Labor market affiliation of patients with myeloproliferative neoplasms: a population-based matched cohort study.

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs) suffer from substantial symptoms and risk of debilitating complications, yet observational data on their labor market affiliation are scarce. MATERIAL AND METHODS: We conducted a descriptive cohort study using data from Danish nationwide registries, including patients diagnosed with MPN in 2010-2016. Each patient was matched with up to ten comparators without MPN on age, sex, level of education, and region of residence. We assessed pre- and post-diagnosis labor market affiliation, defined as working, unemployed, or receiving sickness benefit, disability pension, retirement pension, or other health-related benefits. Labor market affiliation was assessed weekly from two years pre-diagnosis until death, emigration, or 31 December 2018. For patients and comparators, we reported percentage point (pp) changes in labor market affiliation cross-sectionally from week -104 pre-diagnosis to week 104 post-diagnosis. RESULTS: The study included 3,342 patients with MPN and 32,737 comparators. From two years pre-diagnosis until two years post-diagnosis, a larger reduction in the proportion working was observed among patients than comparators (essential thrombocythemia: 10.2 [95% CI: 6.3-14.1] vs. 6.8 [95% CI: 5.5-8.0] pp; polycythemia vera: 9.6 [95% CI: 5.9-13.2] vs. 7.4 [95% CI: 6.2-8.7] pp; myelofibrosis: 8.1 [95% CI: 3.0-13.2] vs. 5.8 [95% CI: 4.2-7.5] pp; and unclassifiable MPN: 8.0 [95% CI: 3.0-13.0] vs. 7.4 [95% CI: 5.7-9.1] pp). Correspondingly, an increase in the proportion of patients receiving sickness benefits including other health-related benefits was evident around the time of diagnosis. CONCLUSION: Overall, we found that Danish patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN had slightly impaired labor market affiliation compared with a population of the same age and sex. From two years pre-diagnosis to two years post-diagnosis, we observed a larger reduction in the proportion of patients with MPN working and a greater proportion receiving sickness benefits compared with matched individuals.

Healthcare resource utilization in patients with myeloproliferative neoplasms: A Danish nationwide matched cohort study.

Few studies have assessed healthcare resource utilization (HRU) in patients with Philadelphia-negative myeloproliferative neoplasms (MPN) using a matched cohort design. Further, no detailed assessment of HRU in the years preceding an MPN diagnosis exists. We conducted a registry-based nationwide Danish cohort study, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN diagnosed between January 2010 and December 2016. HRU data were summarized annually from 2 years before MPN diagnosis until emigration, death, or end of study (December 2017). We included 3342 MPN patients and 32 737 comparisons without an MPN diagnosis, matched on sex, age, region of residence, and level of education. During the study period, the difference in HRU (rate ratio) between patients and matched comparisons ranged from 1.0 to 1.5 for general practitioner contacts, 0.9 to 2.2 for hospitalizations, 0.9 to 3.8 for inpatient days, 1.0 to 4.0 for outpatient visits, 1.3 to 2.1 for emergency department visits, and 1.0 to 4.1 for treatments/examinations. In conclusion, MPN patients had overall higher HRU than the matched comparisons throughout the follow-up period (maximum 8 years). Further, MPN patients had substantially increased HRU in both the primary and secondary healthcare sector in the 2 years preceding the diagnosis.

[Elevated blood cell counts and vascular disease with the myeloproliferative neoplasms as model diseases].

Recent studies have shown the Philadelphia-negative myeloproliferative neoplasms (MPN) to be massively underdiagnosed and often preceded by a long pre-diagnostic phase of several years, in which many patients suffer serious vascular events. In this review, we focus on the urgent need for earlier diagnosis and treatment of MPN. Such efforts are foreseen to decrease morbidity and mortality for the individual patients and potentially reduce costs for health and social care systems.

Health-Related Quality of Life in Patients with Philadelphia-Negative Myeloproliferative Neoplasms: A Nationwide Population-Based Survey in Denmark.

