Risk of fractures and use of bisphosphonates in adult patients with immune thrombocytopenia-A nationwide population-based study.

Corticosteroids remain the first-line treatment of immune thrombocytopenia (ITP), but increase the risk of osteoporosis and fractures. Bisphosphonates are used for the treatment of osteoporosis, but their usage among patients with ITP has not been systemically described. We investigated the risk of fractures and the use of bisphosphonates in adult patients with primary (pITP) and secondary ITP (sITP) compared with matched comparators in a nationwide registry-based cohort study. We identified 4030 patients with pITP (median age 60 years [IQR, 40-74]), 550 with sITP (median age 59 years [IQR, 43-74]) and 182 939 age-sex-matched general population comparators. All individuals were followed for incident fractures. Bisphosphonate use was estimated for calendar-years and in temporal relation to the ITP diagnosis. Adjusted cause-specific hazard ratio (csHR) for any fracture was 1.37 (95% confidence interval [CI] 1.23; 1.54) for pITP and 1.54 (1.17; 2.03) for sITP. The first-year csHR was 1.82 (1.39; 2.40) for pITP and 2.78 (1.58; 4.91) for sITP. Bisphosphonate use over calendar-years and in the early years following ITP diagnosis was higher among patients with ITP diagnosis compared with the general population. In conclusion, the risk of fractures and the use of bisphosphonates are higher in patients with ITP compared with the general population.

Primary autoimmune haemolytic anaemia is associated with increased risk of ischaemic stroke: A binational cohort study from Denmark and France.

Primary autoimmune haemolytic anaemia (AIHA) causes the destruction of red blood cells and a subsequent pro-thrombotic state, potentially increasing the risk of ischaemic stroke. We investigated the risk of ischaemic stroke in patients with AIHA in a binational study. We used prospectively collected data from nationwide registers in Denmark and France to identify cohorts of patients with primary AIHA and age- and sex-matched general population comparators. We followed the patient and comparison cohorts for up to 5 years, with the first hospitalization of a stroke during follow-up as the main outcome. We estimated cumulative incidence, cause-specific hazard ratios (csHR) and adjusted for comorbidity and exposure to selected medications. The combined AIHA cohorts from both countries comprised 5994 patients and the 81 525 comparators. There were 130 ischaemic strokes in the AIHA cohort and 1821 among the comparators. Country-specific estimates were comparable, and the overall adjusted csHR was 1.36 [95% CI: 1.13-1.65], p = 0.001; the higher rate was limited to the first year after AIHA diagnosis (csHR 2.29 [95% CI: 1.77-2.97], p < 10-9 ) and decreased thereafter (csHR 0.89 [95% CI: 0.66-1.20], p = 0.45) (p-interaction < 10-5 ). The findings indicate that patients diagnosed with primary AIHA are at higher risk of ischaemic stroke in the first year after diagnosis.

Mental health and use of psychotropic prescription drugs in adult patients with primary immune thrombocytopenia: a nationwide population-based cohort study.

Patients with primary immune thrombocytopenia (ITP) suffer from reduced survival and quality of life, but the underlying reasons for this are largely undescribed. Mental health and the use of psychotropic drugs in ITP is unknown. We investigated the risk of hospital registered mental health events including fatigue and the use of psychotropic drugs in adult patients with ITP compared with the general population, using nationwide registry-data. We identified 3,749 patients with ITP and 149,849 age-sex matched general population comparators in the Danish Health Registries in the period 1997-2016. The median age was 60 years (IQR 40-73) and 53% were women. We followed the individuals for incident mental health events and estimated the use of psychotropic drugs over calendar-years and in temporal relation to diagnosis of ITP. The first year cumulative incidence of any mental health event was 2.3% (95% confidence interval, 1.9-2.9) in patients and 0.7% (0.6-0.7) in comparators, yielding an adjusted cause-specific hazard ratio (csHR) of 3.57 (2.84-4.50). The corresponding estimates for depression were 1.2% (0.9-1.6) and 0.3% (0.3-0.4) respectively, with an adjusted csHR of 3.53 (2.56-4.85). We found similar findings for anxiety and fatigue, but risks generally diminished after 1-5 years. The use of opioids, antidepressants, and benzodiazepines increased in temporal relation to diagnosis of ITP. The risk of mental health events and the use of psychotropic drugs is higher in adult patients with ITP compared with the general population, and has a temporal relation to diagnosis of ITP emphasizing that mental health in ITP is a concern.

Survival in adult patients with chronic primary and secondary immune thrombocytopenia: A population-based study.

