International Multidisciplinary Consensus on the Definition and Clinical Approach for Monogenic Inflammatory Immune Dysregulation Disorders

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Methods A multi-step, evidence-based, multidisciplinary consensus process was employed, consisting of: 1) a systematic literature review across four electronic databases (Cochrane Library, Web of Science, Scopus, and MEDLINE via PubMed), updated through December 31, 2024; 2) a pre-Delphi electronic survey completed by 95 international adult and pediatric immunologists and rheumatologists; and 3) a modified online Delphi process with an international multidisciplinary expert panel, where statements were iteratively analyzed and refined until achieving consensus (≥ 80% agreement among panelists). Results Fifteen experts from 12 countries participated in two rounds of the Delphi process, resulting in the development of eight overarching principles and 10 consensus statements. These were categorized into five domains: 1) definitions and conceptual framework, 2) diagnostic and monitoring considerations, 3) treatment and therapeutic strategies, 4) multidisciplinary and collaborative care, and 5) patient education and support. Conclusion This consensus defines MIIDDs and provides a structured clinical framework to streamline research efforts and improve patient outcomes. inborn errors of immunity genetic inflammatory autoimmune autoinflammatory immune dysregulation consensus Introduction Primary immunodeficiencies (PIDs) traditionally describe inherited immune system disorders that impair the human defense against infections. In the 1970s, the World Health Organization formed a committee to classify PIDs [ 1 ], a responsibility later assumed by the International Union of Immunological Societies (IUIS) in the 1990s [ 2 ]. Over time, it became evident that PIDs are associated with a spectrum of autoinflammatory, autoimmune, atopic manifestations, and susceptibility to malignancy. Notably, noninfectious manifestations are often the primary or initial clinical features of many of these disorders [ 3 ]. The growing understanding of their genetic basis, supported by advancements in molecular genetic testing, has led to the adoption of the term inborn errors of immunity (IEIs) due to the identification of mutations without immune deficiency (loss-function) but rather immune over-activation (gain-of-function) [ 4 ]. In the most recent IUIS classification update, 555 distinct IEIs are categorized into 10 groups based on immunologic and genetic defects [ 5 ]. However, certain disorders from different groups exhibit overlapping features, such as pronounced inflammation alongside immune dysregulation, highlighting the need for unifying term. The term ‘Monogenic Inflammatory Immune Dysregulation Disorders’ (MIIDDs) has been introduced as an umbrella concept for a heterogeneous group of conditions. It describes patients with pathogenic gene mutations affecting both innate and adaptive immunity, clinical features of inflammation, and evolving features of immune dysregulation. This unifying term may facilitates the grouping of related disorders within single conceptual framework, supporting research integration on overlapping disorders regardless of their underlying pathophysiology, as seen in monogenic lupus. Establishing this framework is important for advancing research and improving patient outcomes. To address this, we conducted a systematic literature review and a modified online Delphi study, engaging an international panel of experts. This process aimed to achieve consensus on the definition and clinical management for patients with MIIDDs. Materials and methods Study design and overview Given the limited empirical evidence on disorders categorized under MIIDDs, a modified Delphi method was utilized. This systematic, iterative approach was selected for its ability to gather consensus among geographically dispersed experts while maintaining participant anonymity, minimizing dominance effects, and ensuring balanced input. The development of the consensus involved a multi-step process (see Supplement, Figure I). Step one: Establishment of the core group The project was initiated by SMA, who formed a core group comprising three additional members (LOM, IAA, and HMA). The team included two pediatric rheumatologists, one adult rheumatologist, and one clinical allergist/immunologist. The core group was tasked with overseeing the study’s design and implementation, focusing on patients with combined clinical features of non-infectious sterile inflammation (autoimmune or autoinflammatory disorders), immune dysregulation, and confirmed