Neurological phenotype of adenosine deaminase 2 deficient patients: a cohort study.

BACKGROUND AND PURPOSE: Patients with adenosine deaminase 2 (ADA2) deficiency can present with various neurological manifestations due to vasculopathies and autoinflammation. These include ischaemic and hemorrhagic stroke, but less clearly defined neurological symptoms have also been reported. METHODS: In this cohort study, patients with confirmed ADA2 deficiency from seven university hospitals in the Netherlands were included. The frequency and recurrence rates of neurological manifestations before and after initiation of tumor necrosis factor α (TNF-α) inhibiting therapy were analyzed. RESULTS: Twenty-nine patients were included with a median age at presentation of 5 years (interquartile range 1-17). Neurological manifestations occurred in 19/29 (66%) patients and were the presenting symptom in 9/29 (31%) patients. Transient ischaemic attack (TIA)/ischaemic stroke occurred in 12/29 (41%) patients and was the presenting symptom in 8/29 (28%) patients. In total, 25 TIAs/ischaemic strokes occurred in 12 patients, one after initiation of TNF-α inhibiting therapy and one whilst switching between TNF-α inhibitors. None was large-vessel occlusion stroke. Two hemorrhagic strokes occurred: one aneurysmatic subarachnoid hemorrhage and one spontaneous intracerebral hemorrhage. Most neurological symptoms, including cranial nerve deficits, vertigo, ataxia and seizures, were caused by TIAs/ischaemic strokes and seldom recurred after initiation of TNF-α inhibiting therapy. CONCLUSIONS: Neurological manifestations, especially TIA/ischaemic stroke, are common in patients with ADA2 deficiency and frequently are the presenting symptom. Because it is a treatable cause of young stroke, for which antiplatelet and anticoagulant therapy are considered contraindicated, awareness amongst neurologists and pediatricians is important. Screening for ADA2 deficiency in young patients with small-vessel ischaemic stroke without an identified cause should be considered.

Clinical Symptoms, Laboratory Parameters and Long-Term Follow-up in a National DADA2 Cohort.

Deficiency of adenosine deaminase-2 (DADA2) is an autosomal recessive autoinflammatory disease with an extremely variable disease presentation. This paper provides a comprehensive overview of the Dutch DADA2 cohort. We performed a retrospective cohort study in 29 ADA2-deficient patients from 23 families with a median age at inclusion of 26 years. All patients had biallelic pathogenic variants in the ADA2 gene. The most common clinical findings included cutaneous involvement (79.3%), (hepato)splenomegaly (70.8%) and recurrent infections (58.6%). Stroke was observed in 41.4% of the patients. The main laboratory abnormalities were hypogammaglobulinemia and various cytopenias. Patients presented most often with a mixed phenotype involving vasculopathy, immunodeficiency and hematologic manifestations (62.1%). In this cohort, malignancies were reported in eight patients (27.6%), of whom five presented with a hematologic malignancy and two with a basal cell carcinoma. Four patients developed hemophagocytic lymphohistiocytosis (HLH) or an HLH-like episode, of whom three passed away during or shortly after the occurrence of HLH. TNF-inhibitors (TNFi) were effective in treating vasculopathy-associated symptoms and preventing stroke, but were hardly effective in the treatment of hematologic manifestations. Three patients underwent hematopoietic cell transplantation and two of them are doing well with complete resolution of DADA2-related symptoms. The overall mortality in this cohort was 17.2%. In conclusion, this cohort describes the clinical, genetic and laboratory findings of 29 Dutch DADA2 patients. We describe the occurrence of HLH as a life-threatening disease complication and report a relatively high incidence of malignancies and mortality.

Clinical Practice Audit on the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in the Netherlands.

