Comorbidities in childhood atopic dermatitis: A population-based study.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease that is associated with allergic comorbidities. However, studies examining comorbidities in childhood AD are incomplete, which may contribute to suboptimal care. OBJECTIVE: The objective was to compare the risk of developing different allergic and non-allergic comorbidities among children with AD to that of a matched non-AD reference cohort in Sweden. METHODS: This was a nationwide population-based cohort study using longitudinal data from primary and specialist care registers. Patients with AD were identified by confirmed diagnosis in primary or specialist care. The non-AD reference cohort was randomly drawn from the general population and matched 1:1 with the AD patients. The risk of developing the following conditions was evaluated: hypersensitivity and allergic disorders, neurological disorders, psychiatric disorders, infections, immunological and inflammatory disorders, Type 1 diabetes (T1D), endocrine and metabolic disorders, skeletal disorders, ocular disorders and malignancies. RESULTS: This study included 165,145 patients with AD (mild-to-moderate [n = 126,681] and severe [n = 38,464]) and an equally sized reference cohort. Patients with AD displayed a higher risk of developing comorbid conditions for all investigated categories, except for T1D and skeletal disorders, compared with the reference cohort. The highest risk compared with the reference cohort was observed for hypersensitivity and allergic disorders (hazard ratio [HR]: 3.87), followed by malignancies (HR: 2.53) and immunological and inflammatory disorders (HR: 2.36). Patients with AD also had higher risk of developing multiple comorbidities (≥2). The risk of comorbidity onset increased alongside AD severity and patients with active AD were associated with increased risk of comorbidity onset compared with patients in remission. CONCLUSIONS: The clinical burden of AD is substantial for children with AD and patients are at an increased risk of developing several comorbid conditions extending beyond the atopic march. Our results also showed a positive association between worsening severity of AD and an increased risk of comorbidity onset.

Economic burden of osteoarthritis - multi-country estimates of direct and indirect costs from the BISCUITS study.

Data from 'BISCUITS', a large Nordic cohort study linking several registries, were used to estimate differences in average direct and indirect costs between patients with osteoarthritis and controls (matched 1:1 based on birth year and sex) from the general population in Sweden, Norway, Finland and Denmark for 2017. Patients ≥18 years with ≥1 diagnosis of osteoarthritis (ICD-10: M15-M19) recorded in specialty or primary care (the latter available for a subset of patients in Sweden and for all patients in Finland) during 2011-2017 were included. Patients with a cancer diagnosis (ICD-10: C00-C43/C45-C97) were excluded. Productivity loss (sick leave and disability pension) and associated indirect costs were estimated among working-age adults (18-66 years). In 2017, average annual incremental direct costs among adults with osteoarthritis (n=1,157,236) in specialty care relative to controls ranged between €1,259 and €1,693 (p<0.001) per patient across all countries. Total average annual incremental costs were €3,224-€4,969 (p<0.001) per patient. Healthcare cost differences were mainly explained by osteoarthritis patients having more surgeries. However, among patients with both primary and secondary care data, primary care costs exceeded the costs of surgery. Primary care constituted 41 and 29 % of the difference in direct costs in Sweden and Finland, respectively. From a societal perspective, the total economic burden of osteoarthritis is substantial, and the incremental cost was estimated to €1.1-€1.3 billion yearly for patients in specialty care across the Nordic countries. When including patients in primary care, incremental costs rose to €3 billion in Sweden and €1.8 billion in Finland. Given the large economic impact, finding cost-effective and safe therapeutic strategies for these patients will be important.

Healthcare cost and survival in patients with non-functioning pituitary adenoma.