genetic mutations. Step two: Statement development via systematic literature review Two authors (SMA and HMA) conducted a systematic literature review (SLR) across four electronic databases: the Cochrane Library, Web of Science, Scopus, and MEDLINE (via PubMed). The search included peer-reviewed publications available through October 31, 2023, and was updated through December 31, 2024, with only studies published in English being considered. Reference lists of identified records were also screened for relevant studies. Keywords, Topics, and Medical Subject headings (MeSH) terms were used to broaden the search scope. Disagreements during the review were resolved by reconciliation or consultation with a third reviewer (IAA). Studies related to polygenic disorders, genetic mutations with unclear pathogenic significance, case reports, case series, reviews, editorials, opinions, abstracts-only studies, basic science research, and non-English publications were excluded. Titles and abstracts were initially screened, followed by a full-text review for eligibility (see Supplement for the search strategy and the PRISMA flow diagram). Step three: Pre-Delphi process An online survey derived from the SLR findings was developed to explore current practices and future care needs. The survey was disseminated via SurveyMonkey® to an international cohort of adult and pediatric immunologists and rheumatologists identified through scientific societies and special interest groups. A snowball sampling method was employed to gather more responses. Survey responses were collected between November 30, 2023, and January 4, 2024, with 95 participants completing the survey (see Supplement documents, Table-S1 for participant demographics). The results of this exercise yielded valuable insight that was incorporated into the main Delphi process. Step four: Delphi panel selection and process The core group identified potential panelists from different disciplines (allergy/immunology, immunogenetics, rheumatology, and infectious diseases) based on expertise and interest as identified through special interest groups and previous publications. A total of 15 panelists from 12 countries (spanning Africa, Asia, Europe, and South America) participated in two rounds of an online Delphi exercise conducted via SurveyMonkey®. The modified Delphi process comprised 20 statements organized under five domains (Table I). The first round included both open- and closed-ended questions, while the second round refined statements for agreement scoring on a 5-point Likert scale. After each round, results were summarized and tabulated. The percentage agreement and descriptive statistics were calculated. Statements not reaching consensus were modified by the core group and then re-sent to panelists in an iterative process until consensus (≥ 80% agreement) was achieved. Informed consent and ethical approval All participants received an introductory statement at the start of each survey outlining the study’s purpose, the voluntary nature of participation, and assurances of confidentiality and anonymity. The participants’ decision to proceed with the survey implied consent. The Research Advisory Council (RAC) at King Faisal Specialist Hospital and Research Center (RAC2231314) granted ethical approval for the study. Results All 15 panelists successfully completed the two rounds of the modified Delphi process. After the first round, eight statements were rephrased to improve clarity, while two statements were omitted (see Supplement, Table S2 for results from the First Round of Voting and Table S3 for modifications after the first round). Ultimately, eight overarching principles and ten consensus recommendation statements were finalized and organized into five core domains (see Table I). The eight overarching principles provide a contemporary perspective on defining and managing MIIDDs, establishing a framework for the subsequent recommendations (see Table II). Domain A: Definitions and Conceptual Framework The term MIIDDs is proposed as a unifying umbrella term encompassing a heterogeneous group of conditions. These disorders are characterized by pathogenic gene mutations, leading to autoimmune or autoinflammatory manifestations, or features of immune system dysregulation, with clinical features evolving over time. Domain B: Diagnostic and Monitoring Considerations The availability, accessibility, and accurate interpretation of genetic testing are crucial for identifying MIIDDs patients and improving their overall care outcomes. Molecular genetic testing has revolutionized the diagnosis of immune-mediated inflammatory conditions and advanced our understanding