INTRODUCTION: Managing complex and rare systemic autoimmune diseases such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) can be challenging and is often accompanied by undesirable variations in clinical practice. Adequate understanding of clinical practice can help identify essential issues to improve the care for AAV patients. Therefore, we studied the real-life management and outcomes of AAV patients in the Netherlands. METHODS: In this cohort study, we investigated clinical practice in university and nonuniversity teaching hospitals with respect to patients with a clinical diagnosis of AAV. We retrospectively collected clinical data encompassing clinical variables, medication details, and outcome parameters. RESULTS: Data of 230 AAV patients were collected in 9 Dutch hospitals. Of these, 167 patients (73%) were diagnosed with granulomatosis with polyangiitis, 54 (24%) with microscopic polyangiitis and 9 (4%) with eosinophilic granulomatosis with polyangiitis. One hundred sixty-six patients (72%) had generalized disease. The median year of diagnosis was 2013 (range 1987-2018). Besides steroids, oral cyclophosphamide was the most used drug (50%) for induction therapy and azathioprine (68%) for maintenance therapy. Adverse outcomes were major infections in 35%, major relapses in 23%, malignancy in 10%, major cardiovascular events in 8%, and end-stage renal disease in 7%. CONCLUSION: Oral cyclophosphamide was the most frequently used induction therapy, azathioprine for maintenance therapy; over time, the use of rituximab is increasingly employed. Major infection and relapses are the most prevalent adverse outcomes. This audit resulted in important indicators for treatment of AAV patients that can be implemented for future, national audits to improve the outcomes of AAV patients.

Systemic autoimmune disease as a cause of death: mortality burden and comorbidities.

OBJECTIVES: Systemic autoimmune diseases (SAIDs) have chronic trajectories and share characteristics of self-directed inflammation, as well as aspects of clinical expression. Nonetheless, burden-of-disease studies rarely investigate them as a distinct category. This study aims to assess the mortality rate of SAIDs as a group and to evaluate co-occurring causes of death. METHODS: We used death certificate data in the Netherlands, 2013-2017 (N = 711 247), and constructed a SAIDs list at the fourth-position ICD-10 level. The mortality rate of SAIDs as underlying cause of death (CoD), non-underlying CoD, and any-mention CoD was calculated. We estimated age-sex-standardized observed/expected (O/E) ratios to assess comorbidities in deaths with SAID relative to the general deceased population. RESULTS: We observed 3335 deaths with SAID on their death certificate (0.47% of all deaths). The mortality rate of SAID was 14.6 per million population as underlying CoD, 28.0 as non-underlying CoD, and 39.7 as any-mention CoD. The mortality rate was higher for females and increased exponentially with age. SAID-related deaths were positively associated with all comorbidities except for solid neoplasms and mental conditions. Particularly strong was the association with diseases of the musculoskeletal system (O/E = 3.38; 95% CI: 2.98, 3.82), other diseases of the genitourinary system (O/E = 2.73; 95% CI: 2.18, 3.38), influenza (O/E = 2.71; 95% CI: 1.74, 4.03), blood diseases (O/E = 2.02; 95% CI: 1.70, 2.39), skin and subcutaneous tissue diseases (O/E = 1.95; 95% CI: 1.54, 2.45), and infectious diseases (O/E = 1.85; 95% CI: 1.70, 2.01). CONCLUSION: Systemic autoimmune diseases constitute a rare group of causes of death, but contribute to mortality through multiple comorbidities. Classification systems could be adapted to better encompass these diseases as a category.

Lifestyle and gout.

PURPOSE OF REVIEW: This review summarizes recent epidemiologic research findings on gout, and attempts to put them into the context of clinical and public health decision-making aimed at prevention and improved management of gout. RECENT FINDINGS: A large prospective study found that coffee consumption was inversely associated with risk of gout and that consumption of sugar-sweetened soft drinks or fructose was strongly associated with an increased gout risk. Studies based on the Third National Health and Nutrition Examination Survey (NHANES III) suggest that these consumptions affect serum uric acid levels parallel to the direction of gout risk. Furthermore, data from NHANES III show a remarkably high prevalence of the metabolic syndrome among individuals with gout. Prospective studies found an increased risk of myocardial infarction and cardiovascular mortality in gout patients. SUMMARY: Lifestyle and dietary recommendations for gout patients should consider other health benefits, since gout is often associated with major chronic disorders such as the metabolic syndrome and an increased risk for cardiovascular disease and mortality. In addition to recent dietary recommendations, gout patients should be advised to limit fructose intake. The inverse link between coffee and the risk of gout suggests that coffee could be allowed among gout patients.

High-dose testosterone is associated with atherosclerosis in postmenopausal women.

