Mortalidad debida a enfermedades raras en Europa: enfermedad de Huntington, ataxias hereditarias y enfermedades de la motoneurona

La Unión Europea ha definido a las Enfermedades Raras (ER) como aquella afección con riesgo vital o crónica debilitante con una prevalencia inferior a 5 casos por cada 10000 habitantes. Las características propias de estas enfermedades determinan ciertas dificultades en su investigación epidemiológica, asociadas al bajo número de casos, el alto grado de complejidad diagnóstica y su difícil identificación en los sistemas de información sanitaria, al utilizar clasificaciones orientadas a enfermedades más comunes. Dentro de las ER, el grupo de las afecciones del sistema nervioso presenta gran interés debido a que son de las más prevalentes. Además, se ha descrito un incremento de las enfermedades neurológicas en la población, pero estos estudios se centran en enfermedades comunes y no en las raras. Por otro lado, la mortalidad es un importante indicador de salud, siendo su reducción el objetivo de cualquier política de intervención en salud pública. Las tasas de mortalidad son monitorizadas a nivel local y nacional mediante indicadores específicos y obligatorios que miden la situación de salud de país. La unión de los datos de mortalidad procedentes de varios países puede contribuir a la mejora del conocimiento de las ER, al considerar series con mayor número de casos. Consecuentemente, el análisis de la mortalidad referente a ER neurológicas a escala europea puede aportar información de utilidad para conocer la situación actual de estas patologías..

Familial Mediterranean Fever in Spain: Time Trend and Spatial Distribution of the Hospitalizations

Familial Mediterranean Fever (FMF) is a rare, hereditary, auto-inflammatory disease. The aims of this study were to explore the time trend and geographical distribution of hospitalizations in Spain from 2008 to 2015. We identified hospitalizations of FMF from the Spanish Minimum Basic Data Set at hospital discharge, using ICD-9-CM code 277.31. Age-specific and age-adjusted hospitalization rates were calculated. The time trend and the average percentage change were analyzed using Joinpoint regression. Standardized morbidity ratios were calculated and mapped by province. A total of 960 FMF-related hospitalizations (52% men) were identified across the period 2008-2015, with an increase in hospitalizations of 4.9% per year being detected (p 1) in 13 provinces (5 in the Mediterranean area), and lower (SMR < 1) in 14 provinces (3 in the Mediterranean area). There was an increase in hospitalizations of patients with FMF in Spain throughout the study period, with a risk of hospitalization that was higher, though not exclusively so, in provinces along the Mediterranean coast. These findings contribute to the visibility of FMF and provide useful information for health planning. Further research should take into account new population-based information, in order to continue monitoring this disease.S

A population-based study of mortality due to muscular dystrophies across a 36-year period in Spain

Muscular dystrophies (MD) are a group of rare hereditary degenerative diseases. Our aim was to analyze the mortality pattern in Spain from 1981 to 2016 to assess the temporal trend and discern possible geographic differences using population-based data. Annual deaths related to MD were obtained from the National Statistics Institute with codes 359.1 of the ICD-9 (1981-1998) and G71.0 of the ICD-10 (1999-2016). Age-adjusted mortality rates were calculated and changes in mortality trends were identified. The standardized mortality ratios (SMR) and their respective 95% confidence intervals were calculated by district for 1999-2016. Smoothed SMRs and posterior probability were also assessed and then mapped to look for patterns or geographic distribution. All rates were expressed per 1,000,000 inhabitants. A total of 2,512 deaths (73.8% men) were identified. The age-adjusted mortality rates varied from 0.63 (95% CI 0.40-0.95) in 1981 to 1.51 (95% CI 1.17-1.93) in 2016. MD mortality showed a significant increase of 8.81% per year (95% CI 5.0-12.7) from 1981 to 1990, remaining stable afterwards. Areas with risk of death higher than expected for Spain as a whole were identified, not showing a specific regional pattern. In conclusion, the rising trend in MD mortality might be attributable to advanced improvements in diagnostic techniques leading to a rise in prevalence. Further research on the districts with the highest mortality would be necessary.This research was funded by Instituto de Salud Carlos III, Spanish Strategy Action for Health (AESI), project PI14CIII/00067, TPY 1238/15.S

Diagnostic Process in Rare Diseases: Determinants Associated with Diagnostic Delay

