Involvement of the central nervous system (CNS) in multiple myeloma (MM) is very uncommon; it has been observed in approximately 1% of the MM patients. This review summarizes the clinical and laboratory characteristics and treatment modalities of 109 patients with CNS myelomatosis (CNS MM) reported in the literature. CNS MM has a wide spectrum of neurological symptoms and signs. No guidelines for therapy of CNS MM are available, which has resulted in a large variation in the treatment schedules. Treatment options include intrathecal chemotherapy (IT), systemic chemotherapy (SC), cranial irradiation (CI) or a combination. The prognosis of CNS MM remains poor, with an overall median survival from the time of diagnosis to death of 2.0 months (range 0.1–25 months). Patients who were treated with CI had a significantly (P = 0.004) longer survival when compared with patients without CI.

Background Treatment of patients with hemophilia has advanced over the past decades, but it is unknown whether this has resulted in a normal life expectancy in the Netherlands. Objective This observational cohort study aimed to assess all‐cause and cause‐specific mortality in patients with hemophilia in the Netherlands between 2001 and 2018 and to compare mortality and life expectancy with previous survival assessments from 1973 onward. Patients/methods All 1066 patients with hemophilia who participated in a nationwide survey in 2001 were followed until July 2018. Results Information on 1031 individuals (97%) was available, of whom 142 (14%) deceased during follow‐up. Compared with the general Dutch male population, mortality of patients with hemophilia was still increased (standardized mortality ratio: 1.4, 95% confidence interval: 1.2–1.7). Intracranial bleeding and malignancies were the most common causes of death. Estimated median life expectancy of patients with hemophilia was 77 years, 6 years lower than the median life expectancy of the general Dutch male population (83 years). Over the past 45 years, death rates of patients with hemophilia have consistently decreased, approaching the survival experience of the general population. Over the past decades, mortality due to human immunodeficiency virus and hepatitis C virus infections has decreased, death due to intracranial hemorrhages has increased, and death due to ischemic heart disease has remained consistently low over time. Conclusions Survival in patients with hemophilia in the Netherlands has improved over time but is still lower than that of the general population.

Patients with hereditary rare bleeding disorders (RBDs) present with diverse hemorrhagic symptoms. Correlation between factor activity levels and clinical bleeding severity is poor for most RBDs. Threshold factor activity levels have been previously described in relation to bleeding severity but have not yet been validated. The Rare Bleeding Disorders in the Netherlands (RBiN) study is a nationwide cross-sectional study of patients registered in all 6 Dutch Haemophilia Treatment Centers with a known RBD and who are age 1 to 99 years. Bleeding scores were determined, and laboratory and clinical data were extracted from patient files. In all, 263 patients were included, of whom 202 (77%) attended the scheduled study visit. The median International Society of Thrombosis and Haemostasis (ISTH) bleeding assessment tool (BAT) score was 9. Correlations between baseline factor activity levels and ISTH BAT scores were strong for deficiencies in factor II (FII) (r = –0.792) and FX (r = –0.838) and were moderate for deficiencies of fibrinogen (r = –0.683), FV (r = –0.623), FVII (r = –0.516), FXIII (r = –0.516), and α2-antiplasmin (r = –0.594). There was no correlation for FXI deficiency (r = –0.218). The RBD BAT identified more women (94% vs 83%) and children (100% vs 71%) with an RBD than the ISTH BAT did. Importantly, 48% of patients had more severe bleeding than predicted for their baseline factor activity level. In addition, 34% of patients were predicted to be asymptomatic, but they actually had grade 2 (31%) or 3 (3%) bleeding. Bleeding severity in patients with RBDs is more pronounced than previously anticipated. The previously determined threshold factor activity levels to ensure no (spontaneous) bleeding in patients with an RBD are inaccurate. This trial was registered at www.clinicaltrials.gov as #NCT03347591.

Background In recent years, more awareness is raised about sex-specific dilemmas in inherited bleeding disorders. However, no large studies have been performed to assess differences in diagnosis, bleeding phenotype and management of men and women with bleeding disorders. Therefore, we investigated sex differences in a large cohort of well-defined patients with autosomal inherited bleeding disorders (von Willebrand disease (VWD), rare bleeding disorders (RBDs) and congenital platelet defects (CPDs)). Methods We included patients from three nationwide cross-sectional studies on VWD, RBDs and CPDs in the Netherlands, respectively the WiN, RBiN and TiN study. In all studies a bleeding score (BS) was obtained, and patients filled in an extensive questionnaire on the management and burden of their disorder. Findings We included 1092 patients (834 VWD; 196 RBD; 62 CPD), of whom 665 (60.9%) were women. Women were more often referred because of a bleeding diathesis than men (47.9% vs 36.6%, p = 0.002). Age of first bleeding was similar between men and women, respectively 8.9 ± 13.6 (mean ±sd) years and 10.6 ± 11.3 years ( p = 0.075). However, the diagnostic delay, which was defined as time from first bleeding to diagnosis, was longer in women (11.6 ± 16.4 years) than men (7.7 ± 16.6 years, p = 0.002). Similar results were found when patients referred for bleeding were analyzed separately. Of women aging 12 years or older, 469 (77.1%) had received treatment because of sex-specific bleeding. Interpretation Women with autosomal inherited bleeding disorders are more often referred for bleeding, have a longer diagnostic delay, and often require treatment because of sex-specific bleeding. Funding The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda), and CSL Behring (unrestricted grant).

