The utilisation of primary health care system concepts positively impacts the assistance of patients with rare diseases despite limited knowledge and experience by health care professionals: A qualitative synopsis of the evidence including approximately 78 000 individuals

Background Individuals with rare diseases (RD) have been historically understudied. Previous publications reported that existing primary health care (PHC) workforces and associated infrastructure had been shown to improve their access and health-related outcomes in low- and middle-income countries (LMICs). As current evidence about the impact of PHC on patients diagnosed with RD is yet highly dispersed, this scoping review aimed to collate available evidence of the impact of PHC on patients with RD and summarize published information from multiple stakeholders about the perceived usefulness and barriers to effective use of the PHC system. Methods We searched Embase, Health System Evidence, PubMed, LILACS / BVS, and The Cochrane Library, from inception to September 1, 2022, for publications providing clear expert- or experience-based insights or data from patients living with RD at the PHC level of care. We included publications highlighting barriers to integrated care of patients with RD, reported by multiple social actors involved in caring for patients with RD. Two investigators screened publications, extracted data, and clustered information among records deemed eligible for inclusion. Data synthesis was performed using narrative and thematic-based analysis. Major findings identified and coded through a semantic-driven analysis were processed in vosViewer software and reported using descriptive statistics. Findings Eighty publications were included in this review. Quali-quantitative analyses evidenced that the PHC level is essential for approaching patients with RD, mainly due to its longitudinal, multidisciplinary, and coordinated care delivery. In addition, several publications highlighted that the medical curriculum is inappropriate for preparing health care providers to deal with patients presenting unusual signs and symptoms and being diagnosed with RD. PHC teams are essential in orienting patients and families on emergency events. Technology-related concepts were reported in 19 publications, emphasizing their effectiveness on early diagnosis, optimal treatment definition, improvement of quality of life, and long-lasting follow-up. Conclusions We provided valuable information on the effectiveness of the PHC in fostering a creative, integrative, and supportive environment for patients living with RD. Our results can be helpful to several stakeholders in deciding what actions are still pending to achieve a solid and positive experience for patients with RD in the PHC. Registration PROSPERO (CRD42022332347)

According to the World Health Organization (WHO), rare diseases are pathologies or medical conditions affecting no more than 1.3 in 2000 individuals [1].The interests of several stakeholders (e.g., health care professionals and medical organizations) in understanding and evaluating these diseases have significantly increased over the last years as it is estimated that more than 5500 have been reported worldwide, affecting more than 300 million people [2].Despite the global attempt to obtain concrete epidemiological data regarding rare diseases, health-related agencies have been working to improve the human condition and achieve equal dignity for every citizen.For instance, based on a multi-stakeholder alliance between the public and the private sector, the United Nations and its agencies created the Agenda for Sustainable Development, including 17 assessable Sustainable Development Goals [3,4].This initiative not only fights against poverty (commonly observed among patients with a rare disease) but also aims for the delivery of high-quality education, achievement of gender quality, reduction of country inequalities, and revitalize the global partnership for sustainable development [4].
Along with several available pharmacological and non-pharmacological interventions to treat and long-term manage rare diseases, the primary health care systems and its professionals also stand as a fundamental level of care due to three core elements (meet patients' health needs throughout their life, address the broader determinants of health through multi-sectoral policy and action, and empower individuals, families, and communities to take charge of their health) [5].In countries where a primary health care system is functional and adequately implemented, caring for patients with rare diseases is directly linked to primary health care and the professionals practicing at this level of care.However, many low-, middle-, and high-income countries do not still guarantee the humanization of care, coordination and maintenance of care, implementation of practices that enable early diagnosis, and deployment of actions that expand the autonomy of users and their caregivers [6].
