with clinical MGUS were more likely to have at least one comorbidity (odds ratio=2.24; 95% confidence interval: 1.30-4.19), and on average had more comorbidities than the screened MGUS group (3.23 vs. 2.36, mean difference 0.68; 95% confidence interval: 0.46-0.90). They were also more likely to have rheumatological disease, neurological disease, chronic kidney disease, liver disease, heart failure, or endocrine disorders. These findings indicate that individuals with clinical MGUS have more comorbidities than the general MGUS population and that previous studies have been affected by significant selection bias. Our findings highlight the importance of screening data when studying biological and epidemiological implications of MGUS.
Hemodilution of bone marrow (BM) aspirates is a limitation of multiparameter flow cytometry (MFC) in plasma cell disorders. There is a need for a validated approach for assessing sample quality and ...the distribution of non-plasma cell BM populations by MFC could provide a solution. We evaluated BM-associated cell populations, assessed by next-generation flow cytometry (NGF) and white blood cell (WBC) count in 351 BM aspirated samples from 219 participants with plasma cell disorders in the Iceland Screens, Treats, or Prevents MM study (iStopMM), as markers of hemodilution by their discriminatory ability between first and (generally more hemodiluted) second pull BM aspirated samples. The most discriminating markers were used to derive a novel BM quality index (BMQI). Nucleated red blood cells and myeloid precursors provided the greatest discriminatory ability between first vs second pull samples (area under the curve (AUC): 0.87 and 0.85, respectively), significantly better than B cell precursors (AUC = 0.64; p < 0.001), mast cells (AUC = 0.65; p < 0.001), and the BM WBC count (AUC = 0.77; p < 0.05). We generated a novel BMQI that is intrinsic to current NGF protocols, for evaluating quality of diagnostic BM samples and suggest the use of a BMQI scoring system for interpreting results and guiding appropriate actions.
John Greco (2020) sets out to create a unified virtue-theoretic account of knowledge generation and transmission in his book The Transmission of Knowledge. One of the advantages of his view is that ...it can defend the achievement view from a known strand of counterexamples. To accomplish that, he relies on joint agency being essential to knowledge transmission. Joint agency can be characterized as a sort of interdependent and interactive cooperation between speaker and hearer that share an intention to transmit knowledge. This paper introduces the phenomenon of unwanted knowledge transmission which shows that joint agency, as Greco presents it, is not essential to knowledge transmission. Four types of unwanted knowledge transmissions will be introduced that pose threats to Greco’s account by showing that shared intention, a key characteristic of joint agency, is not present in all instances of knowledge transmission. Finally, some potential ways to defend Greco’s view will be considered and discussed.
Introduction
Smoldering multiple myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM) that carries a higher risk of progression to MM than monoclonal gammopathy of ...undetermined significance (MGUS). This study aimed to identify potential risk factors of SMM by analyzing the association of baseline characteristics, body mass index, smoking, alcohol consumption, prior diagnoses of autoimmune diseases and prior chronic infections and SMM in the screened Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study cohort.
Methods
The iStopMM study is a screening study for MM precursors where 75,422 individuals over 40 years old in Iceland were screened with serum protein electrophoresis (SPEP) and free light chain (FLC) analysis. Those with a positive screening result were randomized to one of the three study arms, with clinical evaluation at the study center, including bone marrow sampling, performed in two of them. MGUS was defined by the presence of a serum M-protein concentration less than 30 g/L and less than 10% clonal plasma cells in the bone marrow, and SMM was defined as 10-60% bone marrow plasma cells and/or M-protein concentration over 30 g/L, both in the absence of MM defining events. IgM MGUS was excluded in this analysis. Height and weight were measured at the first visit to the study center, alcohol and smoking habits were evaluated with questionnaires. Information on previous diagnoses (ICD codes) was obtained from central health registries with almost 100% completeness. Logistic regression models were used to calculate odds ratio (OR) with 95% confidence interval (CI) to compare risk factors in SMM vs. MGUS and SMM vs. controls. All analyses were adjusted for age and sex.
Results
At the first study center evaluation, 210 individuals were diagnosed with SMM and 1,456 with MGUS. Data from 70,627 controls with negative SPEP and normal FLC analysis were included. Individuals with SMM were older and more frequently male than controls, however there was no statistically significant difference between the sex and age distribution of individuals with SMM and MGUS (Figure). Immunoparesis (OR 3.98; 95% CI: 2.74-5.76), abnormal FLC ratio (OR 3.61; 95% CI: 2.59-5.02), IgA isotype (OR 2.64; 95% CI: 1.83-3.83) and increasing M-protein levels (OR per g/L 1.33; 95% CI: 1.27-1.39) were all associated with increased odds of SMM compared to MGUS. BMI measured at the first study visit was not significantly different between individuals with MGUS and SMM (overweight vs. normal weight OR 1.08; 95% CI: 0.74-1.56). Neither current or previous smoking nor alcohol consumption more than once per week (vs. less) was associated with increased risk of SMM compared to MGUS (OR 0.88; 95% CI: 0.60-1.31, and OR 0.97; 95% CI: 0.62-1.53, respectively) or controls (OR 0.92; 95% CI: 0.64-1.33, and OR 0.85; 95% CI: 0.57-1.27, respectively). Prior diagnosis of autoimmune disease was not associated with SMM as compared to MGUS (OR 1.19; 95% CI: 0.81-1.74) or controls (OR 1.21; 95% CI: 0.85-1.73). A previous diagnosis of a chronic infection was not statistically significantly associated with increased risk of being diagnosed with SMM as compared to MGUS (OR 1.53; 95% CI: 1.00-2.34) but an association was seen when compared to controls (OR 1.54; 95% CI: 1.05-2.28). In individuals with SMM, the most common chronic infections were varicella zoster virus and herpes simplex virus, no diagnoses of hepatitis virus or chronic bacterial infections were observed.
Conclusion
In this large population-based screening study we did not find an association of smoking, alcohol consumption, BMI, or a prior diagnosis of autoimmune disease and SMM compared to MGUS. We found an association between a previous diagnosis of a chronic infection and SMM which could be explained by reverse causality, i.e., that SMM leads to immune impairment which increases the risk of viral infections. We found no significant age or sex difference between individuals with MGUS and SMM, but results from blood tests, including immunoparesis, abnormal FLC ratio, IgA-isotype, and higher levels of M-protein were all associated with SMM compared to MGUS. Our results indicate that neither lifestyle factors nor chronic inflammatory conditions increase the risk of SMM, and that the differences between individuals with MGUS and SMM can be detected in blood assessments associated with the plasma cell clone, but not in demographic or behavior related factors.
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