A Clinical Workflow for Cost-Saving High-Rate Diagnosis of Genetic Kidney Diseases.

SIGNIFICANCE STATEMENT: To optimize the diagnosis of genetic kidney disorders in a cost-effective manner, we developed a workflow based on referral criteria for in-person evaluation at a tertiary center, whole-exome sequencing, reverse phenotyping, and multidisciplinary board analysis. This workflow reached a diagnostic rate of 67%, with 48% confirming and 19% modifying the suspected clinical diagnosis. We obtained a genetic diagnosis in 64% of children and 70% of adults. A modeled cost analysis demonstrated that early genetic testing saves 20% of costs per patient. Real cost analysis on a representative sample of 66 patients demonstrated an actual cost reduction of 41%. This workflow demonstrates feasibility, performance, and economic effect for the diagnosis of genetic kidney diseases in a real-world setting. BACKGROUND: Whole-exome sequencing (WES) increases the diagnostic rate of genetic kidney disorders, but accessibility, interpretation of results, and costs limit use in daily practice. METHODS: Univariable analysis of a historical cohort of 392 patients who underwent WES for kidney diseases showed that resistance to treatments, familial history of kidney disease, extrarenal involvement, congenital abnormalities of the kidney and urinary tract and CKD stage ≥G2, two or more cysts per kidney on ultrasound, persistent hyperechoic kidneys or nephrocalcinosis on ultrasound, and persistent metabolic abnormalities were most predictive for genetic diagnosis. We prospectively applied these criteria to select patients in a network of nephrology centers, followed by centralized genetic diagnosis by WES, reverse phenotyping, and multidisciplinary board discussion. RESULTS: We applied this multistep workflow to 476 patients with eight clinical categories (podocytopathies, collagenopathies, CKD of unknown origin, tubulopathies, ciliopathies, congenital anomalies of the kidney and urinary tract, syndromic CKD, metabolic kidney disorders), obtaining genetic diagnosis for 319 of 476 patients (67.0%) (95% in 21 patients with disease onset during the fetal period or at birth, 64% in 298 pediatric patients, and 70% in 156 adult patients). The suspected clinical diagnosis was confirmed in 48% of the 476 patients and modified in 19%. A modeled cost analysis showed that application of this workflow saved 20% of costs per patient when performed at the beginning of the diagnostic process. Real cost analysis of 66 patients randomly selected from all categories showed actual cost reduction of 41%. CONCLUSIONS: A diagnostic workflow for genetic kidney diseases that includes WES is cost-saving, especially if implemented early, and is feasible in a real-world setting.

Systematic literature review on economic implications and pharmacoeconomic issues of rheumatoid arthritis.

OBJECTIVES: To provide a state of the art of economic analyses applied to rheumatoid arthritis (RA). METHODS: A systematic literature review on economic consequences and pharmacoeconomic issues of RA was performed. RESULTS: 127 valid articles were examined in this review. Generally, the financial impact of RA is substantial for health-care systems and society worldwide, although differences exist among national economies. Both direct and indirect (i.e. loss of productivity) costs contribute to economic burden of RA and must be taken into account when estimating overall impact to society. Disease severity, disease activity, age and socioeconomic status have been found to be the most relevant predictors of cost increase in RA. Moreover, introduction of biological anti-rheumatic agents has significantly raised direct medical costs in certain patients, but has also led to marked improvements in reducing disease activity, joint damage, and productivity loss in many of these patients. RA has also a significant impact on all aspects of quality of life; recent publications on health utility scores showed RA to be one of the diseases associated with poorest quality of life. CONCLUSIONS: RA represents a clinical and economic burden for healthcare systems. Although attributable RA costs have been extensively evaluated over the last decades, several issues, especially concerning the use of expensive therapies, must be addressed and frequently updated. Future research should also provide health economic evidence from usual practice settings, and on the economic impact of different therapeutic approaches to pursue specific clinical targets in individual patients.