OBJECTIVES: To study the long-term effects of androgen treatment on atherosclerosis in postmenopausal women. METHODS: In a population-based study in 513 naturally postmenopausal women aged 54-67 years, we studied the association between self-reported intramuscularly administered high-dose estrogen-testosterone therapy (estradiol- and testosterone esters) and aortic atherosclerosis. Aortic atherosclerosis was diagnosed by radiographic detection of calcified deposits in the abdominal aorta, which have been shown to reflect intima atherosclerosis. Hormone therapy users were compared with never users. RESULTS: Intramuscular hormone therapy use for 1 year or longer was reported by 25 women. In almost half of these women severe atherosclerosis of the aorta was present (n=11), while in women without hormone use severe atherosclerosis of the aorta was present in less than 20% (OR 3.1; 95% CI, 1.1-8.5, adjusted for age, years since menopause, smoking, and body mass index). The association remained after additional adjustment for diabetes, cholesterol level, systolic blood pressure, or alcohol use. No association was found for hormone use less than 1 year. CONCLUSION: Our results suggest that high-dose testosterone therapy may adversely affect atherosclerosis in postmenopausal women and indicate that androgen replacement in these women may not be harmless.

Prospective study of plasma carotenoids and tocopherols in relation to risk of ischemic stroke.

BACKGROUND AND PURPOSE: Intake of fruits and vegetables has been related to lower risk of ischemic stroke, but nutrients responsible for this apparent benefit remain ill-defined. Tocopherols (vitamin E) have also been proposed to be protective. METHODS: We conducted a prospective, nested case-control analysis among male physicians without diagnosed cardiovascular disease followed-up for up to 13 years in the Physicians' Health Study. Samples from 297 physicians with ischemic stroke were analyzed with paired controls, matched for age and smoking, for 5 major carotenoids (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene), retinol, and alpha- and gamma-tocopherol. RESULTS: Baseline plasma levels of alpha-carotene and beta-carotene and lycopene tended to be inversely related to risk of ischemic stroke with an apparent threshold effect. As compared with men whose plasma levels were in the lowest quintile, the multivariate adjusted odds ratios (ORs) of ischemic stroke among men with levels in the second through fifth quintiles were 0.59 (95% CI, 0.36 to 0.98) for alpha-carotene, 0.62 (95% CI, 0.38 to 1.01) for beta-carotene, and 0.61 (95% CI, 0.37 to 1.00) for lycopene. A tendency toward an inverse association was found for beta-cryptoxanthin, but the result was not statistically significant. No association was found for lutein, retinol, and tocopherols. CONCLUSIONS: Our data suggest that higher plasma levels of carotenoids, as markers of fruit and vegetable intake, are inversely related to risk of ischemic stroke and provide support for recommendations to consume fruits and vegetables regularly.

Plasma carotenoids and tocopherols and risk of myocardial infarction in a low-risk population of US male physicians.

BACKGROUND: Increased intake of carotenoids and vitamin E may protect against myocardial infarction (MI). However, prospective data on blood levels of carotenoids other than beta-carotene and vitamin E (tocopherol) and risk of MI are sparse. METHODS AND RESULTS: We conducted a prospective, nested case-control analysis among male physicians without prior history of cardiovascular disease who were followed for up to 13 years in the Physicians' Health Study. Samples from 531 physicians diagnosed with MI were analyzed together with samples from paired control subjects, matched for age and smoking, for 5 major carotenoids (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene), retinol, and alpha- and gamma-tocopherol. Overall, we found no evidence for a protective effect against MI for higher baseline plasma levels of retinol or any of the carotenoids measured. Among current and former smokers but not among never-smokers, higher baseline plasma levels of beta-carotene tended to be associated with lower risk (P for interaction=0.02). Men with higher plasma levels of gamma-tocopherol tended to have an increased risk of MI (P for trend=0.01). CONCLUSIONS: These prospective data do not support an overall protective relation between plasma carotenoids or tocopherols and future MI risk among men without a history of prior cardiovascular disease.

Risk factors for progression of atherosclerosis measured at multiple sites in the arterial tree: the Rotterdam Study.