BACKGROUND: Few studies have investigated long-term survival in patients with primary immune thrombocytopenia (pITP). Further, changes in prognosis over the past decades and prognosis of secondary immune thrombocytopenia (sITP) are largely unstudied. Our objectives were to study comorbidity-adjusted prognostic changes and causes of death in chronic pITP and sITP patients. STUDY DESIGN/METHODS: Using nationwide Danish health registries 1980-2016, we identified 1762 patients with chronic pITP (median age 58 (IQR, 37-73) years) and 128 with chronic sITP (median age 59 (IQR, 40-73) years). Patients were age-sex-matched to 74,781 general population comparators. Comorbidity was assessed using Charlson Comorbidity Index (CCI). RESULTS: Overall median survival was reduced by 5.1 years (95% CI, 0.7-9.4) (p < .001) for pITP and 11.1 years (95% CI, 5.8-16.4) (p < .001) for sITP. 5-year survival increased from 69% (95% CI, 59-78) in 1980-89 to 80% (95% CI, 75-83) in 2010-16 for pITP, and decreased from 100% (95% CI, 89-98) to 64% (95% CI, 87-91) for sITP. However, numbers were small for sITP. 5-year survival for pITP with high CCI was 41% (95% CI, 32-49), and 85% (95% CI, 83-87) for low CCI. Bleeding, infection and hematological cancer were relatively frequent causes of death with adjusted subhazard ratios of 3.25 (95% CI, 2.33-4.52), 1.53 (95% CI, 1.08-2.16) and 2.16 (95% CI, 1.12-4.16) in pITP respectively, and 10.52 (95% CI, 1.43-77.36) for hematological cancer in sITP. CONCLUSIONS: Long-term survival is reduced in chronic ITP but seems to be improving. Comorbidity and sITP are associated with a poor prognosis.

Bone marrow biopsy can be omitted in the diagnostic workup of CNS lymphoma of DLBCL origin: a population-based retrospective study in the PET-CT era.

Currently, bone marrow (BM) biopsy (BMB) is recommended in the initial staging of patients with the presumed primary central nervous system (CNS) lymphoma (PCNSL). However, the added value of BMB in the era of positron emission tomography (PET-CT) has been challenged in other lymphoma subtypes. We analyzed BM findings in patients with biopsy-proven CNS lymphoma and a negative PET-CT scan for disease outside CNS. A comprehensive Danish population-based registry search was performed to identify all patients with CNS lymphoma of diffuse large B cell lymphoma (DLBCL) histology with available BMB results and staging PET-CT without systemic lymphoma. A total of 300 patients fulfilled the inclusion criteria. Of them, 16% had a previous history of lymphoma, while 84% were diagnosed with PCNSL. None of the patients had DLBCL in the BM. A minority (8.3%) had discordant BMB findings, mainly low-grade histologies that did not influence treatment choice in any case. In conclusion, the risk of overlooking concordant BM infiltration in patients with CNS lymphoma of DLBCL histology and negative PET-CT scan is negligible. As we did not find any patient with DLBCL in the BMB, our results suggest that BMB can be safely omitted in the diagnostic workup in patients with CNS lymphoma and a negative PET-CT.

Elevated Hemolysis Index is associated with higher risk of cardiovascular diseases.

OBJECTIVES: In vivo hemolysis is associated with thromboembolism. Although an increased Hemolysis Index (HI) can be due to in vitro as well as in vivo hemolysis, both reflects a more fragile erythrocyte population. We therefore hypothesized that HI above upper reference limit would be associated with an increased risk of cardiovascular disease (CVD). METHODS: We identified persons with two elevated HI (HI+) from blood samples analyzed at a university hospital laboratory from 2012 to 2017. We compared their risk of CVD with the risk in matched comparators with normal HI and from the general population. HI+ persons and comparators were followed from start date (date of the second elevated HI) until the first of the main outcome: CVD, emigration, death, or end of observation time on December 31, 2018. RESULTS: In 43,102 unique HI+ persons, the risk of developing CVD was 40% higher compared with the general population and 13% higher compared with the matched blood sample cohort. HI+ was associated with a significantly increased cumulative incidence of both arterial and venous CVD compared with the matched blood sample cohort and the general population (respectively 47 and 14% for arterial CVD; 78 and 24% for venous CVD). Moreover, overall mortality risk was significantly higher in patients with HI+ than in the two comparator groups. CONCLUSIONS: Elevated HI is associated with increased risk of arterial and venous CVD and with increased mortality. Our findings imply that HI may contribute as a CVD risk biomarker.

