Pediatría
ISSN impreso:0120-4912
e-ISSN:2444-9369
DOI: 10.14295/rp.v56i4.491

Artíuclo de Investigación

Follow-up patterns and Multidisciplinary Clinical Approaches in Patients with Mucopolysaccharidosis Type IVA in Colombia

Patrones de seguimiento y manejo clínico multidisciplinario en pacientes con Mucopolisacaridosis tipo IVA en Colombia

Gustavo Contreras*^a, Carlos Estrada Serrato^b, Natalia García Restrepo^c, Martha Gómez Castro^d, Yaqueline Ladino Cortes^e, Daniel Mosquera Arango^f, Julie Navarrete Vargas^g, Rita Iris Ortega Rico^h, Blair Ortiz Giraldoⁱ, Gloria Liliana Porras Hurtado^j, Diana Ramírez Montaño^k, Asid Rodríguez Villanueva^l, Jorge Armando Rojas Martínez^m, Diana Sánchez Peñareteⁿ, José María Satizabal Soto^o, Norma Serrano^p, Ana Lorenza Valencia^q

a. Facultad de Salud, Universidad Industrial de Santander Hospital Universitario de Santander
b. Médico Genetista, Clínica Universitaria Colombia. Médico Genetista, IPS Especializada
c. Docente Facultad de Ciencias de la Salud. Universidad de Manizales
d. Unidad de Perinatología y Terapia Fetal del Caribe, Unifetal.
e. Fundación Hospital de la Misericordia, HOMI
f. Hospital internacional de Colombia
g. Médico genetista, Servimed QCL IPS
h. Fundación centro colombiano de epilepsia y enfermedades neurológicas, FIRE
i. Hospital San Vicente Fundación
j. Comfamiliar Risaralda
k. Unidad de Medicina genómica y Genética, Clínica Imbanaco, Grupo Quironsalud, Cali, Colombia
Biotecnología y Genética SAS, Bogotá, Colombia
l. Hospital Universidad del Norte
m. Hospital Universitario San Ignacio
n. Hospital Universitario San Ignacio
o. Universidad Del Valle. Genomics
p. Fundación Cardiovascular de Colombia FCV
q. E.S.E Hospital Departamental Universitario Santa Sofia de Caldas
Centro Visual Moderno (CVM)

Recibido 21 de septiembre de 2023 Aceptado 14 de noviembre de 2023

Como citar: Contreras G, Estrada Serrato C, García Restrepo N, Gómez Castro M, Ladino Cortes Y, Mosquera Arango D. et al. Follow-up patterns and Multidisciplinary Clinical Approaches in Patients with Mucopolysaccharidosis Type IVA in Colombia. Pediatr.2024;57(1): e491.

*Autor de correspondencia: Gustavo Contreras.
Correo electrónico: gacontre@uis.edu.co

Editor en Jefe: Álvaro León Jácome Orozco.

Abstract

Background: There is limited data on the follow-up and management of patients with mucopolysaccharidosis IVA (MPS-IVA) undergoing enzyme replacement therapy (ERT) in Colombia.
Objective: We aim to assess the real-world data of patients with MPS-IVA undergoing ERT in Colombia to understand patient profiles, follow-up patterns, and treatment dynamics.
Methods: A convenience sample of geneticists and pediatric neurologists were recruited from November-2020 to January-2021. The physicians responded to a questionnaire-based report for each patient under their care regarding the patient profiles, follow-up patterns, and treatment dynamics.
Results: A total of 24 physicians (geneticists [92%] and pediatric neurologists [8%]) provided data on 107 patients with MPS-IVA. Patients were diagnosed through molecular (36%) and/or enzymatic assays (97%). The mean age of patients was 19.5 years and 51% were male. The average time from first symptom to diagnosis was 7.1 years. The mean age at first symptoms was 4 years and at diagnosis was 11 years, further, the mean age at first ERT was 15 years. There was an increase in assessments after ERT initiation; parameters most frequently evaluated were weight, height, and echocardiography; quality of life, 6MWT, and 3-minute stair-climb test were the least frequent. ERT interruptions >2 months were observed in 63% patients.
Conclusions: Monitoring of MPS-IVA patients receiving ERT remains suboptimal in Colombia. Establishing national management guidelines and implementing centralized reference centers, where patients can receive comprehensive care are warranted for ensuring appropriate systems, services, and support as a priority, with a potential positive effect in the course of the disease.

Keywords: Mucopolysaccharidosis type IVA; enzyme replacement therapy; patient preference; Colombia; patient journey; patient follow-up.