of the link between IEIs and inflammatory conditions [ 6 ]. Delayed diagnosis has been reported in patients with monogenic IEIs, promoting calls to expand access to genetic testing and functional assessment of variant of uncertain significance (VUS) [ 7 ]. Panelists emphasized the importance of clinical monitoring and documenting improvements in laboratory indices as treatment responses. Future research endeavors should focus on identifying tailored biomarkers, establishing standardized definitions for disease remission, and developing validating indices for disease activity and damage. Domain C. Treatment and Therapeutic Options Achieving clinical improvement is a feasible goal for MIIDDs patients. Depending on the clinical presentation and immunologic profile, different treatment modalities may be employed. These include corticosteroids, conventional disease-modifying antirheumatic drugs, intravenous immunoglobulin, and antibiotic prophylaxis [ 8 ]. The identification of pathogenic mutations and deciphering disease mechanisms has facilitated the development of precision medicine, offering tailored treatments such as hematopoietic stem cell transplant, gene therapy, and the use of targeted biologics or small molecules [ 9 ]. Domain D: Multidisciplinary and Collaborative Care Depending on the dominant clinical presentation, the primary healthcare provider may be either a rheumatologist or an immunologist. However, panelists unanimously agreed that joint rheumatology/immunology care or clinics are advocated for optimizing care for MIIDDs patients [ 10 ]. Furthermore, collaboration with other subspecialties is occasionally necessary due to the diverse spectrum of MIIDDs, underscoring the importance of a multidisciplinary approach. Patients should also be screened for additional non-inflammatory autoimmune conditions or malignancies. Domain E: Patient Education and Support Patient education and ongoing support are strongly advocated, given the limited availability of publicly accessible information on rare disorders. Discussion This study introduces the concept of MIIDDs as a unifying framework for a heterogeneous subgroup of IEIs characterized by pathogenic genetic mutations, immune dysregulation, and prominent inflammatory features. Through an SLR and a modified Delphi process, we sought to address the current gaps in defining and approaching these rare disorders. The MIIDDs framework recognizes the overlap between immunodeficiencies, autoimmunity, and autoinflammation in IEIs, integrating clinical and genetic features under a single umbrella [ 11 – 15 ]. This approach promotes a deeper understanding of shared pathophysiological mechanisms, streamlining research efforts, and fostering cohesive clinical guidelines. Our findings highlight the critical role of genetic testing in identifying MIIDDs. Expanding access to genetic testing and training clinicians in interpreting molecular genetic data are essential for early diagnosis and effective management [ 16 – 20 ]. The consensus underscores the need for validated tools, such as standardized definitions of disease remission and activity indices, to monitor disease progression and treatment outcomes [ 21 – 23 ]. Treatment strategies for MIIDDs are diverse and evolving [ 24 ]. While conventional approaches, such as corticosteroids and immunosuppressants, remain pivotal, advances in precision medicine, including biologics, small molecules, and gene therapies, offer promising, targeted, and more effective interventions [ 25 – 28 ]. Individualized treatment plans based on specific pathogenic mutations could significantly improve patient outcomes [ 29 , 30 ]. Given the diverse clinical manifestations of MIIDDs, joint immunology-rheumatology clinics, and multidisciplinary care teams are essential for optimizing patient management. The consensus strongly advocates for integrating subspecialists, including infectious disease experts, geneticists, and other relevant disciplines, into the care model. This collaborative approach addresses the broad spectrum of features and comorbidities observed in MIIDDs. Additionally, patient education and psychosocial support are integral, given the emotional and logistical challenges faced by patients and families [ 23 , 31 ]. In conclusion, this consensus-driven framework established foundational principles for defining and approaching MIIDDs, improving the current classification for IEIs with inflammatory features. Future efforts should focus on validating this framework through clinical and genetic studies, developing disease-specific indices, and fostering international collaboration to advance research and improve outcomes