Previous studies have clarified that many patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) have burdensome symptom profiles and accordingly impaired functioning and quality of life (QoL). In Denmark, all MPN patients are affiliated with public hospitals and because of a healthcare system financed by taxpayers these patients do not have any financial costs related to the hematological disease. Diagnoses are recorded for all patients in hospitals, and diagnosis codes are communicated to the National Patient Register (NPR). Owing to this, it was possible to contribute to the elucidation of Philadelphia-negative MPN patients' health-related quality of life (HRQoL), by conducting a nationwide, population-based, cross-sectional HRQoL survey of these patients with cost-free access to the best available, suitable medical treatment. The survey contained validated questionnaires covering functioning, symptom burden, symptom profile, QoL, and additional questions on lifestyle. Information on comorbid diagnoses was obtained from the NPR. The participants' HRQoL was compared to the general population. Moreover, differences in HRQoL across essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN participants were investigated, adjusted for age, sex, comorbidity, and lifestyle. To the best of our knowledge this is the first survey of HRQoL in patients with unclassifiable MPN. A total of 2228 Philadelphia-negative MPN patients participated. The participants reported their HRQoL to be inferior to the general population, but the difference was minor. The differences in HRQoL across groups of participants with different MPN subtypes were subtle. Fatigue and sexual problems were prevalent and burdensome. Overall, participants reported a slightly healthier lifestyle compared to the general population.

Risk of Inflammatory Bowel Disease in Patients with Chronic Myeloproliferative Neoplasms: A Danish Nationwide Cohort Study.

An association between hematological cancers and inflammatory bowel disease (IBD) has previously been suggested, but the risk of IBD in patients with myeloproliferative neoplasms (MPNs) is unknown. We conducted a nationwide population-based cohort study using Danish registries, to estimate the risk of IBD in individuals diagnosed with essential thrombocythemia, polycythemia vera, myelofibrosis or unclassifiable MPN during 1994-2013. MPN patients were matched 1:10 with sex- and age-matched comparisons. Everyone was followed until a diagnosis of IBD, death/emigration, or 31 December 2013. The risk of IBD overall and according to MPN subtype was calculated using Cox regression and presented as hazard ratios (HRs) with 95% confidence intervals (CI). Of 8207 MPN patients followed for 45,232 person-years, 80 were diagnosed with IBD (61 ulcerative colitis, 19 Crohn's disease). The rate of IBD per 1000 person-years was 1.8 (95% CI:1.4-2.2) in patients vs. 0.8 (95% CI:0.7-0.8) in comparisons, and the absolute 10-year risk of IBD was 0.8% (95% CI:0.6-1.0) in patients vs. 0.4% (95% CI:0.4-0.5) in comparisons. The HR of IBD was 2.4 (95% CI:2.1-2.9) with similar HRs for ulcerative colitis and Crohn's disease. MPN subtype risks varied from 2.1 (95% CI:1.6-2.7) to 2.8 (95% CI:2.1-3.7). Our unselected cohort study showed a more than 2-fold increased risk of IBD in MPN patients.

[Myeloproliferative neoplasms and chronic inflammatory bowel disease].

Studies have suggested a possible association between inflammatory bowel disease (IBD) and the Philadelphia-negative chronic myeloproliferative neoplasms (MPNs). The mechanisms behind this association have not been investigated yet, but in this review, we find it most likely to involve complex interactions between genetic, treatment-related and inflammation- and immune-mediated factors. When patients with IBD present with persistent leukocytosis and/or thrombocytosis, it may reflect concomitant MPN, and early detection and treatment of MPNs may prevent some of the complications related to these diseases.

Smoking, blood cells and myeloproliferative neoplasms: meta-analysis and Mendelian randomization of 2·3 million people.