Many people living with rare disease (RD) report a difficult diagnostic process from the symptom onset until they obtain the definitive diagnosis. The aim of this study was thus to ascertain the diagnostic process in RDs, and explore the determinants related with having to wait for more than one year in this process (defined as “diagnostic delay”). We conducted a case–control study, using a purpose-designed form from the Spanish Rare Diseases Patient Registry for data-collection purposes. A descriptive analysis was performed and multivariate backward logistic regression models fitted. Based on data on 1216 patients living with RDs, we identified a series of determinants associated with experiencing diagnostic delay. These included: having to travel to see a specialist other than that usually consulted in the patient’s home province (OR 2.1; 95%CI 1.6–2.9); visiting more than 10 specialists (OR 2.6; 95%CI 1.7–4.0); being diagnosed in a region other than that of the patient’s residence at the date of symptom onset (OR 2.3; 95%CI 1.5–3.6); suffering from a RD of the nervous system (OR 1.4; 95%CI 1.0–1.8). In terms of time taken to see a specialist, waiting more than 6 months to be referred from the first medical visit was the period of time which most contributed to diagnostic delay (PAR 30.2%). In conclusion, this is the first paper to use a collaborative study based on a nationwide registry to address the diagnostic process of patients living with RDs. While the evidence shows that the diagnostic process experienced by these persons is complex, more studies are needed to determine the implications that this has for their lives and those of their families at a social, educational, occupational, psychological, and financial level.This research was supported by the Spanish State Research Agency, State R&D Program Oriented to the Challenges of the Society, project no. RTI2018-094035-A-I00. J.B-L enjoys a Grant PRE2019-091508 funded by MCIN/AEI/10.13039/501100011033 by “ESF Investing in your future”.S

Psychosocial impact at the time of a rare disease diagnosis

Over half of all persons with rare diseases (RDs) in Spain experience diagnostic delay (DD) but little is known about its consequences. This study therefore aimed to analyze the psychological impact of obtaining a diagnosis of an RD, and to ascertain what social determinants are influenced and what the personal consequences are, according to whether or not patients experienced DD. Data were obtained from a purpose-designed form completed by persons registered at the Spanish Rare Diseases Patient Registry. The following were performed: a descriptive analysis; a principal component analysis (PCA); and logistic regressions. Results revealed that while searching for a diagnosis, people who experienced DD were more in need of psychological care than those diagnosed in less than one year (36.2% vs 23.2%; p = 0.002; n = 524). The PCA identified three principal components, i.e., psychological effects, social implications, and functional impact. Reducing DD would improve psychological effects, such as irritability (OR 3.6; 95%CI 1.5-8.5), frustration (OR 3.4; 95%CI 1.7-7.1) and concentration on everyday life (OR 3.3; 95%CI 1.4-7.7). The influence of the social implications and functional repercussions of the disease was greater in persons with DD (scores of 22.4 vs 20 and 10.6 vs 9.4, respectively) in terms of the difficulty in explaining symptoms to close friends and family (3.3 vs 2.9), and loss of independence (3.3 vs 2.9). In conclusion, this is the first study to analyze the psychosocial impact of diagnosis of RDs in Spain and one of few to assess it in the patients themselves, based on data drawn from a purpose-designed form from a national registry open to any RD. People affected by RDs who underwent DD experienced greater psychosocial impact than did those who were diagnosed within the space of one year.This research was supported by the Spanish State Research Agency, State R&D Program Oriented to the Challenges of the Society, project no. RTI2018-094035-A-I00. J.B-L enjoys a research grant funded by the Spanish Ministry of Science, Innovation and Universities (no. PRE2019-091508). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

Diagnostic delay in rare diseases: data from the Spanish rare diseases patient registry