Survival in autoimmune hemolytic anemia remains poor, results from a nationwide cohort with 37 years of follow-up.

INTRODUCTION: Autoimmune hemolytic anemia (AIHA) is considered a chronic disease, with an overall good prognosis. However, recent reports indicate pre-mature mortality. Causes of death have not been evaluated previously. METHODS: In a nationwide setting, we identified all patients with warm type AIHA or cold agglutinin disease (CAD), and age-sex-matched comparators from Denmark, 1980-2016. We estimated overall survival and cause-specific mortality from anemia, infection, cardiovascular causes, hematological or solid cancer, bleeding, or other causes, using cumulative incidence proportions. RESULTS: We identified 1460 patients with primary AIHA, 1078 with secondary AIHA, 112 with CAD, and 130 801 comparators. One-year survival and median survival were, 82.7% and 9.8 years for primary AIHA, 69.1% and 3.3 years for secondary AIHA, and 85.5% and 8.8 years for CAD. Prognosis was comparable to the general population only in patients with primary AIHA below 30 years. In all other age and subgroups, the difference was considerable. Cumulated cause-specific mortality at 1 year was increased among patients versus comparators. DISCUSSION: All groups of autoimmune hemolytic anemia are associated with increased overall and cause-specific mortality compared to the general population. This probably reflects unmet needs in both treatment and follow-up programs.

Priapism in patients with hemolytic disorders: a nationwide retrospective cohort study.

Priapism is a persistent, painful erection, which can lead to permanent penile damage and reduced quality of life. Patients with sickle cell disease have an increased risk of priapism which has been related to chronic hemolysis. This study investigates the prevalence of priapism in all major hereditary and acquired forms of hemolytic disorders. Patients with hemolytic disorders were identified in the nationwide Danish Hemolysis Cohort. Each patient was age-sex-matched with 50 comparisons from the general population without hemolysis. We identified the episodes of hospital-registered priapism events for both patients with hemolysis disorders and comparisons in the Danish National Patient Register between 1977 and 2016. We identified 4181 male patients with hemolytic disorders and 205,994 male comparisons, with 2,294,027 person-years of total observation time. Totally, 101 episodes of priapism occurred during follow-up period. Six episodes of priapism were recorded in three patients with a hemolytic disorder, all affected by sickle cell disease. Two of these patients had verified genotype HbSS. The incidence rate for first priapism in sickle cell disease was 432.8 per 100,000 person-years [95% CI: 139.6; 1341.8] versus 0.84 per 100,000 person-years [95% CI 0.54; 1.32] in comparisons. Using a large nationwide cohort, we found that only sickle cell disease is associated with priapism among patients with hemolytic disorders. The incidence rate of priapism in patients with sickle cell disease was lower than previously reported.

Evans syndrome in adults - incidence, prevalence, and survival in a nationwide cohort.

Patients with Evans syndrome have both immune thrombocytopenia and autoimmune hemolytic anemia, but little is known about the epidemiology of this rare syndrome. Evans syndrome can be primary or secondary. This nationwide retrospective study linked health registries to identify 242 patients with Evans syndrome in Denmark in 1977-2017. For comparison, we identified three age-matched and sex-matched cohorts of patients with only immune thrombocytopenia or only autoimmune hemolytic anemia, and a general population cohort. The Evans syndrome cohort had a mean age of 58.5 years at diagnosis, 51.2% were women, and 27.3% were classified as secondary Evans syndrome. The annual Evans syndrome incidence and prevalence rose significantly during the study period, to 1.8 per million person-years and 21.3 per million persons, respectively, in 2016. The median survival with Evans syndrome was 7.2 years (primary Evans syndrome: 10.9 years; secondary Evans syndrome: 1.7 years). Secondary Evans syndrome was associated with higher mortality rates than any of the other cohorts, with a 5-year survival of 38%. Among patients with Evans syndrome, the prevailing causes of death were bleeding, infections, and hematological cancer. In conclusion, we found that both primary and secondary Evans syndrome conferred a poor prognosis. Lethal complications probably derive primarily from manifestations of underlying autoimmune hemolytic anemia and immune thrombocytopenia. Our findings suggested that suspicion of Evans syndrome should prompt vigilant clinical follow-up. International collaborations are warranted to advance our knowledge of optimal management of this rare disease.

Optimization of Postprocessing parameters for abdominal Forensic CT scans.