Resumen

Antecedentes: La información sobre el seguimiento y manejo de pacientes con mucopolisacaridosis IVA (MPS-IVA) con terapia de reemplazo enzimático (ERT) en Colombia es limitada.
Objetivos: Nuestro propósito es evaluar datos del mundo real de pacientes con MPS-IVA sometidos a ERT en Colombia para comprender sus perfiles, patrones de seguimiento y dinámicas del tratamiento.
Métodos: Se reclutó una muestra conveniente de genetistas y neurólogos pediátricos desde noviembre 2020 a enero 2021. Para cada paciente bajo su cuidado, los médicos respondieron un reporte basado en preguntas.
Resultados: Un total de 24 médicos (genetistas [92 %] y neuropediatras [8 %]) proporcionaron datos sobre 107 pacientes, diagnosticados mediante pruebas moleculares (36 %) y/o ensayos enzimáticos (97 %). Su edad promedio fue 19.5 años y 51% eran hombres. El tiempo promedio desde el primer síntoma al diagnóstico, del primer síntoma, del diagnóstico y de la primer ERT fue de 7.1, 4, 11 y 15 años, respectivamente. Los controles de seguimiento aumentaron post inicio de ERT; las evaluaciones más frecuentes fueron peso, altura y ecocardiografía; la calidad de vida, la prueba-de-caminata-de-6-minutos y la prueba de escaleras de 3 minutos fueron menos frecuentes. Se observaron interrupciones de ERT >2 meses en el 63 % de los pacientes.
Conclusiones: El monitoreo de pacientes con MPS-IVA que reciben ERT sigue siendo subóptimo en Colombia. Es necesario establecer pautas nacionales de manejo e implementar centros de referencia centralizados, donde los pacientes puedan recibir atención integral para garantizar sistemas, servicios y apoyo adecuados como prioridad, con un potencial efecto positivo en el curso de la enfermedad.

Palabras Clave: Mucopolisacaridosis IV; Terapia de Reemplazo Enzimático; Prioridad del Paciente; Colombia; Recorrido del Paciente; Seguimiento de Pacientes.

Introduction

Mucopolysaccharidosis type IVA (Morquio A syndrome [MPS-IVA]) (OMIM: #253000), is an autosomal recessive progressive lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, leading to glycosaminoglycans (GAGs) accumulation (1-3). Incidence of MPS-IV is the highest among all mucopolysaccharidoses in Colombia, with approximately 0.68 per 100,000 live-births (4, 5). GAGs accumulation results in tissue dysfunction causing symptoms that include skeletal and joint abnormalities (resulting in locomotion deterioration), hepatosplenomegaly, spinal cord compression, corneal opacity, inguinal and umbilical hernias, short stature and cardiorespiratory disorders - often leading to reduced life expectancy (3, 5-8).

Enzyme replacement therapy (ERT) and, less frequently, hematopoietic stem-cell transplantation are the treatment options for MPS-IVA (9, 10). Weekly intravenous infusions of the recombinant enzyme have proven to be clinically effective among MPS-IVA patients, demonstrating an improvement in quality of life (QoL), reduction of urine keratan sulfate levels and long-term stabilization of endurance and respiratory function (11-14).

International evidence - and consensus-based guidance recommend including patient medical history, physical and neurological manifestations of disease, functionality, and disease burden as part of the evaluation parameters for MPS-IVA patients before, during, and after ERT treatment initiation (9, 15). Currently, there is limited data on the follow-up and management of patients with MPS-IVA undergoing ERT in Colombia. Studies published have reported the frequencies and clinical characteristics of MPS (4, 5, 16-18). Likewise, the ENSERI study (19) documented information on the clinical and social needs of patients with orphan diseases such as MPS, especially in relation to the steps needed to reach diagnosis and treatment. To fulfill this gap, we assessed the real-world data of patients with MPS-IVA undergoing ERT in Colombia to understand patient profiles, follow-up patterns, and treatment dynamics.

Methods

Study design 

A convenience sample of geneticists and pediatric neurologists from Colombia, who treated patients with MPS-IVA receiving ERT were recruited for the study from November-2020 to January-2021. The physicians responded to a questionnaire-based report for each patient under their management using an anonymous patient chart available on a web-based portal protected by IQVIA. The online questionnaire included 23 questions regarding the monitoring routine and primary clinical examinations recommended by the global MPS-IVA management guidelines (6, 9, 15)(Supplementary material).

Statistical Analysis

Data were summarized descriptively as averages and percentages (%) for discrete variables, and by measures of central tendency and dispersion for continuous variables. Percentages were calculated for patients with available (non-missing) data.