Meta-analyses and Mendelian randomization (MR) may clarify the associations of smoking, blood cells and myeloproliferative neoplasms (MPN). We investigated the association of smoking with blood cells in the Danish General Suburban Population Study (GESUS, n = 11 083), by meta-analyses (including GESUS) of 92 studies (n = 531 741) and MR of smoking variant CHRNA3 (rs1051730[A]) in UK Biobank, and with MPN in a meta-analysis of six studies (n (total/cases):1 425 529/2187), totalling 2 307 745 participants. In the meta-analysis the random-effects standardized mean difference (SMD) in current smokers versus non-smokers was 0·82 (0·75-0·89, P = 2·0 * 10-108 ) for leukocytes, 0·09 (-0·02 to 0·21, P = 0·12) for erythrocytes, 0·53 (0·42-0·64, P = 8·0 * 10-22 ) for haematocrit, 0·42 (0·34-0·51, P = 7·1 * 10-21 ) for haemoglobin, 0·19 (0·08-0·31, P = 1·2 * 10-3 ) for mean corpuscular haemoglobin (MCH), 0·29 (0·19-0·39, P = 1·6 * 10-8 ) for mean corpuscular volume (MCV), and 0·04 (-0·04 to 0·13, P = 0·34) for platelets with trends for ever/ex-/current smokers, light/heavy smokers and female/male smokers. Analyses presented high heterogeneity but low publication bias. Per allele in CHRNA3, cigarettes per day in current smokers was associated with increased blood cell counts (leukocytes, neutrophils), MCH, red cell distribution width (RDW) and MCV. The pooled fixed-effects odds ratio for MPN was 1·44 [95% confidence interval (CI): 1·33-1·56; P = 1·8 * 10-19 ; I2  = 0%] in current smokers, 1·29 (1·15-1·44; P = 8·0 * 10-6 ; I2  = 0%) in ex-smokers, 1·49 (1·26-1·77; P = 4·4 * 10-6 ; I2  = 0%) in light smokers and 2·04 (1·74-2·39, P = 2·3 * 10-18 ; I2  = 51%) in heavy smokers compared with non-smokers. Smoking is observationally and genetically associated with increased leukocyte counts and red blood cell indices (MCH, MCV, RDW) and observationally with risk of MPN in current and ex-smokers versus non/never-smokers.

Vascular Diseases In Patients With Chronic Myeloproliferative Neoplasms - Impact Of Comorbidity.

BACKGROUND: Patients with chronic myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are at high risk of vascular complications. However, the magnitude of this is risk not well known and the possible effect of comorbidity is poorly understood. AIM: Our aim was to compare the risk of vascular diseases in patients with MPNs and matched comparisons from the general population and to study the effect modification of comorbidity. METHODS: We followed 3087 patients with ET, 6076 with PV, 3719 with PMF or unspecified MPN, and age- and sex-matched general population comparisons to estimate the risks of cardiovascular diseases such as myocardial infarction and stroke. We computed 5-year cumulative incidences (risks) for vascular disease in patients with MPNs and comparisons as well as 1-year and 5-year risks, risk differences, and hazard ratios (HRs) for vascular diseases comparing rates in each group of patients with their comparison cohort by level of comorbidity based on the Charlson Comorbidity Index (CCI) [score of 0 (low comorbidity), of 1-2 (moderate comorbidity), and of >2 (severe comorbidity)], as well as other comorbid conditions. RESULTS: The overall 5-year risk of vascular disease ranged from 0.5% to 7.7% in patients with MPNs, which was higher than the risk in the general population. In the same period, the adjusted HRs for vascular disease were 1.3 to 3.7 folds higher in patients with MPNs compared to the general population. An increase in CCI score was associated with an equally increased rate of most types of vascular diseases during the first 5 years of follow-up in both MPN and comparisons. CONCLUSION: Patients with MPNs have a higher risk of vascular diseases during the first 5 years than that of the general population; however, comorbidity modifies the rates similarly in MPN and in the general population.

Anxiety and depression in patients with Philadelphia-negative myeloproliferative neoplasms: a nationwide population-based survey in Denmark.