Currently, hundreds of publications evaluating multiple features of rare diseases have been registered, suggesting the need for structured and integrated multidisciplinary care and the evolvement of frequently observed health care systems worldwide.Even though these publications reveal crucial elements regarding the diagnosis, treatment, and follow-up of patients presenting rare diseases, no summarization of these components have been published and analysed.Therefore, this systematic review aimed to answer the following guiding questions: "1.What is the state-of-the-art related to the role of the primary healthcare system in the care of individuals affected by rare diseases?";"2.What is the current evidence suggesting the effectiveness of primary healthcare system approach on managing patients with rare diseases?";and "3.What are the practice and structural gaps in the care network that hinders the integrality of care to patients with rare diseases?".

METHODS
To map relevant publications in rare diseases, this study followed the published methodological framework for conducting a scoping review developed by Arksey and O'Malley [7].Our starting point review questions were "What topics and information have been evidenced and published in the body of the literature regarding the use of primary healthcare systems for managing cases of rare diseases?","What is the role of primary healthcare assistance in terms of rare diseases patient's care flow", and "What barriers and facilitators currently exist for the adequate establishment of primary healthcare system applied to rare diseases worldwide?".Furthermore, our findings were reported under the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR) [8].Before executing this review, we registered our protocol on PROSPERO (CRD42022332347).
Regardless of study design and publication type, relevant records were obtained from five databases (Embase, Health System Evidence, PubMed, LILACS / BVS, and The Cochrane Library).The searches were performed on September 1, 2022; therefore, we included records from inception until the before-mentioned date.Publications were included if they: 1. directly reported and evaluated the role and effect of primary health care-derived interventions to the genetic-or clinical-based diagnosis, treatment, management, and prevention of late diagnosis of rare diseases; 2. provided legal or institutional information regarding rare diseases patient's rights; 3. compared the impact of primary health care-related activities to secondary or tertiary level of care; and 4. reported barriers, facilitators, and opportunities to implement long-lasting direct health care programs successfully.It is worthwhile mentioning that the acronym PICO (Population, Intervention, Comparator, Outcome) was used in this review to guide the entire review process.As far as "population" is concerned, patients diagnosed with rare diseases, as internationally defined in the literature, were considered eligible for inclusion.Furthermore, the primary health care system (defined within each included study) was regarded as the direct "intervention" evaluated throughout retrieved studies.We did not exclude studies based on the existence or absence of a comparator or a particular discussed outcome to increase the potential number of records deemed to be included.
We did not impose restrictions on published language and conference proceedings were considered eligible for inclusion.However, records were excluded if they did not assess the impact of primary health care on rare diseases.We used the Orphanet database for rare diseases and orphan drugs, created by the French National Institute for Health and Medical Records [9].Following duplicate removal (using EndNote 20), obtained records were uploaded into Covidence, primarily for the title and abstract screening phase and subsequentially to the full-text screening stage.Screening processes were performed independently by two review authors.Any decision disparity was resolved by group discussion.
An information specialist and medical experts in rare diseases and public health care collaborated to define each database's most sensitive search strategy.Search string levels associated with primary health care included "Primary Health Care", "Physicians, Primary Care", and "Primary Care Nursing" and their synonymous.Additionally, rare disease elements were mostly represented by key terms such as "Rare Diseases" and "Orphan Diseases".A complete description of keywords and identifiers used in each database is displayed in Section 1 in the Online Supplementary Document.References list of shortlisted records for fulltext analysis was evaluated to ensure an exhaustive search.
Data extraction of studies deemed eligible was also performed independently by two research authors and the following variables were extracted: 1. study identification; 2. publication year; 3. journal name; 4. SCImago Journal Rank (SJR) indicator for each journal; 5. study design; 6. publication type; 7. study objective; 8. number of patients or individuals considered in the publication; 9. targeted health care professionals; 10. rare disease evaluated; 11. orphanet code; 12. country; 13. summary of findings or discussed topic; 14. any information platform provided throughout the record; 15. barriers to case management; 16. facilitators for case management; and 17. any future opportunities raised by original authors.If any data extraction conflict occurred, a discussion between the two conflicting authors was carried out to understand which elements should be finally displayed in the final materials.