Ferric carboxymaltose vs. ferrous sulfate for the treatment of anemia in advanced chronic kidney disease: an observational retrospective study and cost analysis.

In non-dialysis-dependent chronic kidney disease (NDD-CKD), erythropoiesis-stimulating agents (ESAs) and iron supplementation are essential for anemia management. Ferric carboxymaltose (FCM) is a relatively novel intravenous iron formulation used in different clinical settings, although scarce data exist in NDD-CKD patients. Primary objective of this study was to retrospectively evaluate the efficacy of FCM compared with oral ferrous sulfate for the treatment of iron-deficiency anemia in a cohort of NDD-CKD patients, considering also the treatment costs. This was a monocentric, retrospective observational study reviewing 349 NDD-CKD patients attending an outpatient clinic between June 2013 and December 2016. Patients were treated by either FCM intravenous infusion or oral ferrous sulfate. We collected serum values of hemoglobin, ferritin and transferrin saturation (TSAT) and ESAs doses at 12 and 18 months. The costs related to both treatments were also analysed. 239 patients were treated with FCM intravenous infusion and 110 patients with oral ferrous sulfate. The two groups were not statistically different for age, BMI and eGFR values. At 18 months, hemoglobin, serum ferritin and TSAT values increased significantly from baseline in the FCM group, compared with the ferrous sulfate group. ESAs dose and rate of infusion decreased only in the FCM group. At 18 months, the treatment costs, analysed per week, was higher in the ferrous sulfate group, compared with the FCM group, and this was mostly due to a reduction in ESAs prescription in the FCM group. Routine intravenous FCM treatment in an outpatient clinic of NDD-CKD patients results in better correction of iron-deficiency anemia when compared to ferrous sulfate. In addition to this, treating NDD-CKD patients with FCM leads to a significant reduction of the treatment costs by reducing ESAs use.

Cost-effectiveness analysis of stand-alone or combined non-invasive imaging tests for the diagnosis of stable coronary artery disease: results from the EVINCI study.

AIM: This study aimed at evaluating the cost-effectiveness of different non-invasive imaging-guided strategies for the diagnosis of obstructive coronary artery disease (CAD) in a European population of patients from the Evaluation of Integrated Cardiac Imaging in Ischemic Heart Disease (EVINCI) study. METHODS AND RESULTS: Cost-effectiveness analysis was performed in 350 patients (209 males, mean age 59 ± 9 years) with symptoms of suspected stable CAD undergoing computed tomography coronary angiography (CTCA) and at least one cardiac imaging stress-test prior to invasive coronary angiography (ICA) and in whom imaging exams were analysed at dedicated core laboratories. Stand-alone stress-tests or combined non-invasive strategies, when the first exam was uncertain, were compared. The diagnostic end-point was obstructive CAD defined as > 50% stenosis at quantitative ICA in the left main or at least one major coronary vessel. Effectiveness was defined as the percentage of correct diagnosis (cd) and costs were calculated using country-specific reimbursements. Incremental cost-effectiveness ratios (ICERs) were obtained using per-patient data and considering "no-imaging" as reference. The overall prevalence of obstructive CAD was 28%. Strategies combining CTCA followed by stress ECHO, SPECT, PET, or stress CMR followed by CTCA, were all cost-effective. ICERs values indicated cost saving from - 969€/cd for CMR-CTCA to - 1490€/cd for CTCA-PET, - 3092€/cd for CTCA-SPECT and - 3776€/cd for CTCA-ECHO. Similarly when considering early revascularization as effectiveness measure. CONCLUSION: In patients with suspected stable CAD and low prevalence of disease, combined non-invasive strategies with CTCA and stress-imaging are cost-effective as gatekeepers to ICA and to select candidates for early revascularization.

Correction to: Cost­effectiveness analysis of stand­alone or combined non­invasive imaging tests for the diagnosis of stable coronary artery disease: results from the EVINCI study.