OBJECTIVE: We sought to determine the prevalence and severity of anxiety and depression among patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) and respective associations of anxiety and depression with demographic and lifestyle factors, comorbidity burden, duration of MPN disease, financial difficulties, and health-related quality of life (QoL). METHODS: This study used data from a nationwide, population-based, cross-sectional survey of health-related QoL in MPN patients in Denmark called the MPNhealthSurvey. Individuals with a diagnosis of MPN in the National Patient Register were invited. The Hospital Anxiety and Depression Scale was used to assess the prevalence and severity of anxiety and depression. The associations of anxiety and depression with age, sex, education, body mass index (BMI), smoking, alcohol intake, physical activity, comorbidity burden, duration of MPN disease, financial difficulties, symptom burden, sexual problems, fatigue, functioning, and global health/QoL were examined. RESULTS: In total, 2,029 patients completed the Hospital Anxiety and Depression Scale. The prevalence of anxiety, depression, and both was 21%, 12%, and 8%, respectively. Many participants who reported anxiety or depression exhibited mild symptoms. Middle-aged and elderly participants had lower odds of experiencing anxiety and depression when compared to younger participants, and females had higher odds of anxiety compared to males. Participants with higher education had lower odds of anxiety compared to those with lower education. Current smokers and ex-smokers had higher odds of anxiety and depression compared to those who had never smoked, and sedentary participants and participants with a lower level of physical activity had higher odds of anxiety and depression compared to participants who performed hard training several times a week. Higher comorbidity burden increased the odds of depression, and greater financial difficulties increased the odds of anxiety and depression. Higher total symptom burden and fatigue burden and higher level of sexual problems increased the odds of anxiety and depression. Finally, lower functional level and global health/quality of life increased the odds of anxiety and depression. BMI, alcohol intake, comorbidity burden, and duration of disease were not substantially associated with anxiety, whereas sex, educational level, and duration of MPN disease were not substantially associated with depression. CONCLUSION: There may be an unmet need in handling psychological distress in MPN patients. Future research might explore the utility of screening for psychological distress and the effectiveness of lifestyle interventions, rehabilitation, and MPN-symptom reduction in preventing and treating psychological distress.

Smoking is associated with increased risk of myeloproliferative neoplasms: A general population-based cohort study.

BACKGROUND: Former studies on smoking as a risk factor for Philadelphia-negative myeloproliferative neoplasms (MPNs) have mainly been carried out in women's cohorts and studies with various definitions of MPNs. Herein, we conducted a cohort study with register-based follow-up of a general population from Denmark, to validate and substantiate prior observations. METHODS: In the Danish Health Examination Survey cohort, we used the Cox proportional-hazards model adjusted for age, sex, body mass index, and level of education, to calculate hazard ratios (HRs), to investigate, whether daily smokers or occasional/ex-smokers had an increased risk of MPNs compared to never-smokers. RESULTS: From the time of data collection (September 2007 to October 2008) until 1 January 2015, 70 individuals were diagnosed with MPNs among 75 896 study participants. Similar results were observed in both the age and sex adjusted analysis and the multivariable analysis. The multivariable HR of any MPN diagnosis for daily smokers was 2.5 (95% CI: 1.3-5.0). For essential thrombocytosis, polycythemia vera, myelofibrosis, and MPN-unclassified, the HRs were 1.8 (95% CI: 0.5-5.8), 1.7 (95% CI: 0.5-5.8), 4.3 (95% CI: 0.9-19), and 6.2 (95% CI: 1.5-25), respectively. Among occasional/ex-smokers the corresponding HRs were 1.9 (95% CI: 1.1-3.3), 1.5 (95% CI: 0.6-3.7), 0.8 (95% CI: 0.3-2.4), 0.9 (95% CI: 0.2-4.4), and 6.2 (95% CI: 1.8-21). Participants, who smoked >15 g/day, had an overall HR of 3.4 (95% CI: 1.4-8.2) for any MPN diagnosis, while participants who smoked ≤15 g/day, had an overall HR of 2.1 (95% CI: 0.9-4.7). CONCLUSION: Smoking was associated with MPN development when comparing smokers and never-smokers. Further studies investigating smoking in MPNs are warranted to substantiate our findings.

Age-Related Macular Degeneration in Patients With Chronic Myeloproliferative Neoplasms.