OBJECTIVE: Pituitary adenomas and their consequences impact mortality and morbidity. We studied the healthcare costs, survival, and cost-effectiveness of growth hormone (GH) vs no GH replacement in patients with non-functioning pituitary adenoma (NFPA). DESIGN AND METHODS: A cohort study including all NFPA patients followed from 1987 or the date of diagnosis until the time of death or December 31, 2019, in the Västra Götaland region, Sweden. Data to assess resource use, costs, survival, and cost-effectiveness were collected from patient records and regional/national healthcare registries. RESULTS: A total of 426 patients with NFPA (274 men) with a follow-up of 13.6 ± 6.8 years (mean ± SD) were included. The total annual healthcare cost was higher in patients receiving GH (€9287) than those without GH (€6770), mainly driven by a higher pharmaceutical cost. Glucocorticoid replacement therapy (P = .02), diabetes insipidus (P = .04), body mass index (BMI) (P < .01), and hypertension (P < .01) were all individually associated with a higher total annual cost. The survival rate was higher in the GH group (HR [hazard ratio] 0.60; P = .01) and reduced in patients with glucocorticoid replacement (HR 2.02; P < .01) or diabetes insipidus (HR 1.67; P = .04). The cost per gained life-year for GH vs no GH replacement was about €37 000. CONCLUSIONS: This healthcare utilization study identified several factors driving the cost of care in NFPA patients, such as GH replacement, adrenal insufficiency, and diabetes insipidus. Life expectancy was increased in those with GH replacement and reduced in patients with adrenal insufficiency and diabetes insipidus.

Factors influencing quality of life in patients with osteoarthritis: analyses from the BISCUITS study.

OBJECTIVES: Osteoarthritis can have a profound effect on patients' quality of life. The Burden of Disease and Management of Osteoarthritis and Chronic Low Back Pain: Health Care Utilization and Sick Leave in Sweden, Norway, Finland and Denmark (BISCUITS) study aimed to describe the impact of osteoarthritis on quality of life and determine the association with factors such as pain severity and pharmacological treatment. METHODS: An observational study was performed with a cross-sectional design including patients with a confirmed osteoarthritis diagnosis enrolled in the National Quality Register for Better management of patients with Osteoarthritis (BOA) between 2016 and 2017 in Sweden. Patient-reported information from BOA was linked to administrative data from three national health registers. The impact of osteoarthritis on quality of life was estimated using the EQ-5D-5L and the first developed experienced-based time-trade-off value set for Sweden to calculate the EQ-5D-5L index scores. EQ-5D-3L index scores were also estimated based on a UK hypothetical value set via a crosswalk method. Ordinary least squares regression models were used to analyse the association between quality of life and potential influencing factors. RESULTS: For the 34,254 patients evaluated, mean EQ-5D-5L index score was 0.792 (SD 0.126). Stratifications showed that the index score varied across different levels of pain severity. Increased pain severity and use of pain-relieving medications remained significantly associated with a lower quality of life index score when controlled for potential confounders. The mean EQ-5D-3L index score was 0.605 (SD 0.192). CONCLUSIONS: This large population-based study from Sweden highlights the substantial impact of osteoarthritis on quality of life amongst different patient groups and that currently available treatment options for osteoarthritis pain do not appropriately address the needs for many osteoarthritis patients.

Validation of Patient Identification Algorithms for Atopic Dermatitis Using Healthcare Databases.

INTRODUCTION: The use of real-world data offers a possibility to perform large-scale epidemiological studies in actual clinical settings. Despite their many advantages, administrative databases were not designed to be used in research, and the validation of diagnoses and treatments in administrative databases is needed. The primary objective of this study was to validate an existing algorithm based on dispensed prescriptions and diagnoses of skin conditions to identify pediatric patients with atopic dermatitis (AD), using a diagnosis of AD in primary care as a gold standard. METHODS: Retrospective observational data were collected from nation-wide secondary care and pharmacy-dispensed medication databases and two regional primary care databases in Sweden. An existing algorithm and a Modified algorithm, using skin-specific diagnoses from secondary care and/or pharmacy-dispensed prescriptions to identify patients with AD, were assessed. To verify the presence of AD, diagnoses from primary care were used in the base case and complemented with diagnoses from secondary care in a sensitivity analysis. RESULTS: The sensitivity (30.0%) and positive predictive value (PPV) (40.7%) of the existing algorithm were low in the pediatric patient population when using primary care data only but increased when secondary care visits were also included in the Modified algorithm (sensitivity, 62.1%; PPV, 66.3%). The specificity of the two algorithms was high in both the base case and sensitivity analysis (95.1% and 94.1%). In the adult population, sensitivity and PPV were 20.4% and 8.7%, respectively, and increased to 48.3% and 16.9% when secondary care visits were also included in the Modified algorithm. CONCLUSION: The Modified algorithm can be used to identify pediatric AD populations using primary and secondary administrative data with acceptable sensitivity and specificity, but further modifications are needed to accurately identify adult patients with AD.