As we retrieved and selected qualitative and quantitative findings, we created a thematic synthesis of the results.The initial main findings of included studies were coded and thematically collated using NVivo software.Statistics data from quantitative studies were shown through text or table-based methods, while qualitative data were clustered by similarity and subsequently graphically presented using the vosViewer software.Moreover, a general summary of findings was created to systematically abstract the review's findings.
We primarily planned to analyse the risk of bias assessment for those included records in which the evaluation was technically feasible and indicated.However, as our study focused on exploring the status quo of the available evidence regarding the delivery of care for rare diseases at the primary level of care, we decided not to evaluate it.Moreover, the quality of the evidence was not appraised because of the methodological and technical singularities of scoping reviews.

RESULTS
Our search strategy retrieved 1351 records (as 1341 single studies), of which 145 were duplicates.The remaining 1206 records were screened, and 1078 studies were judged irrelevant.From the 128 shortlisted records, 90 were deemed eligible for inclusion.However, as some included records were literal translations of each other, we ended up with 80 unique publications in the qualitative summarization .Justifications for excluding records during fulltext screening are available in Section 2 in the Online Supplementary Document.A flow diagram of article selection is shown in Figure 1.Eight records were classified as "awaiting classification" either because the full text was not available or the translation of the study could not be done by the time of submission [38,[91][92][93][94][95][96][97][98].Generically, most included studies were published in the Atencíon Primaria (n = 9) [13,25,33,40,41,43,65,89,91], Orphanet Journal of Rare Diseases (n = 5) [20,28,38,73,83], the Journal of the Sociedad Española de Médicos de Atención Primaria (n = 4) [10,14,58,75], and the Revista Brasileira de Medicina da Família e Comunidade (n = 3) [11,53,76].Included records were predominantly cross-sectional studies (n = 26), narrative papers (n = 18), and reviews or case reports (n = 10).Numerically, as far as studies that evaluated patients and their rare diseases are concerned, 73 722 individuals were grouped, while approximately 4445 health care providers were included throughout the eligible studies.Most studies evaluated physicians' knowledge, understandability, perception, and professional attitudes (predominantly general practitioners) and nurses.In addition, included studies assessed common experiences lived by patients and their caregivers or described the importance of establishing guidelines for caring for patients with rare diseases at the primary care level.
Our thematic-based analysis yielded 41 principal codes and scope-related findings, as shown in Table 3 and Figure 2. The four top-ranked results among our included emphasized the following: 1. the elevated health care professional-reported perception of insufficient or inadequate knowledge about rare diseases diagnosis and their management in primary care (weight of occurrence (WO) = 32, 34 conceptual links); 2. highlighted and advocated for the essential characteristics of the primary care system, including the promotion of collaborative care, delivery of patient-and family-centeredness care, integration and coordination of care, sustainability, better management of chronic diseases, and the longitudinal continuity of care and patient-family-professional relationship (WO = 30, 33 conceptual links); 3. primary care and its health care professionals' capacity to identify early signs and symptoms commonly reported and identified in patients with rare diseases (WO = 23, 31 conceptual links); and 4. the need to collaboratively establish emergency protocols for each patient based on their singularity and rare underlying disease, and the need to standardize medical procedures and treatments for these patients (WO = 18, 27 conceptual links).The vast number of consultations until the final diagnosis (usually expensive; WO = 13, 24 conceptual links), the importance of prioritization access to specialists and philanthropic / supporting organizations (WO = 12, 27 conceptual links), and the low interest of pharmaceutical industries in identifying new pharmacological interventions (WO = 10, 27 conceptual links) were also significant findings observed among included studies.The list of all categorical results coded and clustered in our analysis can be accessed in Figure 2.