Results

A total of 24 physicians participated in this study, providing data on 107 patients with MPS-IVA. The surveyed physicians were specialized geneticists (92 %) and pediatric neurologists (8 %) from 11 different geographic locations (Table 1) including the largest centers that are known to provide care to inherited metabolic diseases in Colombia. On average, the physicians had 19 years of practice and monthly attended a total of 167 patients with different inherited metabolic diseases. Among these patients, 5 diagnosed with MPS-IVA undergoing ERT for at least 12-months prior to data collection (0.2 % of the total patients attended by each physician annually).

Table 1.Characteristics of healthcare institutions included in the study

Data from 107 patients were reported by the surveyed physicians. The mean age of patients was 9.5 (4.5-63.5) years and 51% were male. The mean age at first symptoms was four years and at diagnosis was 11 years, with an average time from first symptom to diagnosis of 7.1 years. Patients, were diagnosed with MPS-IVA through molecular (36 %) and/or enzymatic assays (97 %). The mean age at first ERT treatment was 15 years, and from ERT initiation to last follow-up visit was four years. Among the 19 patients (18 %) who used a wheelchair, 15 (79%) utilized it permanently and 4 (21 %) utilized it as needed.

The primary locations for patients were Valle del Cauca (20 %), Caldas (14 %), Santander (8 %), and Bogotá (7 %). Approximately 61% of patients were affiliated to the contributive regimen (which includes those individuals with formal employment or the capacity to pay and is financed through payroll contributions (20)), 36 % to the subsidized regimen (which includes those unable to pay and is financed by the government mostly through general taxation (20)) and 3 % to special regimens (teachers, military, police officers and workers of the national oil company (20)).

ERT interruptions for >2 months were observed in 67 (63 %) patients, with an average of 4 episodes per patient. For all 107 patients, the most common assessments available on medical records before and after ERT initiation were weight (90 %; 97 %, respectively), height (88 %; 98 %, respectively) and echocardiogram (91 %; 83 %, respectively). Assessments less documented before and after ERT initiation were QoL (2.8% each), pain (5.6%; 3.7%, respectively), and 3-minute stair-climb test (1.9% each). Overall, GAGs were less frequently evaluated after ERT initiation than before (24% vs 31%). Detailed information on the MPS-IVA patient journey can be found in Figure 1 which includes the relative frequencies of different age groups for the time between birth and the first symptoms, between first symptoms and diagnosis, and from diagnosis to ERT initiation (A); also, it describes relative frequencies of distinct assessments (i.e., physical examination and laboratory or excise-based tests) performed at baseline and during follow-up (after ERT initiation) (i.e., percentage of patients with at least one assessment) (B) and of the assessments’ results availability during follow-up (C).

Figure 1. Patient journey, assessments performed and follow-up exam results availability of patients with MPS-IVA (patients included in the analysis: 107). A. Patient journey of patients with MPS-IVA; B. Percentage of patients with at least one assessment performed at baseline (before ERT initiation) and during follow-up (after ERT initiation) (%, n=107 patients); C. Percentage of assessments’ results availability during follow up (%, n= assessments performed). 6MWT: 6-minute walk test, Ave: average, CVF: capacidad vital forzada (FVC: forced vital capacity), ECG: Electrocardiogram, Echo: Echocardiogram, ERT: enzyme replacement therapy, FEV1: Forced expiratory volume in the first second, GAGs glycosaminoglycans, MPS-IV-A: mucopolysaccharidosis IVA, stairs: 3-minute stair climb test, yo: years old, VVM: maximal voluntary ventilation.

Discussion

This questionnaire-based report from treating physicians, generated comprehensive real-world data for 107 patients with MPS-IVA receiving ERT from Colombia. We identified critical gaps to the care intricately linked to the absence of a local clinical practice guideline, the fragmented nature of healthcare delivery, and insufficient adherence to international recommendations, primarily due to various access barriers.

Considering the frequency of MPS-IVA in Colombia, with no more than 115 cases reported from 2016-2018 and a prevalence of 0.3 cases per 100,000 inhabitants corresponding to 150 cases for 2019 according to the Colombian National Institute of Health, we present data from a significant study population for a rare disease and expose the situation in different areas of the country other than the central and central-western regions, where previously reports have described most of the cases of orphan diseases (21).

Our study identified a significant time gap between the onset of symptoms and diagnosis (average of 7.1 years). When compared to delay in diagnosis reports of 4.9 years from the International Morquio Registry (8) and of 3.5-3.9 years from certain Latin American countries (Colombia, Ecuador, Mexico, Peru) (22), there is a considerable difference and still falls short of achieving a timely diagnosis that would allow for the implementation of recommended interventions at the appropriate time (23).