SummaryThe combination of interleukin (IL)-4 and IL-10 protects against bloodinduced cartilage damage in vitro. It has been hypothesized that the combination of these cytokines is effective if applied early in the process of cartilage damage. The present study investigated whether a single intra-articular injection of IL-4 plus IL-10 immediately after a joint bleed limits cartilage damage in an in vivo haemophilia mouse model of blood-induced joint damage. Factor VIII knockout mice with severe haemophilia A were punctured once with a needle below the patella to induce a joint haemorrhage. Subsequently IL-4 plus IL-10 (n = 24) or vehicle (n = 24) was injected intra-articularly. After 35 days, the time needed for development of detectable joint degeneration, knee joints were examined for cartilage damage by macroscopic and microscopic evaluation. A single intra-articular injection of IL-4 plus IL-10 ameliorated progression of cartilage degeneration caused by a single joint bleed to a certain extent. No effect on inflammation was observed at this time point. A single intra-articular injection of IL-4 plus Il-10 directly after a single joint bleed limits progression of cartilage degeneration over time. Improved bioavailability (half-life) of both cytokines might improve their protective ability in the development of cartilage degeneration, and probably also inflammation.

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Recurrent joint bleeding is the most common manifestation of severe haemophilia resulting in haemophilic arthropathy (HA). Iron plays a central role in the pathogenesis of the two main features of HA: synovitis and cartilage destruction. The aim of this study was to investigate the synovial presence of the iron regulator proteins ferroportin (FPN), hepcidin, haemoglobin scavenger receptor CD163 (CD163), feline leukaemia virus subgroup C (FLVCR), and heme carrier protein 1 (HCP-1). A comparison of the expression in HA with rheumatoid arthritis (RA), osteoarthritis (OA), and healthy controls (HC) is made. Synovial expression of iron regulators was investigated by immunohistochemistry in human synovial tissue and in a murine haemophilia model. We demonstrate for the first time the synovial presence of the investigated iron regulator proteins. Expression of the iron regulator proteins FPN, CD163, FLVCR, and HCP-1 was enhanced in HA in comparison to RA, OA, and HC synovium. In addition, in a murine haemophilia model of acute joint bleeding, synovial expression of FPN, CD163, and HCP-1 was increased. In both human and murine experiment, synovial expression of hepcidin was not altered. These findings indicate the presence of iron regulator proteins in the synovium, demonstrate an enhanced expression of FPN, CD163, FLVCR, and HCP-1 in HA, and suggest a synovial adaptation mechanism to maintain synovial iron homeostasis in HA.

Introduction We conducted six cross‐sectional nationwide questionnaire studies among all patients with hemophilia in the Netherlands from 1972 until 2019 to assess how health outcomes have changed, with a special focus on patients >50 years of age. Methods Data were collected on patient characteristics, treatment, (joint) bleeding, joint impairment, hospitalizations, human immunodeficiency virus and hepatitis C infections, and general health status (RAND‐36). Results In 2019, 1009 patients participated, of whom 48% had mild, 15% moderate, and 37% severe hemophilia. From 1972 to 2019, the use of prophylaxis among patients with severe hemophilia increased from 30% to 89%. Their median annual bleeding rate decreased from 25 to 2 bleeds. Patients with severe hemophilia aged <16 years reported joint impairment less often over time, but in those aged >40 years joint status did not improve. In 2019, 5% of all 1009 patients were positive for the human immunodeficiency virus. The proportion of patients with an active hepatitis C infection drastically decreased from 45% in 2001 to 2% in 2019 due to new anti‐hepatitis C treatment options. Twenty‐five percent had significant liver fibrosis even after successful therapy. Compared to the general male population, patients aged >50 years reported much lower scores on the RAND‐36, especially on physical functioning. Discussion/Conclusion Our study shows that increased use of prophylactic treatment and effective hepatitis C treatment have improved joint health and nearly eradicated hepatitis C infection in patients with hemophilia in the Netherlands. However, patients still suffer from hemophilia‐related complications, especially patients aged >50 years.