Aim: Postmortem Computed Tomography (PMCT) is gradually introduced at forensic institutes. Image reconstruction software can increase diagnostic potential in CT by increasing distinction between structures and reduction of artifacts. The aim of this study was to develop and evaluate novel image reconstruction parameters for postmortem conditions, to increase image quality and diagnostic potential of CT scans. Method: Twenty PMCT scans of deceased hereof two in severe decay were subjected to four reconstruction techniques: a standard reconstruction algorithm, the detail reconstruction algorithm and two novel algorithms based on the standard algorithm, but with different Hounsfield settings. Image quality was evaluated by visual grading analysis (VGA) by four forensic radiologist observers. Results: The VGA did not prove that any of the reconstruction techniques were superior to the others. For standard and detail, the two pre-defined reconstruction algorithms, VGA scores were indiscernible and were superior to the equally indiscernible Hounsfield reconstructions on parameters translated into Sharpness and Low Contrast Resolution. The two alternative Hounsfield settings were superior with respect to Noise and Artifacts/Beam Hardening. Conclusion: The study elucidates the possiblity for multiple reconstructions specialized for PMCT conditions, to accommodate the special conditions when working with the deceased. Despite the lack of clear improvements in the tested reconstructions, this study provides an insight into some of the possibilities of improving PMCT quality using reconstruction techniques.

New expert advice on cancer in pregnancy.

Cancer in pregnancy is rare, and most physicians lack knowledge in handling pregnant cancer patients. This review summarises the present knowledge on this condition. In the Netherlands, an Advisory Board on Cancer in Pregnancy was established in 2012. The board supports Dutch physicians' decisions in the management of pregnant patients with cancer. In 2021 the International Advisory Board on Cancer in Pregnancy was established, and in continuation, the Danish Advisory Board on Cancer in Pregnancy (DABCIP) has now been founded. DABCIP consists of 22 members from 13 different medical disciplines.

[Neuropsychological deficits following thrombotic thrombocytopenic purpura].

Despite significant improvements in the prognosis of thrombotic thrombocytopenic purpura (TTP), long-term neuropsychological deficits are frequent but probably under-recognised. Regular assessment of cognitive impairment using screening tools is therefore recommended. In this case report we describe two patients with neuropsychological late effects severely affecting their work capacity and quality of life. These late effects were not diagnosed until neuropsychological testing. We conclude that screening tools may not be sufficient to capture neuropsychological late effects in TTP.

Genomic profiling of a randomized trial of interferon-α vs hydroxyurea in MPN reveals mutation-specific responses.

Although somatic mutations influence the pathogenesis, phenotype, and outcome of myeloproliferative neoplasms (MPNs), little is known about their impact on molecular response to cytoreductive treatment. We performed targeted next-generation sequencing (NGS) on 202 pretreatment samples obtained from patients with MPN enrolled in the DALIAH trial (A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms; #NCT01387763), a randomized controlled phase 3 clinical trial, and 135 samples obtained after 24 months of therapy with recombinant interferon-alpha (IFNα) or hydroxyurea. The primary aim was to evaluate the association between complete clinicohematologic response (CHR) at 24 months and molecular response through sequential assessment of 120 genes using NGS. Among JAK2-mutated patients treated with IFNα, those with CHR had a greater reduction in the JAK2 variant allele frequency (median, 0.29 to 0.07; P < .0001) compared with those not achieving CHR (median, 0.27 to 0.14; P < .0001). In contrast, the CALR variant allele frequency did not significantly decline in those achieving CHR or in those not achieving CHR. Treatment-emergent mutations in DNMT3A were observed more commonly in patients treated with IFNα compared with hydroxyurea (P = .04). Furthermore, treatment-emergent DNMT3A mutations were significantly enriched in IFNα-treated patients not attaining CHR (P = .02). A mutation in TET2, DNMT3A, or ASXL1 was significantly associated with prior stroke (age-adjusted odds ratio, 5.29; 95% confidence interval, 1.59-17.54; P = .007), as was a mutation in TET2 alone (age-adjusted odds ratio, 3.03; 95% confidence interval, 1.03-9.01; P = .044). At 24 months, we found mutation-specific response patterns to IFNα: (1) JAK2- and CALR-mutated MPN exhibited distinct molecular responses; and (2) DNMT3A-mutated clones/subclones emerged on treatment.

Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine.