The development and incorporation of digital health technologies (mainly computerized clinical decision support systems) were endorsed and suggested in several publications [20,22,24,30,34,43,45,52,54,56,57,65,71,72,78,80,81,90].The use of newcomer technologies for early diagnosis, delivery of care, and long-lasting follow-up of patients with rare diseases was indicated in 16 publications.Mainous and colleagues suggested a significant improvement in managing sick cell disease patients in primary care following the implementation of clinical decision support appliances [57].Additionally, Ehsani-Moghaddam et al. launched a Näive Bayes classification algorithm using symptoms and clinical data of patients with mucopolysaccharidosis type II registered in the Canadian Primary Sentinel Surveillance Network [30].The classifier has effectively assisted physicians at the primary care level in diagnosing the syndrome and allowing optimal patient long-term management.Likewise, Buendia et al. developed and implemented a primary care rare disease case-finding tool based on data from pseudo-anonymized electronic medical records data [20].This study validated that a rare disease case-finding software could be appropriately designed and implemented following patients' data security recommendations.Moreover, it demonstrated the feasibility of using patients' phenotypes documented within primary care electronic records as the basis for case algorithms.In addition, some records superficially pinpointed the benefits of such digital health technologies, improving interprofessional communication (in particular between the specialist and the primary care physician), democratizing access to health-related information, and facilitating the obtention of technical information for Diagnoses of rare diseases is difficult [18,21,25,[35][36][37][38]48,52,57,58,[72][73][74]] Finding 32 Patients and families experience an extensive number of consultations until a definitive diagnosis if a misdiagnose is not established priorly [8,9,18,25,43,45,50,58,63,68] Finding 17 The feeling of general practitioners to prioritize access to secondary and tertiary levels of care is relevant [4,7,11,17,23,25,34,42,43,45,53, 57] Finding 15 There is a notable low interest in pharmaceutical industries in identifying new drugs for rare diseases because of their low prevalence [4,14,15,25,33,35,45,49,58,61,77] Finding 31 Primary health care system is the gateway for approaching and following up with patients with rare diseases [8,11,15,26,30,34,39,47,59,69,71] Finding 23 Healthcare providers usually seek information about rare diseases on websites and in peer-to-peer discussions [4][5][6]8,15,22,23,29,53,61] Finding 27 Continuous educational and training programs are primarily unknown by health care providers [6,11,40,41,56,61,62,73,75,78] Finding 30 Translating results from genetic counselling to "patients and parent's language" should be endorsed and performed [7,14,26,34,41,52,56,57,74,78] Finding 36 The care for patients with rare diseases must be multidisciplinary [11,14,21,30,32,58,60,67,73,75] Finding 35 The prevalence of rare diseases is globally unknown and controversial [10,18,25,43,45,50,58,63,68] Finding 16 Lawmakers and multiple stakeholders are alert and engaged in improving the quality of life of patients with rare diseases [4,14,19,35,42,46] Finding 21 Family and advocacy agencies commonly request actions to offer an integrated and person-centred delivery of care [4,23,32,34,35,42,67,72] Finding 3 There is a remarkable difference in-between medical specialty [25,40,50,53,54,58,76,78] Finding 18 The global impact of rare diseases on patient's lives is still unknown by health care providers [4,-6,8,14,37,39,81] Finding 9 There is a substantial economic impact caused by rare diseases in households, mostly related to expensive medications and diagnosis tests [23,37,45,49,52,58,72] Finding 10 Pre-natal and post-natal screening is essential to identify some rare diseases [16,19,41,49,67,78] Finding 11 Current health care systems settings do not allow a good experience for patients with rare diseases [22,30,42,48,72,77] Finding 33 Patients' and family's needs and concerns are not addressed by most health care professionals [8,25,26,36,45,79] Finding 25 Physicians fear delaying diagnosis because of lack of experience and believe that they have an active role in managing patients with rare diseases [5, 25,47,53,78] Finding 7 Knowledge diffusion might help with diseases misunderstanding and lack of knowledge [16,22,27,34,58] Finding 19 Current state of medical education for approaching rare diseases is adequate [4,10,22] Finding 37 Judicialization is beneficial for patients with rare diseases [49,55,77] Finding 14 The complex knowledge needed for the management of rare diseases is incompatible with the primary health care [2,81] Finding 22 A critical complaint reported by health care providers is associated with the difficulty to information