In the Published article, the value in the abstract has been published incorrectly. The correct abstract section is as follows.

HIV coinfection and antiretroviral therapy enhances liver steatosis in patients with hepatitis C, but only in those infected by HCV genotype other than 3.

BACKGROUND: Liver steatosis is a common finding in hepatitis C virus (HCV) infection and is associated with an increased progression of the disease. However, HCV genotype 3 steatosis presents a peculiar and virus-induced pathogenesis. We analysed the effect of HIV coinfection and antiretroviral therapy on hepatic steatosis and the effect of the steatosis on fibrosis in patients with or without HCV genotype 3 infection. METHODS: All consecutive HIV-infected and uninfected patients who had undergone a liver biopsy for evaluation of HCV infection at the Infectious Diseases Clinic (Modena, Italy) were included in this study. Primary outcomes were the presence or absence of steatosis or the presence of moderate or advanced fibrosis. RESULTS: A total of 284 patients were enrolled: 187 infected by HCV and 97 coinfected with HIV and HCV. In HCV genotype 3 patients, only HCV-related variables, such as plasma HCV RNA levels (odds ratio [OR] per log10 1.68, P < 0.001) and estimated duration of HCV infection (OR per year 1.17, P = 0.004) were associated with steatosis. In patients infected with other HCV genotypes, steatosis was associated with older age (OR per 5 years 1.47, P < 0.001), with exposure to d-drugs in HIV-HCV-coinfected patients (OR 2.60, P = 0.04) and specifically exposure to stavudine (OR 2.76 HIV-HCV-coinfected versus not HIV-infected patients, P = 0.04). Steatosis was independently associated with bridging fibrosis only in patients infected by HCV genotype other than 3 (OR 4.03, P = 0.01). CONCLUSIONS: Hepatic steatosis, in both HCV-monoinfected and in HIV-HCV-coinfected patients, is strongly correlated with HCV genotype 3, probably through interactions between HCV virus and liver cells. HIV-related increase of steatosis in patients with HCV is probably related to antiretroviral drugs, especially stavudine, in patients infected by HCV genotype other than 3.

Risk of cancer following immunosuppression in organ transplant recipients and in HIV-positive individuals in southern Europe.

This investigation highlighted the risk of cancer in 8074 HIV-infected people and in 2875 transplant recipients in Italy and France. Observed and expected numbers of cancer were compared through sex- and age-standardised incidence ratios (SIRs) and 95% confidence intervals (CIs). After 15 years of follow-up, the cumulative probability of cancer was 14.7% in transplant recipients and 13.3% in HIV-positives. The SIRs for all cancers were 9.8 in HIV-positives and 2.2 in transplants. Kaposi's sarcoma (SIR=451 in HIV-positives, 125 in transplants) and non-Hodgkin lymphoma (SIR=62 and 11.1, respectively) were the most common cancers. A significantly increased SIR for liver cancer also emerged in both groups. The risk of lung cancer was significantly elevated in heart transplant recipients (SIR=2.8), and of borderline statistical significance in HIV-positive people (95% CI:0.9-2.8). Immune depression entails a two-fold increased overall risk of cancers, mainly related to cancers associated with a viral aetiology.

Kaposi's sarcoma in transplant and HIV-infected patients: an epidemiologic study in Italy and France.