The findings of our study are in line with the report of the ENSERio study (19). More than half of the patients with orphan diseases in the country, including MPS, receive a late diagnosis and, generate consequences such as delays in the initiation of treatment, not receiving support or treatment, worsening of the disease and the need to receive psychological support.

It is crucial to reflect on the necessity of educating and raising awareness about the importance of early identification of signs and symptoms for prompt diagnosis that would allow interdisciplinary management, treatment options, and genetic counseling being just a few of the strategies that can provide greater benefits when implemented early (3, 10, 22).

In Colombia, there have been some studies related to the development of molecular tests in patients with MPS. Moreno-Giraldo et al. 2018 (24)analyzed the molecular characteristics of 12 patients diagnosed with MPS IV1 and highlighted the importance of having molecular analysis, predictive bioinformatics tools, pharmacogenomics and proteomics to improve the diagnosis, treatment and prognosis of patients affected by MPS IVA.

Observational study of Moreno-Giraldo et al. 2020 (25) determined the allelic frequency of variants present in 320 patients without diagnosis of MPS. The results of this study allowed to determine the population frequency of each of the variants associated with MPS, facilitating the timely identification of patients with the disease. Similarly, the investigations of Romo-Erazo et al. 2022 and Tapiero-Rodriguez et al. 2018 (26, 27) performed a genotypic characterization of patients with MPS. These investigations support the fact that our Colombian cases generally exhibit a severe phenotype and ample objective evidence to support this information is lacking-the distribution of homozygous and compound heterozygous mutations among our patients - remains unknown (21).

The development of molecular tests is indispensable for the optimal diagnosis and appropriate clinical management of patients with MPS. In our study, only 36 % of diagnoses underwent molecular studies. This highlights the pressing need for a unified effort to establish guidelines or a consensus regarding molecular and genetic testing that can then inform decision-making and facilitate personalized treatment approaches.

It is interesting to note that there was an increase in assessments after ERT initiation, with a broader difference for physical examination measures such as weight and height (60.7 vs. 92.5 % and 55.1 vs. 84.1 %), echocardiography (43.0 vs. 68.2 %), and exercise-based tests such as the 6MWT (19.6 vs. 39.3 %). These differences can be explained in part by the indirect effect of treatment initiation on the need for a closer monitoring; also, the possible interference of the fact that patients receiving ERT are managed by physicians who are more aware and adhere strictly to international guidelines recommendations cannot be ruled out.

The extended periods of therapy interruptions, as compared to existing regional literature (63 % vs. 48 %) (22), raise concerns regarding the potential impact on outcomes. Several factors could contribute to these interruptions including drug availability, financial constraints, and logistical issues with treatment administration, as well as patient non-compliance or difficulties in accessing healthcare facilities. Since ERT is designed to replace deficient enzymes and mitigate disease progression, any disruption in treatment may lead to a decline in therapeutic efficacy, increased morbidity, and potentially irreversible organ damage (28-30); hence, it is crucial to address the underlying reasons and implement strategies to minimize their occurrence through collaborative efforts among healthcare providers, policymakers, and patient support groups.

Another important finding was the availability of results during follow-up. Just over half of GAGs results (60 %) were available and this was followed by respiratory function tests (70-77 %), 6MWT (85 %), and echocardiogram (83 %) results. This indicates that despite the test being ordered or performed, the completeness of the results availability during follow-up is not satisfactory. Furthermore, despite the significant impact of pain and its effect on quality of life in this condition (19, 31, 32)., it is concerning how little these aspects are evaluated and addressed in our local clinical practice. By incorporating these assessments, we can gain a more comprehensive understanding of the disease and develop holistic management approaches that address not only physical symptoms but also the emotional and social well-being.

When comparing the frequency of assessments in our study to recommendations by international guidelines, a physical examination including (among others) growth parameters should be performed during every visit (15); however, we found that measures of weight and height were performed in just over half of patients before ERT initiation (60.7 and 55.1 %, respectively). Regarding laboratory or exercise-based tests, 6MWT are recommended on annual basis and respiratory function tests on annual basis until children stop growing, and every 2–3 years thereafter (15); meanwhile, the current study found that those assessment were performed in far less than half of patients before and after ERT initiation.