for these complex disorders. Abbreviations PIDs Primary Immunodeficiencies IUIS International Union of Immunological Societies IEIs Inborn Errors of Immunity MIIDDs Monogenic Inflammatory Immune Dysregulation Disorders SLR Systematic Literature Review PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses RAC Research Advisory Council Declarations Supplementary Information The attached document contains the supplementary material. Acknowledgments None. Author contributions Conception and design of study: SMA, HMA. Data analysis and/ or interpretation of data: HMA, SMA, LOM, IAA, All authors made substantial contributions to the interpretation of data for the work. SE, HA, SJ, HM, MO, AA, TA, WC, GE, MF, AG, DH, NM, HW contributed to data interpretation, manuscript drafting, or critical revision for intellectual content. All authors reviewed and approved the final manuscript. All authors are accountable for all aspects of the work. Funding: No specific funding was received for this study. Data availability: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Declarations and Competing Interests: The authors declare that they have neither competing financial nor non-financial interests in relation to this work. Also, no potential conflict of interest is relevant to this article. LOM and MLF received a grant from the USP-COFECUB programme (AuBraFra-autoinflmmation Brazil-France) reference 49906-YC. 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Curr Opin Allergy Clin Immunol. 2023 Feb 1;23(1):51-62. doi: 10.1097/ACI.0000000000000876. Nicholson B, Goodman R, Day J, Worth A, Carpenter B, Sandford K, et al. Quality of Life and Social and Psychological Outcomes in Adulthood Following Allogeneic HSCT in Childhood for Inborn Errors of Immunity. J Clin Immunol. 2022 Oct;42(7):1451-1460. doi: 10.1007/s10875-022-01286-6. Tables Table I. Core Domains Addressed in the Consensus Domain A Definitions and Conceptual Framework Domain B Diagnostic and Monitoring Considerations Domain C Treatment and Therapeutic Options Domain D Multidisciplinary and Collaborative Care Domain E Patient Education and Support Table II. Overarching Principles and Final Recommendations for Patients with MIIDDs Agreement Descriptive Statistics Percentage (%) Mean Standard deviation Interquartile range Overarching Principles A.1 Monogenic Inflammatory Immune-Dysregulation Disorders (MIIDDs) is an umbrella term for a heterogeneous group of disorders. 100 4.93 0.24 0.0 A.2 A patient with Monogenic Inflammatory Immune-Dysregulation Disorder (MIIDD) is defined as having a pathogenic gene mutation, immune system dysregulation, and inflammatory manifestations with clinical features that can evolve over time. 100 4.66 0.47 1.0 B.3 The availability, accessibility, and accurate interpretation of genetic testing will enhance patient identification and improve overall care outcomes. 93.33 4.73 0.99 0.0 B.4 There is a need for the development of a definition of disease remission in patients with MIIDDs. 100 4.6 0.48 1.0 B.5 There is a need for the development and validation of disease activity and damage indices for patients with MIIDDs. 100 4.4 0.48 1.0 C.6 Clinical improvement while on treatment is a feasible goal in the management of patients with MIIDDs. 93.33 4.26 0.57 1.0 C.7 More effective therapeutic options for the management of patients with MIIDDs should be explored and tested. 100 4.8 0.4 0.0 C.8 There is a need for the development of therapeutic guidelines for the management of patients with MIIDDs. 100 4.8 0.4 0.0 Recommendations B.1 Clinical and laboratory improvement should be used to assess the response to treatment. 100 4.6 0.48 1.0 C.2 Corticosteroids may serve as a therapeutic option for some patients with MIIDDs, depending on the clinical context and individual patient needs. 93.33 4.13 0.71 0.5 C.3 Both conventional and/or biologic disease-modifying antirheumatic drugs may serve as therapeutic options for some patients with MIIDDs, depending on the clinical context and individual patient needs. 100 4.4 0.48 1.0 C.4 Intravenous immunoglobulin (IVIG) may serve as a therapeutic option for some patients with MIIDDs, depending on the clinical context and individual patient needs. 100 4.33 0.47 1.0 C.6 Antibiotic prophylaxis may be required for some patients with MIIDDs, depending on the clinical context and individual patient needs. 86.67 3.93 0.44 0.0 C.6 A hematopoietic stem cell transplant may be needed for some patients with MIIDDs, depending on the clinical context and individual patient needs. 