BACKGROUND: A follow-up study was conducted in Italy and in France to compare the epidemiology of Kaposi's sarcoma (KS) between human immunodeficiency virus (HIV)-infected people and transplant recipients. METHODS: In all, 8,074 HIV-positive individuals (6,072 from France and 2,002 HIV-seroconverters from Italy) and 2,705 Italian transplant recipients (1,844 kidney transplants, 702 heart transplants, and 159 liver transplants) were followed-up between 1970 and 2004. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were computed to estimate the risk of KS, as compared to sex- and age-matched Italian and French populations. Incidence rate ratios (IRRs) were used to identify risk factors for KS. RESULTS: A 451-fold higher SIR for KS was recorded in HIV-infected subjects and a 128-fold higher SIR was seen in transplant recipients. Significantly increased KS risks were observed in HIV-infected homosexual men (IRR=9.7 in France and IRR=6.7 in Italy vs. intravenous drug users), and in transplant recipients born in southern Italy (IRR=5.2 vs. those born in northern Italy). HIV-infected patients with high CD4+ cell counts and those treated with antiretroviral therapies had reduced KS risks. In relation to duration of immunosuppression, KS occurred earlier in transplant patients than in HIV-seroconverters. CONCLUSIONS: This comparison highlighted that the risk of KS was higher among HIV-infected individuals than in transplant recipients, and that different co-factors are likely to influence the risk of KS. Moreover, the early KS occurrence in transplant recipients could be associated with different patterns of progressive impairment of the immune function.

Diagnosis and referral of rheumatoid arthritis by primary care physician: results of a pilot study on the city of Pisa, Italy.

The aims of the present study were to evaluate, in the city of Pisa: (1) the prevalence of rheumatoid arthritis; (2) the reliability of the prevalence estimated by primary care physicians, using the rheumatologist's diagnosis as the "gold standard" and (3) the economic impact of the disease. The Tuscany registry of primary care physicians constituted the framework from which a sample of subjects was selected. The rheumatoid arthritis (RA) subjects >18 years followed by each primary care physician constituted the population studied. Each general practitioner (GP) was asked to fill out a questionnaire regarding their patients affected by RA and to send it to the tertiary rheumatologic centre, where the diagnosis was confirmed/discarded, the clinical and epidemiological data were collected in a standardized form and a number of data for the estimation of costs were gathered. The estimated prevalence of RA was 5.1 per thousand (CI, 4.4-5.7). The reliability of general practitioners in the diagnosis of rheumatoid arthritis was on the whole 69%. However, when an analysis of every physician was carried out, a high degree of heterogeneity in the prevalence of RA per physician was found. Overall, the mean annual cost per patient with RA was estimated at about 5,878 euro (euro; median, 6,434 euro; inter quartile range, 669-7,052 euro), with a high variability mainly dependent on the degree of patient disability. More than 90% of the overall annual cost per patient was due to the medical and non-medical direct components of costs. The prevalence of RA in Tuscany seems highly comparable with similar prevalence studies in Italy. The annual cost per patient with RA was highly variable and strictly dependent on the level of disability. More than 90% of the overall cost was due to the direct burden of costs.

Late presenters in an HIV surveillance system in Italy during the period 1992-2006.

OBJECTIVES: The objectives of this study are to describe trends over time from 1992 to 2006 in the number of newly diagnosed HIV-infected individuals in Modena (Italy) and to describe their clinical and immunological characteristics. We also identify risk factors associated with presenting at late stages of HIV disease. METHODS: All new HIV diagnoses with at least 1 CD4 cell count and known stage of HIV disease were included. Using multivariate logistic regression models, we examined factors associated with being a late presenter, defined as individuals presenting with CD4 cell count <200 cells per microliter or AIDS within 3 months of their HIV-positive test. A quantile regression model was used to examine changes in CD4 cell count at presentation and trends over time. RESULTS: Of 844 newly diagnosed individuals included in analyses, 332 (39%) were late presenters, and this proportion remained constant over time (P = 0.106). Older age, male sex, and foreign born were the only determinants of being a late presenter. Persons newly diagnosed in 2002-2006 were less likely to present with an advanced clinical status. DISCUSSION: A substantial proportion of new HIV diagnoses are still at advanced stages of disease. In particular, foreign-born and heterosexual males still represent the largest part of AIDS presenters. Efforts are needed to encourage HIV testing and reduce the proportion who first seek HIV care at such a late stage.