Background: According to the International Rare Diseases Research Consortium (IRDiRC), a known rare disease (RD) should be diagnosable within a year. This study sought: firstly, to ascertain how long it takes to obtain the diagnosis of a RD in Spain, along with its associated time trend; and secondly, to identify and measure diagnostic delay (defined by the IRDiRC as any period exceeding a year) by reference to the characteristics of RDs and the persons affected by them. Methods: Using data sourced from the Spanish Rare Diseases Patient Registry, we performed a descriptive analysis of the time elapsed between symptom onset and diagnosis of each RD, by sex, age and date of symptom onset, and type of RD. We analysed the time trend across the period 1960-2021 and possible change points, using a Joinpoint regression model and assuming a Poisson distribution. The multivariate analysis was completed with backward stepwise logistic regression. Results: Detailed information was obtained on 3304 persons with RDs: 56.4% had experienced delay in diagnosis of their RDs, with the mean time taken being 6.18 years (median = 2; IQR 0.2-7.5). Both the percentage of patients with diagnostic delay and the average time to diagnosis underwent a significant reduction across the study period (p < 0.001). There was a higher percentage of diagnostic delays: in women (OR 1.25; 95% CI 1.07-1.45); in cases with symptom onset at age 30-44 years (OR 1.48; 95% CI 1.19-1.84): and when analysed by type of RD, in mental and behavioural disorders (OR 4.21; 95% CI 2.26-7.85), followed by RDs of the nervous system (OR 1.39; 95% CI 1.02-1.88). Conclusions: This is the first study to quantify time to diagnosis of RDs in Spain, based on data from a national registry open to any RD. Since over half of all persons affected by RDs experience delay in diagnosis, new studies are needed to ascertain the factors associated with this delay and the implications this has on the lives of patients and their families.This research was supported by the Spanish State Research Agency, State R&D Program Oriented to the Challenges of the Society, project no. RTI2018094035-A-I00. JB enjoys a research grant funded by the Spanish Ministry of Science, Innovation and Universities (no. PRE2019-091508).S

Rare Diseases in Spain: a nationwide registry-based mortality study

Poster presented at the 9th European Conference on Rare Diseases and Orphan Products (ECRD Vienna 2018). Vienna, Austria. May 10-12, 2018.Background: Rare diseases (RD) are still lacking of population-based data and epidemiological indicators. The aim of this study is to assess 15-years’ time trends of mortality attributed to RD in Spain. Methods: Mortality statistics from the Spanish National Statistics Institute provide population-based data [1]. Deaths due to RD were extracted from official annual databases (1999-2013). Only those ICD-10 codes considered as RD by SpainRDR experts were included in this study [2]. Annual sex- and age-specific adjusted mortality rates per 100,000 inhabitants were calculated and time trends were performed by joinpoint regression analysis. Results: RD mortality represents 1.2% of all registered deaths from 1999 to 2013 in Spain. Mortality attributed to RD is higher in males (51.2%) than females (48.8%). Children (<15 years old) account for 15.2% of deceases. Distribution of RD deaths according to main ICD-10 groups is displayed in Fig. 1. Regarding time trends of RD mortality (Fig. 2), there has been a 0.95% decline in the annual age-adjusted death rates due to all RD (-0.95%, p<0.001). In addition: Decrease trends were also observed in the following subgroups: RD of the blood and blood-forming organs and certain rare disorders involving the immune mechanism (-2.06%, p<0.001), RD of the circulatory system (-3.90%, p<0.01), and rare congenital malformations, deformations and chromosomal abnormalities (-5.39%, p<0.01). Increase trends of annual age-adjusted death rates were detected for RD of the nervous system (1.85%, p<0.01), RD of the respiratory system (2.39%, p<0.01), RD of the digestive system (1.83%, p<0.05) and those RD affecting the genitourinary system (9.38% p<0.05). Other RD groups have not showed any significant change in this period. Conclusion: Official mortality statistics share criteria for analysing uniform and robust time series, which is useful for studying low-prevalence diseases. Assessed RD mortality trends are valuable information for the health authorities in Spain.Spanish Strategy Action for Health (AESI) supported this research, project No. TPY1238/15.N

Geographic Analysis of Motor Neuron Disease Mortality and Heavy Metals Released to Rivers in Spain

The etiology of motor neuron disease (MND) is still unknown. The aims of this study were to: (1) analyze MND mortality at a fine-grained level; and (2) explore associations of MND and heavy metals released into Spanish river basins. MND deaths were extracted from the Spanish nationwide mortality registry (2007–2016). Standardized mortality ratios (SMRs) for MND were estimated at a municipal level. Sites that emitted quantities of heavy metals above the regulatory thresholds were obtained from the European Pollutant Release and Transfer Register database (2007–2015). The relative risks for non-exposed and exposed municipalities (considering a downstream 20 km river section) by type of heavy metal were analyzed using a log-linear model. SMRs were significantly higher in central and northern municipalities. SMRs were 1.14 (1.10–1.17) higher in areas exposed to heavy metals than in non-exposed areas: 0.95 (0.92–0.96). Considering the different metals, we found the following increased MND death risks in exposed areas: 20.9% higher risk for lead, 20.0% for zinc, 16.7% for arsenic, 15.7% for chromium, 15.4% for cadmium, 12.7% for copper, and 12.4% for mercury. This study provides associations between MND death risk and heavy metals in exposed municipalities. Further studies investigating heavy metal exposure are needed to progress in MND understanding