86.67 3.93 0.44 0.0 D.7 Based on the predominant clinic picture in patients with MIIDDs, the primary healthcare provider can be a rheumatologist or an immunologist. However, joint rheumatology/immunology care or clinics are advocated to provide optimum care for patients with MIIDDs. 100 4.73 0.44 0.5 D.8 Collaboration with other subspecialties as needed is advocated in the care of patients with MIIDDs. 100 4.8 0.4 0.0 D.9 Patients with MIIDDs should be screened for other non-inflammatory autoimmune conditions, such as autoimmune thyroiditis. 86.67 4.26 0.67 1.0 E.10 Patients with MIIDDs should be educated regarding their disease and provided with ongoing support. 100 4.8 0.4 0.0 MIIDDs: Monogenic Inflammatory Immune-Dysregulation Disorders Additional Declarations No competing interests reported. Supplementary Files MIIDDsSupplementdocuments.docx Cite Share Download PDF Status: Published Journal Publication published 14 May, 2025 Read the published version in Pediatric Rheumatology → Version 1 posted Editorial decision: Revision requested 23 Mar, 2025 Reviews received at journal 19 Mar, 2025 Reviewers agreed at journal 26 Feb, 2025 Reviews received at journal 12 Feb, 2025 Reviewers agreed at journal 10 Feb, 2025 Reviewers invited by journal 05 Feb, 2025 Editor assigned by journal 04 Feb, 2025 Submission checks completed at journal 04 Feb, 2025 First submitted to journal 01 Feb, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Winnie","middleName":"KY","lastName":"Chan","suffix":""},{"id":411828623,"identity":"91c12114-1cec-41c1-852a-958e01978e10","order_by":11,"name":"Graciela Espada","email":"","orcid":"","institution":"Hospital de Niños Dr Ricardo Gutiérrez","correspondingAuthor":false,"prefix":"","firstName":"Graciela","middleName":"","lastName":"Espada","suffix":""},{"id":411828624,"identity":"e7ac1400-b5c4-46fe-9ee0-ab4cac2f6f2e","order_by":12,"name":"Marie-Louise Frémond","email":"","orcid":"","institution":"Necker Hospital","correspondingAuthor":false,"prefix":"","firstName":"Marie-Louise","middleName":"","lastName":"Frémond","suffix":""},{"id":411828625,"identity":"091080e1-b813-4d7b-acd7-721fbb760c7d","order_by":13,"name":"Ahmet Gül","email":"","orcid":"","institution":"Istanbul 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Münster","correspondingAuthor":false,"prefix":"","firstName":"Helmut","middleName":"","lastName":"Wittkowski","suffix":""},{"id":411828629,"identity":"ef8b9086-1929-4941-81a6-dc04238ff6d4","order_by":17,"name":"Sulaiman M Al-Mayouf","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIie3OsQrCMBCA4ROHOpy4FqSPILQcBIegrxIpdAouLo5uLsVd8CH0DQIFXaquhS5KwalDx26aOjlF3QTzTxe4jxyAzfazce47C3yOrcVnJIp8VF+S5AsyWKZBgeJM2Dvuqxq4t1XOtTIRlkoiFDlDdxquY4hoq5BcI1GS9bt1zscuUhsgmWgCZnIuWR/FiWMvbchdE6eojSSTDVEMQTZEaQLM/Et2mwUbERK6klqxH9I6QTY0HxbuLqUYBbE+DOr5yFsdlkVmIgAd/+XRzG3zvs65vF2x2Wy2P+8Bdi5GQQKenjcAAAAASUVORK5CYII=","orcid":"","institution":"King Faisal Specialist Hospital \u0026 Research Centre","correspondingAuthor":true,"prefix":"","firstName":"Sulaiman","middleName":"M","lastName":"Al-Mayouf","suffix":""}],"badges":[],"createdAt":"2025-02-01 15:38:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5942561/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5942561/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12969-025-01109-z","type":"published","date":"2025-05-14T15:57:38+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83067931,"identity":"bdf21527-52df-4dd4-a46b-9d4fa4972b81","added_by":"auto","created_at":"2025-05-19 16:08:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":939952,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5942561/v1/83dc966d-0c91-497b-8e82-058f4beede41.pdf"},{"id":75589698,"identity":"f71d9caf-3ebf-4b3a-81d8-e135d42e5d29","added_by":"auto","created_at":"2025-02-06 06:58:02","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":72448,"visible":true,"origin":"","legend":"","description":"","filename":"MIIDDsSupplementdocuments.docx","url":"https://assets-eu.researchsquare.com/files/rs-5942561/v1/ed03901bc0944f4c793da49e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"International Multidisciplinary Consensus on the Definition and Clinical Approach for Monogenic Inflammatory Immune Dysregulation Disorders","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePrimary immunodeficiencies (PIDs) traditionally describe inherited immune system disorders that impair the human defense against infections. In the 1970s, the World Health Organization formed a committee to classify PIDs [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], a responsibility later assumed by the International Union of Immunological Societies (IUIS) in the 1990s [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Over time, it became evident that PIDs are associated with