The majority of JAK2V617F-negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin (CALR), resulting in a common carboxyl-terminal mutant fragment (CALRMUT), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALRMUT-specific T cells are rare in patients with CALRMUT MPN for unknown reasons. We examined class I major histocompatibility complex (MHC-I) allele frequencies in patients with CALRMUT MPN from two independent cohorts. We observed that MHC-I alleles that present CALRMUT neoepitopes with high affinity are underrepresented in patients with CALRMUT MPN. We speculated that this was due to an increased chance of immune-mediated tumor rejection by individuals expressing one of these MHC-I alleles such that the disease never clinically manifested. As a consequence of this MHC-I allele restriction, we reasoned that patients with CALRMUT MPN would not efficiently respond to a CALRMUT fragment cancer vaccine but would when immunized with a modified CALRMUT heteroclitic peptide vaccine approach. We found that heteroclitic CALRMUT peptides specifically designed for the MHC-I alleles of patients with CALRMUT MPN efficiently elicited a CALRMUT cross-reactive CD8+ T cell response in human peripheral blood samples but not to the matched weakly immunogenic CALRMUT native peptides. We corroborated this effect in vivo in mice and observed that C57BL/6J mice can mount a CD8+ T cell response to the CALRMUT fragment upon immunization with a CALRMUT heteroclitic, but not native, peptide. Together, our data emphasize the therapeutic potential of heteroclitic peptide-based cancer vaccines in patients with CALRMUT MPN.

Epidemiology of Secondary Warm Autoimmune Haemolytic Anaemia-A Systematic Review and Meta-Analysis.

BACKGROUND: Warm autoimmune haemolytic anaemia (wAIHA) is a haemolytic disorder, most commonly seen among adults and is classified as either primary or secondary to an underlying disease. We describe the age and sex distribution and the proportion of secondary wAIHA. METHOD: We retrieved 2635 published articles, screened abstracts and titles, and identified 27 articles eligible for full-text review. From these studies, we extracted data regarding number of patients, sex distribution, age at diagnosis, number of patients with secondary wAIHA, and whether the patients were diagnosed through local or referral centres. All data were weighted according to the number of included patients in each study. RESULTS: 27 studies including a total of 4311 patients with wAIHA, of which 66% were females, were included. The median age at diagnosis was 68.7 years, however, wAIHA affected all ages. The mean proportion of secondary wAIHA was 49%, most frequently secondary to systemic lupus erythematosus. The proportions of secondary wAIHA reported from primary vs. referral centres were 35% vs. 59%, respectively. CONCLUSION: This review consolidates previously reported gender distribution. The higher proportion of secondary wAIHA in referral centres suggests that the most severely affected patients are disproportionally more frequent in such facilities.

[Thrombotic thrombocytopenic purpura].

Distinguishing thrombotic thrombocytopenic purpura (TTP) from other thrombotic microangiopathies requires measurement of ADAMTS13 enzyme activity, but treatment must often be commenced before results from the ADAMTS13 analysis is available. Scoring systems to facilitate prediction of severe ADAMTS13 deficiency and therefore immediate clinical management have been developed. This combined with advances in treatment and monitoring holds optimism for improvements in late effects and survival in future patients. In this review, we discuss status in diagnosing, managing, and follow-up of patients with TTP.

Evans syndrome in adults: an observational multicenter study.

Evans syndrome (ES) is a rare condition, defined as the presence of 2 autoimmune cytopenias, most frequently autoimmune hemolytic anemia and immune thrombocytopenia (ITP) and rarely autoimmune neutropenia. ES can be classified as primary or secondary to various conditions, including lymphoproliferative disorders, other systemic autoimmune diseases, and primary immunodeficiencies, particularly in children. In adult ES, little is known about clinical features, disease associations, and outcomes. In this retrospective international study, we analyzed 116 adult patients followed at 13 European tertiary centers, focusing on treatment requirements, occurrence of complications, and death. ES was secondary to or associated with underlying conditions in 24 cases (21%), mainly other autoimmune diseases and hematologic neoplasms. Bleeding occurred in 42% of patients, mainly low grade and at ITP onset. Almost all patients received first-line treatment (steroids with or without intravenous immunoglobulin), and 23% needed early additional therapy for primary refractoriness. Additional therapy lines included rituximab, splenectomy, immunosuppressants, thrombopoietin receptor agonists, and others, with response rates >80%. However, a remarkable number of relapses occurred, requiring ≥3 therapy lines in 54% of cases. Infections and thrombotic complications occurred in 33% and 21% of patients, respectively, mainly grade ≥3, and correlated with the number of therapy lines. In addition to age, other factors negatively affecting survival were severe anemia at onset and occurrence of relapse, infection, and thrombosis. These data show that adult ES is often severe and marked by a relapsing clinical course and potentially fatal complications, pinpointing the need for high clinical awareness, prompt therapy, and anti-infectious/anti-thrombotic prophylaxis.