Cost-effectiveness of apixaban versus warfarin and aspirin in Sweden for stroke prevention in patients with atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF), one of the major risk factors for stroke, imposing a substantial burden to the Swedish health care system. Apixaban has demonstrated superiority to warfarin and aspirin in stroke prevention amongst patients with AF in two large randomised clinical trials. The aim of this study was to assess the economic implications of apixaban against warfarin and aspirin in these patients from a Swedish societal perspective. MATERIALS AND METHODS: A Markov cohort model was constructed to characterise the consequences of anticoagulant treatment with regards to thromboembolic and bleeding events, as well as the associated health care costs, life-years and quality-adjusted life years (QALYs) for patients with AF treated with apixaban, warfarin or aspirin. Incremental cost-effectiveness ratios (ICERs) per QALY gained of apixaban relative to warfarin (among patients suitable for warfarin treatment) and aspirin (among patients unsuitable for warfarin treatment) were calculated. Costs (in 2011 SEKs) and QALYs were discounted at 3% per annum. RESULTS: The model estimated the ICER of apixaban versus warfarin amongst patients who are suitable for warfarin therapy to be SEK 33,458/QALY gained and that of apixaban versus aspirin amongst those unsuitable for warfarin therapy to be SEK 41,453/QALY gained. Probabilistic sensitivity analyses indicate that apixaban is an optimal treatment option compared with warfarin and aspirin, when the willingness-to-pay is above SEK 35,000 and SEK 45,000 per QALY, respectively. CONCLUSIONS: Apixaban was found to be a cost-effective alternative to warfarin and aspirin for stroke prevention in patients with AF in Sweden.

The microenvironment of human neuroblastoma supports the activation of tumor-associated T lymphocytes.

Tumor infiltration by lymphocytes has been linked to improved clinical outcome in children with neuroblastoma (NB) but T-cell activation has never been demonstrated to occur within the NB microenvironment. Here we show that tumor-associated lymphocytes (TALs) obtained from lesions representing all genetic subsets of NB and autologous peripheral blood lymphocytes (PBLs) analyzed on the day of tumor excision differed in composition, phenotype and functional characteristics. The NB microenvironment appeared to promote the accumulation of CD3+CD8+ T cells and contained a larger proportion of T cells expressing the interleukin-2 receptor α chain (CD25) and manifesting an effector memory (CCR7-CD45RA-) phenotype. Accordingly, the stimulation of PBLs with autologous tumor cells in short-term cultures increased the proportion of effector memory T cells, upregulated CD25, stimulated the expression of the TH1 cytokines interferon γ and tumor necrosis factor α, and reduced the expression of transforming growth factor ß. In situ proliferation as well as a characteristic pattern of T-cell receptor aggregation at the contact sites with malignant cells was revealed by the immunohistochemical staining of TALs in primary tumors, indicating that the NB milieu is compatible with the activation of the immune system. Our results are compatible with the hypothesis that CD8+ T cells are specifically activated within the NB microenvironment, which appears to be permissive for effector memory responses.

A cross-country review of data collected on non-small cell lung cancer (NSCLC) patients in cancer registries, databases, retrospective and non-randomized prospective studies.