a spectrum of autoinflammatory, autoimmune, atopic manifestations, and susceptibility to malignancy. Notably, noninfectious manifestations are often the primary or initial clinical features of many of these disorders [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The growing understanding of their genetic basis, supported by advancements in molecular genetic testing, has led to the adoption of the term inborn errors of immunity (IEIs) due to the identification of mutations without immune deficiency (loss-function) but rather immune over-activation (gain-of-function) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the most recent IUIS classification update, 555 distinct IEIs are categorized into 10 groups based on immunologic and genetic defects [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, certain disorders from different groups exhibit overlapping features, such as pronounced inflammation alongside immune dysregulation, highlighting the need for unifying term.\u003c/p\u003e \u003cp\u003eThe term \u0026lsquo;Monogenic Inflammatory Immune Dysregulation Disorders\u0026rsquo; (MIIDDs) has been introduced as an umbrella concept for a heterogeneous group of conditions. It describes patients with pathogenic gene mutations affecting both innate and adaptive immunity, clinical features of inflammation, and evolving features of immune dysregulation. This unifying term may facilitates the grouping of related disorders within single conceptual framework, supporting research integration on overlapping disorders regardless of their underlying pathophysiology, as seen in monogenic lupus.\u003c/p\u003e \u003cp\u003eEstablishing this framework is important for advancing research and improving patient outcomes. To address this, we conducted a systematic literature review and a modified online Delphi study, engaging an international panel of experts. This process aimed to achieve consensus on the definition and clinical management for patients with MIIDDs.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and overview\u003c/h2\u003e \u003cp\u003eGiven the limited empirical evidence on disorders categorized under MIIDDs, a modified Delphi method was utilized. This systematic, iterative approach was selected for its ability to gather consensus among geographically dispersed experts while maintaining participant anonymity, minimizing dominance effects, and ensuring balanced input. The development of the consensus involved a multi-step process (see Supplement, Figure I).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStep one: Establishment of the core group\u003c/h3\u003e\n\u003cp\u003eThe project was initiated by SMA, who formed a core group comprising three additional members (LOM, IAA, and HMA). The team included two pediatric rheumatologists, one adult rheumatologist, and one clinical allergist/immunologist. The core group was tasked with overseeing the study\u0026rsquo;s design and implementation, focusing on patients with combined clinical features of non-infectious sterile inflammation (autoimmune or autoinflammatory disorders), immune dysregulation, and confirmed genetic mutations.\u003c/p\u003e\n\u003ch3\u003eStep two: Statement development via systematic literature review\u003c/h3\u003e\n\u003cp\u003eTwo authors (SMA and HMA) conducted a systematic literature review (SLR) across four electronic databases: the Cochrane Library, Web of Science, Scopus, and MEDLINE (via PubMed). The search included peer-reviewed publications available through October 31, 2023, and was updated through December 31, 2024, with only studies published in English being considered. Reference lists of identified records were also screened for relevant studies. Keywords, Topics, and Medical Subject headings (MeSH) terms were used to broaden the search scope. Disagreements during the review were resolved by reconciliation or consultation with a third reviewer (IAA).\u003c/p\u003e \u003cp\u003eStudies related to polygenic disorders, genetic mutations with unclear pathogenic significance, case reports, case series, reviews, editorials, opinions, abstracts-only studies, basic science research, and non-English publications were excluded. Titles and abstracts were initially screened, followed by a full-text review for eligibility (see Supplement for the search strategy and the PRISMA flow diagram).