access about rare diseases [54,81] Finding 26 The impact of rare diseases on families stimulates health care providers to improve their knowledge [5,23] Finding 28 By anticipating and recognizing available regional interventions, health care providers can increase the delivery of care to patients with rare diseases [7,30] Finding 34 Strong medications are commonly prescribed for patients with rare diseases until a definite diagnose [8,61] Finding 38 Patients with rare diseases have significantly lower social interaction than patients without rare diseases [48,79] Finding 39 "Expert patients" might have a conflicting relationship with physicians during the management of their disorders [23,29] Finding 5 Fast identification of a rare disease results in the decrease of impact provoked by the disease and allow fast delivery of medical interventions [47,19] Finding 2 Nutritional follow-up of patients with rare diseases is crucial, particularly among patients with inborn errors of metabolism [38] Finding 4 The shortage of patients for research, including rare diseases patients, can be overcome with online recruiting platforms [39] Finding 6 Domestic (in-house) delivery of medical treatment should be considered in some rare diseases [11]

Finding 8
Non-pharmacological interventions are effective and should be investigated [30] Finding 24 Social health care workers have a slightly increased experience than other health care providers in assessing and managing rare diseases  health care professionals.However, as stressed by Terry and Krokosky, there is an ongoing concern about these digital solutions as the media tends to show digital solutions with commercial denotations [81].Interestingly, one study evidenced the inefficiency of computer-based predictive model alerts to physicians in diagnosing rare diseases [71].
Government agencies have also suggested the creation of tools and regulations and the use of digital health technologies for addressing cases of rare diseases assisted in the primary health care sector [19,22,39,52,65,68,72].In 2013, the Department of Healthcare of Buenos Aires (Argentina) endorsed a group of normative guidelines that focused on developing health policies and tools digitally structured for accurate diagnosis and local investigation of rare diseases [22].Similarly, as stated by García-Ribes et al. [40] and Morales-Piga et al. [65], the use of online systems and assistance protocols in Spain has been well-established for diagnosis support, information provision, coordination of care, and delivery of epidemiological data to register centres.In the Brazilian scenario, specialized care coordination is provided by laws that focus on health promotion, early diagnosis, appropriate and timely secondary and tertiary care referral, and humanized and patient-centred care [68].One study reported the improvement and creation of an online register connecting the primary and secondary care levels, which might provide better patient data due to the completeness of data [72].

DISCUSSION
This qualitative synopsis and thematic-based assessment highlighted several connected components between primary care and rare diseases.Eighty publications were published within the past 18 years, indicating an increasing interest of researchers and other stakeholders (e.g., government and patient support organizations) in understanding the importance of primary care as a system that delivers holistic, coordinated, and long-lasting care.However, a focused and in-depth evaluation of a determined disease could not be carried out as most publications regarded "rare diseases in general" or several other targeted diseases.Eighteen publications suggested the importance of digital health technologies in diagnosing rare diseases promptly to enhance patients' and caregivers' experiences throughout the natural course of the disease.Most importantly, health care professionals stressed the insufficient knowledge of managing patients with rare diseases (stating that the topic was rarely approached in universities).Nevertheless, despite limited training and knowledge regarding these patients' diagnosis, management, and long-term follow-up, these professionals ensured the power and high effectiveness attributed to the primary health care system to guarantee the delivery of essential health elements for individuals living with rare diseases.Furthermore, the primary health care sector's ability and responsibility to identify signs and symptoms presented in daily medical consultations were notably observed among included publications.The least frequently generated codes related to the existence and effectiveness of non-pharmacological interventions (integrative health practices) in treating patients with rare diseases, the importance of strengthening the primary health care system, and the potential advantages social health care workers have over other professionals in dealing with individuals living with rare diseases.