INTRODUCTION: An increased number of pharmacotherapies exist to treat advanced NSCLC. This necessitates a review of the available information on routine-care treatment patterns, the outcome of treatment, and resource utilization for patients diagnosed and treated with advanced NSCLC that could inform evidence-based treatment decisions and aid decisions on the most cost-effective treatment alternatives. METHODS: PubMed and the Health Economic Evaluations Database were searched for retrospective or non-randomized prospective studies between January 2000 and May 2012 that included information on treatment patterns, treatment outcomes including health-related quality-of-life (HRQoL), and resource utilization. In addition, registries and databases were identified from retrieved publications and internet searches. Data collected in registries and databases was summarized for eight European countries (Belgium, France, Germany, Italy, Sweden, Turkey, the Netherlands, the UK), Australia, and Canada. RESULTS: The literature search resulted in 410 studies, whereof 87 studies met the study inclusion criteria. In total, 49 were retrospective chart reviews or database analyses, 30 non-randomized prospective studies, and eight HRQoL studies. Two studies compared treatment patterns and/or treatment outcomes across countries. Altogether, 181 cancer registries in the countries studied were identified. Clinical cancer-specific patient registries were identified in Australia and Germany. Databases or linkage systems that enable retrieval of complete information of patient disease history were found in Australia, Canada, the Netherlands, Sweden, and the UK. Cancer registries and databases were found to collect information on NSCLC patient demographics, NSCLC or lung cancer diagnosis, disease stage, performance status, treatment, treatment outcomes, and resource use. Differences existed between country registries and databases in whether information was collected on each of these data points. CONCLUSION: The literature review revealed few published NSCLC studies on treatment, treatment outcomes, and resource use in routine clinical practice and on HRQoL. Registries and databases were found to collect some of this information, however not systematically.

Modulation of the tumor cell phenotype by IFN-gamma results in resistance of uveal melanoma cells to granule-mediated lysis by cytotoxic lymphocytes.

IFN-gamma, a pleiotropic immune regulator, is implicated in both tumor immune surveillance and selection of tumor variants resistant to immune control, i.e., immunoediting. In uveal melanoma patients, elevated serum levels of IFN-gamma correlate with the spread of metastasis and represent a negative prognostic marker. Treatment with IFN-gamma boosted the MHC class I presentation machinery in uveal melanoma cells but suppressed their MHC class I-restricted CTL lysis. Tumor cells exposed to IFN-gamma efficiently activated specific CTL but were less susceptible to permeabilization by perforin and exhibited a decreased capacity to bind and incorporate granzyme B. These results define a novel mechanism of resistance to granule-mediated CTL lysis in human tumors. Furthermore, the data suggest that immunoediting is not limited to genetic or epigenetic changes resulting in stable cellular phenotypes but also involves an inducible modulation of tumor cells in response to a microenvironment associated with immune activation.

Differentiation induced by physiological and pharmacological stimuli leads to increased antigenicity of human neuroblastoma cells.

Sympathetic neuronal differentiation is associated with favorable prognosis of neuroblastoma (NB), the most common extra-cranial solid tumor of early childhood. Differentiation agents have proved useful in clinical protocols of NB treatment, but using them as a sole treatment is not sufficient to induce tumor elimination in patients. Therefore, complementary approaches, such as immunotherapy, are warranted. Here we demonstrate that differentiation of NB cell lines and ex vivo isolated tumor cells in response to physiological or pharmacological stimuli is associated with acquisition of increased antigenicity. This manifests as increased expression of surface major histocompatibility class I complexes and ICAM-1 molecules and translates into increased sensitivity of NB cells to lysis by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. The latter is paralleled by enhanced ability of differentiated cells to form immune conjugates and bind increased amounts of granzyme B to the cell surface. We demonstrate, for the first time, that, regardless of the stimulus applied, the differentiation state in NBs is associated with increased tumor antigenicity that enables more efficient elimination of tumor cells by cytotoxic lymphocytes and paves the way for combined application of differentiation-inducing agents and immunotherapy as an auxiliary approach in NB patients.

Soluble factors released by activated cytotoxic T lymphocytes interfere with death receptor pathways in neuroblastoma.

Neuroblastoma (NB) is often described as an unfavorable target for both HLA-restricted and death receptor-mediated elimination by cytotoxic T lymphocytes (CTLs) due to low or absent HLA class I and caspase-8 expression. We investigated the effects of soluble factors released by CTLs activated by TCR triggering (named as activated supernatant; AS) on the levels and composition of cell surface molecules involved in HLA-restricted and HLA-independent NB cell recognition (surface immune phenotype). Using a panel of long-term propagated NB cell lines and freshly isolated primary human NB cells, we analyzed surface expression of the (1) cognate receptors for TNFalpha, Fas and TRAIL; (2) HLA class I and II heterodimers; (3) adhesion molecules; (4) the intracellular expression and activation of caspase-8, as well as (5) the susceptibility of NB cells to death receptor-mediated killing prior to and after exposure to AS. The exposure of NB cells to soluble factors released by activated CTLs skewed the surface immune phenotype of both long term cultured and primary NB cells, induced the expression and activation of caspase-8 and increased the susceptibility of tumor cells to lysis by TRAIL and Fas-agonistic antibody. Blocking experiments identified IFNgamma and TNFalpha as main factors responsible for modulating the surface antigens of NB cells by AS. Our data suggest that recruitment of CTLs activated on third party targets into the vicinity of the NB tumor mass, may override the "silent" immune phenotype of NB cells via the action of soluble factors.