\u003c/p\u003e\n\u003ch3\u003eStep three: Pre-Delphi process\u003c/h3\u003e\n\u003cp\u003eAn online survey derived from the SLR findings was developed to explore current practices and future care needs. The survey was disseminated via SurveyMonkey\u0026reg; to an international cohort of adult and pediatric immunologists and rheumatologists identified through scientific societies and special interest groups. A snowball sampling method was employed to gather more responses. Survey responses were collected between November 30, 2023, and January 4, 2024, with 95 participants completing the survey (see Supplement documents, Table-S1 for participant demographics). The results of this exercise yielded valuable insight that was incorporated into the main Delphi process.\u003c/p\u003e\n\u003ch3\u003eStep four: Delphi panel selection and process\u003c/h3\u003e\n\u003cp\u003eThe core group identified potential panelists from different disciplines (allergy/immunology, immunogenetics, rheumatology, and infectious diseases) based on expertise and interest as identified through special interest groups and previous publications. A total of 15 panelists from 12 countries (spanning Africa, Asia, Europe, and South America) participated in two rounds of an online Delphi exercise conducted via SurveyMonkey\u0026reg;.\u003c/p\u003e \u003cp\u003eThe modified Delphi process comprised 20 statements organized under five domains (Table I). The first round included both open- and closed-ended questions, while the second round refined statements for agreement scoring on a 5-point Likert scale.\u003c/p\u003e \u003cp\u003eAfter each round, results were summarized and tabulated. The percentage agreement and descriptive statistics were calculated. Statements not reaching consensus were modified by the core group and then re-sent to panelists in an iterative process until consensus (\u0026ge;\u0026thinsp;80% agreement) was achieved.\u003c/p\u003e \u003cp\u003e \u003cb\u003eInformed consent and ethical approval\u003c/b\u003e \u003c/p\u003e \u003c/p\u003e \u003cp\u003eAll participants received an introductory statement at the start of each survey outlining the study\u0026rsquo;s purpose, the voluntary nature of participation, and assurances of confidentiality and anonymity. The participants\u0026rsquo; decision to proceed with the survey implied consent. The Research Advisory Council (RAC) at King Faisal Specialist Hospital and Research Center (RAC2231314) granted ethical approval for the study.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAll 15 panelists successfully completed the two rounds of the modified Delphi process. After the first round, eight statements were rephrased to improve clarity, while two statements were omitted (see Supplement, Table S2 for results from the First Round of Voting and Table S3 for modifications after the first round). Ultimately, eight overarching principles and ten consensus recommendation statements were finalized and organized into five core domains (see Table I). The eight overarching principles provide a contemporary perspective on defining and managing MIIDDs, establishing a framework for the subsequent recommendations (see Table II).\u003c/p\u003e\n\u003ch3\u003eDomain A: Definitions and Conceptual Framework\u003c/h3\u003e\n\u003cp\u003eThe term MIIDDs is proposed as a unifying umbrella term encompassing a heterogeneous group of conditions. These disorders are characterized by pathogenic gene mutations, leading to autoimmune or autoinflammatory manifestations, or features of immune system dysregulation, with clinical features evolving over time.\u003c/p\u003e\n\u003ch3\u003eDomain B: Diagnostic and Monitoring Considerations\u003c/h3\u003e\n\u003cp\u003eThe availability, accessibility, and accurate interpretation of genetic testing are crucial for identifying MIIDDs patients and improving their overall care outcomes. Molecular genetic testing has revolutionized the diagnosis of immune-mediated inflammatory conditions and advanced our understanding of the link between IEIs and inflammatory conditions [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Delayed diagnosis has been reported in patients with monogenic IEIs, promoting calls to expand access to genetic testing and functional assessment of variant of uncertain significance (VUS) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Panelists emphasized the importance of clinical monitoring and documenting improvements in laboratory indices as treatment responses. Future research endeavors should focus on identifying tailored biomarkers, establishing standardized definitions for disease remission, and developing validating indices for disease activity and damage.