Importance: It has been suggested that systemic inflammation increases the risk of age-related macular degeneration (AMD). Given that chronic immune modulation is present in patients with myeloproliferative neoplasms (MPNs), the risk of AMD in these patients may be increased. Objective: To compare the risk of AMD in patients with MPNs with the risk of AMD in matched controls from the general population. Design, Setting, and Participants: A nationwide population-based cohort study using Danish registers was conducted of all patients in Denmark who received a diagnosis between January 1, 1994, and December 31, 2013, of essential thrombocythemia, polycythemia vera, myelofibrosis, or unclassifiable MPNs. For each patient, 10 age- and sex-matched controls were included. All patients without prior AMD were followed up from the date of diagnosis (or corresponding entry date for the controls) until the first AMD diagnosis, death or emigration, or December 31, 2013, whichever occurred first. Data analysis was performed from April 1, 2015, to October 31, 2016. Main Outcomes and Measures: Incidence of AMD recorded in specialized hospital-based care. The rates and absolute risk of AMD were calculated. Using Cox proportional hazards regression models, smoking and risk-time adjusted hazard ratios (HRs) between patients and controls were calculated. In addition, HRs of neovascular AMD after 2006 were calculated since antivascular endothelial growth factor treatment was introduced nationwide at hospitals thereafter. Results: A total of 7958 patients with MPNs (4279 women [53.8%] and 3679 men [46.2%]; mean [SD] age at diagnosis, 66.4 [14.3] years) were included in the study. The rate of AMD per 1000 person-years at risk was 5.2 (95% CI, 4.6-5.9) for patients with MPNs (2628 with essential thrombocythemia, 3063 with polycythemia vera, 547 with myelofibrosis, and 1720 with unclassifiable MPNs) and 4.3 (95% CI, 4.1-4.4) for the 77 445 controls, while the 10-year risk of AMD was 2.4% (95% CI, 2.1%-2.8%) for patients with MPNs and 2.3% (95% CI, 2.2%-2.4%) for the controls. The risk of AMD was increased overall for patients with MPNs (adjusted HR, 1.3; 95% CI, 1.1-1.5), with adjusted HRs for the subtypes of 1.2 (95% CI, 1.0-1.6) for essential thrombocythemia, 1.4 (95% CI, 1.2-1.7) for polycythemia vera, 1.7 (95% CI, 0.8-4.0) for myelofibrosis, and 1.5 (95% CI, 1.1-2.1) for unclassifiable MPNs. In addition, patients with MPNs had a higher risk of neovascular AMD (adjusted HR, 1.4; 95% CI, 1.2-1.6). Conclusions and Relevance: Our results suggest that patients with MPNs are at increased risk of AMD, supporting the possibility that systemic inflammation is involved in the pathogenesis of AMD.

A retrospective analysis of the impact of treatments and blood counts on survival and the risk of vascular events during the course of polycythaemia vera.

Vascular and non-vascular complications are common in patients with polycythaemia vera. This retrospective study of 217 patients with polycythaemia vera aimed to determine whether blood counts with respect to different treatments influenced the complication rate and survival. We found that 78 (36%) patients suffered from at least one complication during follow-up. Older age and elevated lactate dehydrogenase at diagnosis were found to be risk factors for vascular complications. When the vascular complication occurred, 41% of the patients with a complication had elevated white blood cells (WBC) compared with 20% of patients without a complication (P = 0·042). Patients treated with hydroxycarbamide (HC; also termed hydroxyurea) experienced significantly fewer vascular complications (11%) than patients treated with phlebotomy only (27%) (P = 0·013). We also found a survival advantage for patients treated with HC, when adjusted for age, gender and time period of diagnosis (Hazard ratio for phlebotomy-treated patients compared to HC-treated patients at 5 years was 2·42, 95% confidence interval 1·03-5·72, P = 0·043). Concerning survival and vascular complications, HC-treated patients who needed at least one phlebotomy per year were not significantly different from HC-treated patients with a low phlebotomy requirement. We conclude that complementary phlebotomy in HC-treated patients in order to maintain the haematocrit, is safe.

The Danish National Chronic Myeloid Neoplasia Registry.