BACKGROUND AND PURPOSE: Studies investigating determinants of atherosclerotic disease progression are relatively rare. Moreover, although atherosclerotic disease can be assessed noninvasively in different vascular beds, previous studies have not considered progression of atherosclerosis at >1 site. The present study was designed to identify risk factors for progression of atherosclerosis measured at multiple sites in the arterial tree. METHODS: The Rotterdam Study is a population-based cohort study of 7983 men and women > or =55 years of age. Carotid plaques and intima-media thickness were assessed by ultrasound, aortic atherosclerosis by x-ray, and lower-extremity atherosclerosis by the ankle-arm index. Data on progression of atherosclerosis over an average period of 6.5 years were available for 3409 participants. Associations of established cardiovascular risk factors with mild, moderate, and severe progression of atherosclerosis were investigated through multinomial regression analysis. RESULTS: Age, smoking, total cholesterol, and systolic blood pressure and/or hypertension were strong, independent predictors of moderate and severe progression of atherosclerosis at multiple sites. Diabetes mellitus predicted only severe progression of atherosclerosis. Associations of sex with progression of atherosclerosis were remarkably modest. CONCLUSIONS: Age, smoking, total cholesterol, and systolic blood pressure and/or hypertension strongly predict progression of extracoronary atherosclerosis in the elderly, but sex remarkably does not. These results emphasize the need for prevention of progression of extracoronary atherosclerotic disease in men and women alike.

C-reactive protein predicts progression of atherosclerosis measured at various sites in the arterial tree: the Rotterdam Study.

UNLABELLED: Background and Purpose- C-reactive protein (CRP) predicts myocardial infarction and stroke. Its role as a predictor of the progression of subclinical atherosclerosis is not yet known. We investigated whether CRP predicts progression of atherosclerosis measured at various sites in the arterial tree. METHODS: CRP levels were measured in a random sample of 773 subjects >/=55 years of age who were participating in the Rotterdam Study. Subclinical atherosclerosis was assessed at various sites at 2 points in time, with a mean duration between measurements of 6.5 years. RESULTS: After adjustment for age, sex, and smoking habits, odds ratios (ORs) associated with CRP levels in the highest compared with the lowest quartile were increased for progression of carotid (OR, 1.9; 95% CI, 1.1 to 3.3), aortic (OR, 1.7; 95% CI, 1.0 to 3.0), iliac (OR, 2.0; 95% CI, 1.2 to 3.3), and lower extremity (OR, 1.9; 95% CI, 1.0 to 3.7) atherosclerosis. The OR for generalized progression of atherosclerosis as indicated by a composite progression score was 4.5 (95% CI, 2.3 to 8.5). Except for aortic atherosclerosis, these estimates hardly changed after additional adjustment for multiple cardiovascular risk factors. In addition, ORs for progression of atherosclerosis associated with high CRP levels were as high as those associated with the traditional cardiovascular risk factors high cholesterol, hypertension, and smoking. Geometric mean levels of CRP increased with the total number of sites showing progression of atherosclerosis (P=0.002 for trend). CONCLUSIONS: CRP predicts progression of atherosclerosis measured at various sites in the arterial tree.

The association between coronary calcification assessed by electron beam computed tomography and measures of extracoronary atherosclerosis: the Rotterdam Coronary Calcification Study.

OBJECTIVES: The present study was designed to examine the associations of coronary calcification assessed by electron beam computed tomography (CT) with measures of extracoronary atherosclerosis. BACKGROUND: Although measures of extracoronary atherosclerosis have been used to predict coronary events, it is not yet known to what extent those measures reflect coronary atherosclerosis. METHODS: The Rotterdam Coronary Calcification Study is a population-based study in subjects age 55 years and over. Participants of the study underwent an electron beam CT scan. Coronary calcification was quantified according to the Agatston calcium score. Measures of extracoronary atherosclerosis included common carotid intima media thickness (IMT), carotid plaques, ankle-arm index (AAI) and aortic calcification. We used the first 2,013 participants for the present analyses. Age-adjusted geometric mean calcium scores were computed for categories of extracoronary measures using analyses of variance. RESULTS: Graded associations with coronary calcification were found for the carotid and aortic measures. Associations were strongest for carotid plaques and aortic calcification; coronary calcification increased from the lowest category (no plaques) to the highest category 9-fold and 11-fold in men and 10-fold and 20-fold in women, respectively. A nonlinear association was found for AAI with an increase in coronary calcification only at lower levels of AAI. CONCLUSIONS: In this population-based study, graded associations were found between coronary calcification and common carotid IMT, carotid plaques and aortic calcification. A nonlinear association was found between coronary calcification and the AAI.