As suggested in our findings, empowering the primary health care system positively affects patients with rare diseases.However, it might also improve the application intelligibility of this system in more complex medical conditions and emergencies, such as pandemics, health emergencies, and natural catastrophes [35,36].The primary health care system can coordinate local and regional networks, address the population's needs, and integrate care, prevention, promotion, and education.In addition, the system significantly improves overall health care performance by decreasing governmental expenditure and offering a holistic delivery of care [40].However, considering the global and growing rhetoric focusing on dismantling the primary health system structure, it is essential to assess the risks of these attempts to organize counteracting plans to strengthen the system.Likewise, educational programs (such as television or radio communications as well as social media publishing) focusing on the beneficial relationship between the primary health care system, rare diseases, and other conditions should also be part of core actions to enhance the system's popularity, acceptability, and awareness of efficacy, always considering each population's cultural, social, and financial singularities.Moreover, courses and update workshops for health care professionals, discussing features such as the management, diagnosis, treatment, and long-term follow-up in the primary health care system, should also be encouraged by municipalities and governments elsewhere.Notably, working with multiple health-related specialties and teams (emphasizing the importance of multidisciplinary teams) could effectively improve the client and professional experience with the system.
The singularities of each health care system (considering social, political, and economic variables) and the particularities of different diseases directly affect rare disease management and how patients experience care delivery within the health care system.Although health care systems in several places have increased their focus on a better understanding of the processes in that patients with rare diseases are involved, some features and concepts are still misunderstood, outdated, or disregarded by health providers and local administrative agencies, resulting in totally different perception of an identical condition [41,55,60].Notably, worldwide, health care systems still struggle to develop a valuable and comparable notification system for registering patients with rare diseases diagnosed.This issue creates a profound gap in the understandability of the same condition identified in a different location as the comparison of data are hindered by the contrasting information about patients and confounders inherent in the data collection period [41,62,64,70].This problem becomes even worse when health care professionals do not see the importance of establishing and assessing regional or national indicators associated with a rare disease, as data collection is usually simply related to "random and unnecessary" obtention of epidemiological indexes for the creation of statistical analyses.However, it is worthwhile mentioning that understanding the prevalence and incidence of a particular rare disease within a community not only guarantees cost-efficient resource use but also allows the foundation of a better framework of what needs this specific population will need in the long run.Therefore, to tackle the differences between health care systems worldwide, a structural change in the health care system's format to deal with rare diseases is needed to create equivalent and comparable data and overcome interregional disparities.
From a theoretical perspective, the achievement of the United Nations' Sustainable Development Goals (SDGs) is directly affected by countries' health care systems and institutionalized strategies for delivering care.Although a remarkable global improvement in population health outcomes has been observed over the last decades, the divisive private-based health care system will continue to set millions of people apart from a less unequal and unhealthy life.To note, it is inevitable not to assimilate the primary health care approach and public health care-based systems, as both processes are rooted in the capacity to respond equitably, inclusively, and cost-effectively to the health need of citizens.As our findings show, the primary health care approach of care positively affects health outcomes for the rarest diseases, from diagnosis to palliative care, making the creation of initiatives against the public health care system dismantling rhetoric critical.As advocated by the American Academy of Family Physicians and National Health System England, the call for action poses a significant starting point to counteract the long-dated initiatives to set primary and public care apart [99,100].However, more is needed from a provider, institution, community, region, and national perspective.
Enhancing the number of high-quality genetics, experimental, and clinical research devoted to rare diseases, or improving the knowledge of the impact of primary care services for rare diseases are cornerstones of scientific improvement toward achieving Universal Health Coverage (UHC).Our data clearly suggested that several publications evidenced the minimum interest of pharmaceutical industries to identify and formulate new pharmacological therapies because of the low profitability and limited growth capacity attributed to rare diseases.Ultimately, the little research and production of new drugs directly hinder the achievement of SDG Goal 3 as highly advanced technologies and qualified professionals are not involved in improving health quality.Indeed, no substantial evidence has shown that pharmaceutical companies have been actively developing new drugs in a broad and non-selective way.For instance, although Pzifer has taken measures to create pharmacological alternatives for various diseases, 104 discovery projects have been reported as of July 28, 2022 [101].Of those, only 11 compounds cover patients with rare diseases.Nevertheless, these "research discoveries and development" might be inflated as in-house development has been recorded to be relatively low [102].Therefore, third parties as universities and health educational institutions play an essential role in fulfilling the current comprehension gaps, as pharmaceutical industries do not offer outstanding improvements for patients at the pace needed, specifically for rare diseases.Likewise, as far as recent advances in mRNA and DNA technology are concerned (making the new era of genetics therapy a reality), exploring this new (and potentially unknown) area of expertise is of utmost importance to improve the general delivery of care to patients with rare disorders, regardless the level of care.