Also, initial cardiac evaluation including echocardiogram, and 12-lead electrocardiogram (ECG) is recommended at the time of diagnosis (15), but we found that before ERT initiation they were performed in only 43 (echocardiogram) and 15 % (ECG) of patients; conversely, proportions were higher but not optimal after ERT initiation (68.2 and 27.1 %) where it is recommended annually initially and extended to every 2–3 years when there is no evidence of cardiac abnormality (15). Annual assessment of disease burden through patient-reported outcomes is also recommended for pain, QoL, and daily activities performance (15); yet, as previously mentioned, those were the three less common assessments both before and after ERT initiation (Pain: 3.7 and 5.6 %; QoL both 2.8 %; Stairs both 1.9 %).

Urinary GAGs levels may be also used prior to ERT and every 6 months thereafter to assess the effect of treatment (15); nevertheless, we found that it was performed in less than one third of patients before (24.3 %) and after ERT initiation (30.8 %). This finding has important implications for understanding the scarcity of performance of several assessment measures and raise intriguing questions regarding the nature and extent of measurement bias when evaluating the adherence to international guidelines and the real-world benefit of the therapy. Furthermore, a note of caution is due here since as MPS-IVA phenotypes may differ, clinical monitoring and therapeutic goals must be individualized (15).

The lack of comprehensive patient management is a glaring issue in our local context. While Colombia has the "Resolution 651 of 2018: Establishing the conditions for the accreditation of Diagnostic, Treatment, and Pharmacy Reference Centers for the comprehensive care of Rare Diseases, as well as the formation of the network and sub-networks of reference centers for their care,"(33) patient management remains fragmented across various healthcare facilities. Therefore, some studies such as ENSERio Colombia (19) have designed recommendations in the socio-health, political and governmental sphere for the diagnosis, monitoring and care of patients with orphan diseases such as mucopolysaccharidosis.

Low adherence to international recommendations may be related to local challenges in clinical care, as intrinsic barriers of access -such as availability of medication and specialized laboratories-, socioeconomic characteristics -major rural population in Colombia as well as geographical barriers due to limited mobility, transportation, and financial resources- and healthcare system fragmentation may contribute to difficulties in accessing proper care, along with disease burden (cardiorespiratory and mobility impairment) (22). Nevertheless, the fact that data was more complete during follow-up, may evidence an effort of clinical care teams to provide comprehensive and dedicated care despite local difficulties.

Although this study provides substantial data on disease follow-up patterns in Colombia, selection and ascertainment bias may occur due to the convenience sample of recruited physicians with patients on ERT only. While acknowledging the limitations of the methodology, it is worth highlighting that a significant population of MPS-IV patients was included in this study, providing valuable insights into the condition. Our study endeavors to bridge the evidence gap in clinical care and generate regional real-world data for MPS-IVA.

Conclusion

The most significant conclusion to emerge from this study is that the clinical monitoring in terms of follow-up patterns, and treatment dynamics of MPS IVA patients receiving ERT remains suboptimal in Colombia. First improvement steps may include a national guideline for MPS-IVA to steer clinical professionals through high-quality long-term local recommendations. It is also crucial to emphasize the need for the implementation of centralized reference centers, where patients can receive authorized comprehensive care. After underlying this gaps, greater efforts are needed to ensure standardized follow-up practices, closer monitoring, individualized treatment, and a multidisciplinary management approach, as well as disease awareness campaigns targeting patients and caregivers. This would ensure appropriate systems, services, and support as a priority with a potential direct positive effect in the course of the disease.

Further studies are needed to assess remaining knowledge gaps, particularly regarding reasons for treatment interruptions and underlying barriers for both patients and healthcare providers that could then improve adherence and treatment outcomes. Additionally, evaluating the long-term effectiveness and safety, as well as the impact of the proposed intervention strategies, will be necessary to establish evidence-based practices for optimal care.

Declarations

Ethics approval: Ethics committee approval was not required for this study since anonymized surveys of opinion do not require approval from an ethics committee. The study was done in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and per applicable regulatory requirements.

Funding source: This study was funded by BioMarin.

Conflict of Interest: The authors declare no conflict of interest specifically related to this manuscript.

Acknowledgments: BioMarin Pharmaceutical Inc. (Novato, CA, US) financially supported the development of this manuscript, but the authors are responsible for the scientific content. IQVIA Colombia assisted with data collection and analysis and provided medical writing services. The authors are grateful to Lilian Rodrigues da Silva and Nadia Yudenitsch of IQVIA for patient diary survey support, and to Marion Coting Braga Piazza, Melissa Díaz, Guilherme Silva Julian, Vibha Dhamija, and Kevin Maldonado of IQVIA for medical writing and editorial support.

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