AIM: The Danish National Chronic Myeloid Neoplasia Registry (DCMR) is a population-based clinical quality database, introduced to evaluate diagnosis and treatment of patients with chronic myeloid malignancies. The aim is to monitor the clinical quality at the national, regional, and hospital departmental levels and serve as a platform for research. STUDY POPULATION: The DCMR has nationwide coverage and contains information on patients diagnosed at hematology departments from January 2010 onward, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, unclassifiable myeloproliferative neoplasms, chronic myelomonocytic leukemia, and chronic myeloid leukemia. MAIN VARIABLES: Data are collected using standardized registration forms (so far up to four forms per patient), which are consecutively filled out online at time of diagnosis, after 2-year and 5-year follow-ups, and at end of follow-up. The forms include variables that describe clinical/paraclinical assessments, treatment, disease progression, and survival - disease-specific variables - as well as variables that are identical for all chronic myeloid malignancies. DESCRIPTIVE DATA: By the end of 2014, the DCMR contained data on 2,690 patients with an inclusion rate of ∼500 patients each year. Since the registry was established, annual reports have shown consistently high national coverage and data completeness, ≥90% and ≥88%, respectively. CONCLUSION: The DCMR is a national database used for monitoring the quality of patient care in patients with chronic myeloid malignancies, but until validation has been conducted, the data must be used with caution. However, the DCMR is a valuable data source accessible to clinicians and researchers.

High rate of abnormal blood values and vascular complications before diagnosis of myeloproliferative neoplasms.

BACKGROUND: Vascular complications occurring before the diagnosis of myeloproliferative neoplasms (MPN) in 612 patients from four centers in Sweden, Denmark and France were retrospectively studied. RESULTS: Vascular complications were observed in 151 (25%) of the 612 patients. Of these, 66% occurred during the two years preceding diagnosis. The majority of events were thromboembolic (95%), and included myocardial infarction (n=46), ischemic stroke (n=43), transient ischemic attack (TIA) (n=22), deep vein thrombosis/pulmonary embolism (n=19), splanchnic vein thrombosis (n=7), and peripheral embolism (n=7). Bleeding was observed in only 7 (5%) of the 151 patients with vascular events (3 with intracranial bleeding, 2 with epistaxis and 2 with gastrointestinal bleeding). Full blood counts obtained at least 3 months prior to the MPN diagnosis showed that 269 (44%) had abnormal blood values, fulfilling the diagnostic criteria for MPN. During the time from the abnormal blood test to the diagnosis of MPN, 50 patients suffered from a vascular complication. CONCLUSION: We therefore conclude that a large proportion of MPN patients suffer severe thromboembolic complications prior to diagnosis. If MPN were diagnosed earlier, a large proportion of these events might be prevented. An MPN should always be suspected and ruled out in patients with unexplained elevated hematocrit, leukocyte and/or platelet counts.

A randomized, controlled trial comparing local infiltration analgesia with epidural infusion for total knee arthroplasty.

BACKGROUND: There have been few studies describing wound infiltration with additional intraarticular administration of multimodal analgesia for total knee arthroplasty (TKA). In this study, we assessed the efficacy of wound infiltration combined with intraarticular regional analgesia with epidural infusion on analgesic requirements and postoperative pain after TKA. METHODS: 40 consecutive patients undergoing elective, primary TKA were randomized into 2 groups to receive either (1) intraoperative wound infiltration with 150 mL ropivacaine (2 mg/mL), 1 mL ketorolac (30 mg/mL), and 0.5 mL epinephrine (1 mg/mL) (total volume 152 mL) combined with intraarticular infusion (4 mL/h) of 190 mL ropivacaine (2 mg/mL) plus 2 mL ketorolac (30 mg/mL) (group A), or (2) epidural infusion (4 mL/h) of 192 mL ropivacaine (2 mg/mL) combined with 6 intravenous administrations of 0.5 mL ketorolac (30 mg/mL) for 48 h postoperatively (group E). For rescue analgesia, intravenous patient-controlled-analgesia (PCA) morphine was used. Morphine consumption, intensity of knee pain (0­100 mm visual analog scale), and side effects were recorded. Length of stay and corrected length of stay were also recorded (the day-patients fulfilled discharge criteria). RESULTS: The median cumulated morphine consumption, pain scores at rest, and pain scores during mobilization were reduced in group A compared to group E. Corrected length of stay was reduced by 25% in group A compared to group E. INTERPRETATION: Peri- and intraarticular analgesia with multimodal drugs provided superior pain relief and reduced morphine consumption compared with continuous epidural infusion with ropivacaine combined with intravenous ketorolac after TKA.