Reducing social and economic disparities (SDG Goal 10) among patients (and their families) diagnosed with rare diseases also has particular importance in the 2030 Agenda for Sustainable Development.Rare disease patients regularly face a shortage of health resources, precarious education, and a structured family core, which combined marginalize these patients over the years.Our data showed that the financial impact of rare diseases on the family budget is significant, driven mainly by expensive medications, especially biologics.Based on data reported by Gimenez-Lozano et al., approximately 58% of families with a rare disease-confirmed case reported not being able to afford adjuvant therapies [42].Moreover, the disease brings not only a financial impact but also a psychological and emotional burden [42].Thus, counteracting actions to reduce inequality should focus on active advocacy for the inclusion of rare disease patients in all social spheres, either by using legislative changes or through supportive public programs, as well as strengthening the primary health care system and its core principles.needs, perceived utility, and ability to use such technologies, particularly for physicians who frequently do not have any prior preparation for utilizing health technologies in most medical universities.Additionally, understanding barriers to the success of the intervention must analyse inherent infrastructure and technical difficulties experienced by users, health care providers' personal and psychological issues, legal and ethical variables, and cultural, social, and geopolitical factors.Therefore, the involvement of providers and other social actors in creating and employing digital health technologies, the evaluation of providers' willingness to use the technologies, and the existence of institutional and governmental incentives are of utmost importance.
The creation of standardized and instructive emergency protocols in the event of sudden decompensation or complication was interestingly ranked as the fourth most frequent concept among included publications.Due to inherent features of the primary care consultation approach (e.g., longer consultation times and stronger provider-patient relationship), preparing these simple materials at the primary care level is timely and efficient.Not only does preparing these materials seem critical, but regular health assessments and preventive clinical actions are fundamental.For instance, based on regular lower respiratory tract cultures check-ups performed at the primary care level, previously generated data can guide physicians in managing acute pulmonary exacerbations in patients with cystic fibrosis, essentially due to chronic colonization of some bacteria (e.g., Pseudomonas aeruginosa or Staphylococcus aureus).We strongly recommend preparing such medical instruments early in disease recognition as information obtention in emergency conditions is usually chaotic and challenging.Therefore, there is no better and more controlled place than the primary health care offices to leverage guidelines about rare disease complications and unexpected clinical presentations.To the best of our knowledge, no previous template of an "Emergency Protocol for Patients Living with Rare Diseases" has been published elsewhere.However, we endorse that basic information containing the patient's medical history and background, diagnosis, medications on use, allergies, and description of the acute complication must be written in these protocols.Moreover, intervention contra-indication and dangerous drug-to-drug interactions should also be inserted in these instructive and informative materials.In Section 3 in the Online Supplementary Document, standardized, editable, and adaptable material is shared for health care providers working in primary health care facilities.
Relying on information about the diagnosis, management, and treatment in general websites and by peerto-peer consultation was frequently identified as the leading knowledge resource by health care professionals.Nevertheless, particular attention should be given to rare disease-related information resources as multiple platforms are not official, based on high-quality evidence, and are subjective to clinicians' opinions and expertise.Recently, evidence-based reports have suggested the high prevalence of misinformation and disinformation on online pages with health content and digital devices, which significantly reduces the trustworthiness of unofficial health resources [103].As emphasized in some included publications, accessing information on rare diseases is complex, and consulting the first Google search page might be a reality.However, based on the data retrieved, we reiterate the existence of several credited and expert-authored online platforms available for health care professional consultation, which properly guides professionals during any delivery of assistance for patients with rare diseases.