Cytotoxic T lymphocytes induce caspase-dependent and -independent cell death in neuroblastomas in a MHC-nonrestricted fashion.

The MHC class I- restricted processing and presentation pathway is frequently nonfunctional in tumor cells; therefore, the direct targeting of tumor cells by CTLs may be difficult, if at all possible, to achieve. We used neuroblastoma (NB), which represents a striking example of a tumor with an impaired MHC class I pathway, as a model to study bystander effects of activated T lymphocytes on tumor cells. We found that NB cell lines are susceptible to killing by differentiated CD8(+) CTL clones in a MHC class I-nonrestricted manner that involves two programs of cell death distinguished on the basis of different kinetics, sensitivities to caspase inhibitors, and cytokine-blocking reagents. The "early" death exhibited characteristic features of apoptosis, whereas the "delayed" caspase-independent death exhibited features associated with necrosis and was partially inhibited by TNF-alpha-blocking and prevented by overexpression of Bcl-2 or Bcl-x(L). Our data reveal a previously unappreciated complexity of death pathways induced in tumor cells by immune activation and suggest that redirecting nonspecific effector CTLs to even a small proportion of NB cells or activating CTLs in a tumor's proximity may have therapeutic effects in patients with NB.

Autocrine secretion of Fas ligand shields tumor cells from Fas-mediated killing by cytotoxic lymphocytes.

Mechanisms responsible for resistance of tumors to death receptor-mediated damage by cytotoxic lymphocytes are not well understood. Uveal melanoma cells expressed Fas but were insensitive to Fas triggering induced by bystander cytotoxic T lymphocytes or a Fas-specific agonistic antibody; this could not be ascribed to tumor counterattack against T cells or general resistance of the tumors to apoptosis. Treatment with inhibitors of metalloproteases rendered uveal melanomas sensitive to Fas-mediated cytotoxicity. Metalloprotease inhibitors did not affect the expression of Fas but increased the surface expression of Fas ligand (FasL), which correlated with the disappearance of soluble FasL from culture supernatants of tumor cells. FasL eluted from the surface of uveal melanomas specifically inhibited cytotoxic T lymphocyte lysis of tumor cells pretreated with an inhibitor of metalloproteases. In addition to uveal melanomas, a number of other tumor cell lines of various cellular origins were sensitized to Fas-mediated cytotoxicity by metalloprotease inhibitors. Our results show that autocrine secretion of FasL shields tumor cells from Fas-mediated killing by cytotoxic lymphocytes. This defines a novel mechanism of tumor escape from immune surveillance.

Retinoids act as multistep modulators of the major histocompatibility class I presentation pathway and sensitize neuroblastomas to cytotoxic lymphocytes.

The current therapeutic modalities achieve low response rates in human neuroblastoma, a frequent extracranial malignancy of the early childhood. We have assessed the effect of retinoids, used presently for the treatment of neuroblastoma, on the discrete steps of the MHC class I processing machinery and susceptibility of neuroblastoma cells to CTL-mediated killing. We demonstrate that retinoic acid derivatives induce the expression of proteolytic and regulatory subunits of the immunoproteasome, increase the half-life of MHC class I complexes, and enhance the sensitivity of neuroblastoma cells to both MHC class I-restricted peptide-specific and HLA nonrestricted lysis by CTLs. Importantly, effects of retinoids on the MHC class I pathway appear to be independent of IFN-gamma and/or TNF-alpha as intermediate messengers. To our knowledge, this is the first demonstration of inflammation-unrelated biological molecules that induce systemic modulation of antigen presentation in nonprofessional antigen presenting cells. Our findings suggest that the application of retinoids and T cell-based immunotherapy may be an effective combination for the treatment of neuroblastoma.