Our study has several strengths.First, we strictly followed international and standard methodological recommendations for evidence-based studies.Additionally, we included a relevant number of patients and health care professionals from the primary health care sector, which allows us to upgrade the general certainty of the evidence herein provided.To note, although the creation of a meta-analytic assessment was not feasible, we created a thematic analysis based on the occurrence of similar semantic terms or sentences verified among included publications.This evaluation process is highly subjective and the displayed mathematical results of the weight of occurrences might be affected by this subjectivity.However, we strictly attained critical methodological concepts, including criteria of credibility, transferability, dependability, and confirmability throughout the project execution.Significant limitations might be associated with patients' and health care professionals' selection bias in included studies, the lack of comprehensive description of demographic and epidemiological data from individuals being addressed among included studies, and the limited number of studies outside the Americas and European Regions.This could directly hinder the generalizability of our findings to other scenarios.

CONCLUSION
Our study highlights the commonly reported concepts when merging "primary healthcare" and "rare diseases".We observed relevant evidence suggesting the importance of primary health care level of care in manag-

REFERENCES
ing and supporting individuals living with rare diseases.Our study suggests the strengths and weaknesses within this relationship and shows future perspectives which decision-makers, technology developers, and health care providers must follow to improve the quality of care delivered to patients with rare diseases.

Figure 1 .
Figure 1.PRISMA flowchart diagram.*Studies corresponded to literal translation of main records, therefore, counted only once.

Finding 40 Figure 2 .
Figure 2. Relative frequency of occurrence of all clustered findings from included publication.WO -weight of occurence

Table 1 .
Main characteristics of included studies RTo provide PCP with information about the medical and psychosocial issues commonly experienced by patients with inborn errors of metabolism and their families to allow for ongoing support outside of the genetics clinics * European Journal of Neurology R To describe the holistic patient experience from pre-diagnosis through to long-term treatment 15 Pt N / A Boffin, 2018* Intl J of Environ Res and Public Heal CSS To examine care characteristics of care diseases patients and analyse the importance of RD in GP by its caseload 111 SGP + 121 Pt Phy Brasil, 2014 § Ministério da Saúde Brasileiro GM To establish guidelines for the care of patient with RD in the primary health care CSS To assess the degree of knowledge on rare diseases held by PCP 128 Phy Phy Buenos Aires, 2013 § La APS renovada en la Provincia de Buenos Aires GM It establishes the creation of the Center Provincial Reference, Monitoring and Dissemination of RD and establishes its bases concepts in this document, constituting its pillars of work N / A N / A Byrne, 2020* Irish Journal of Medical Science CSS To complete a pilot survey to estimate the general practice clinical workload attributable to selected RD and assess the use of relevant information sources CR To present a care report of a RD and the delivery of care in the primary care sector 1 Pt N / A Druschke, 2021* Orphanet Journal of Rare Diseases CSS To understand the knowledge about a centre for RD and how it works, in case of cooperation, satisfaction with the services provided by centres, and expectations and needs they have with regard to the centres CS To investigate if having access to primary care or insurance prior to diagnosis is associated with better outcomes for patients in an urban, public hospital with mostly socioeconomically disadvantaged Hispanic patients

Table 1 .
continued DORA project, a joint effort between the Children's Hospital (University of Sao Paulo Medical School) and the Sao Paulo Secretary of State for Health, in order to organize early diagnosis and integrated care of congenital malformations and rare diseases in the State of Sao Paulo National Policy for Comprehensive Care for People with Rare Diseases, approves the Guidelines for Comprehensive Care for People with Rare Diseases within the scope of the Health System (SUS) in Brazil and institutes financial cost incentives CSSTo report the training needs and the perceived shortcomings of Spanish physicians of the public health system in the diagnosis, treatment and monitoring of patients with rare diseases

Table 1 .
continued CSSTo investigate how information and education could be tailored to the needs and preferences of physicians in Belgium to increase their rare disease awareness and support them in diagnosing patients with a RD

Table 3 .
Descriptive mathematical evaluation of identified factors and their in-map representation