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eDomain C. Treatment and Therapeutic Options\u003c/h2\u003e \u003cp\u003eAchieving clinical improvement is a feasible goal for MIIDDs patients. Depending on the clinical presentation and immunologic profile, different treatment modalities may be employed. These include corticosteroids, conventional disease-modifying antirheumatic drugs, intravenous immunoglobulin, and antibiotic prophylaxis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The identification of pathogenic mutations and deciphering disease mechanisms has facilitated the development of precision medicine, offering tailored treatments such as hematopoietic stem cell transplant, gene therapy, and the use of targeted biologics or small molecules [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eDomain D: Multidisciplinary and Collaborative Care\u003c/h2\u003e \u003cp\u003eDepending on the dominant clinical presentation, the primary healthcare provider may be either a rheumatologist or an immunologist. However, panelists unanimously agreed that joint rheumatology/immunology care or clinics are advocated for optimizing care for MIIDDs patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Furthermore, collaboration with other subspecialties is occasionally necessary due to the diverse spectrum of MIIDDs, underscoring the importance of a multidisciplinary approach. Patients should also be screened for additional non-inflammatory autoimmune conditions or malignancies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eDomain E: Patient Education and Support\u003c/h2\u003e \u003cp\u003ePatient education and ongoing support are strongly advocated, given the limited availability of publicly accessible information on rare disorders.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study introduces the concept of MIIDDs as a unifying framework for a heterogeneous subgroup of IEIs characterized by pathogenic genetic mutations, immune dysregulation, and prominent inflammatory features. Through an SLR and a modified Delphi process, we sought to address the current gaps in defining and approaching these rare disorders. The MIIDDs framework recognizes the overlap between immunodeficiencies, autoimmunity, and autoinflammation in IEIs, integrating clinical and genetic features under a single umbrella [\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. This approach promotes a deeper understanding of shared pathophysiological mechanisms, streamlining research efforts, and fostering cohesive clinical guidelines.\u003c/p\u003e \u003cp\u003eOur findings highlight the critical role of genetic testing in identifying MIIDDs. Expanding access to genetic testing and training clinicians in interpreting molecular genetic data are essential for early diagnosis and effective management [\u003cspan additionalcitationids=\"CR17 CR18 CR19\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The consensus underscores the need for validated tools, such as standardized definitions of disease remission and activity indices, to monitor disease progression and treatment outcomes [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTreatment strategies for MIIDDs are diverse and evolving [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. While conventional approaches, such as corticosteroids and immunosuppressants, remain pivotal, advances in precision medicine, including biologics, small molecules, and gene therapies, offer promising, targeted, and more effective interventions [\u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Individualized treatment plans based on specific pathogenic mutations could significantly improve patient outcomes [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the diverse clinical manifestations of MIIDDs, joint immunology-rheumatology clinics, and multidisciplinary care teams are essential for optimizing patient management. The consensus strongly advocates for integrating subspecialists, including infectious disease experts, geneticists, and other relevant disciplines, into the care model. This collaborative approach addresses the broad spectrum of features and comorbidities observed in MIIDDs. Additionally, patient education and psychosocial support are integral, given the emotional and logistical challenges faced by patients and families [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn conclusion, this consensus-driven framework established foundational principles for defining and approaching MIIDDs, improving the current classification for IEIs with inflammatory features. Future efforts should focus on validating this framework through clinical and genetic studies, developing disease-specific indices, and fostering international collaboration to advance research and improve outcomes for these complex disorders.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePIDs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePrimary Immunodeficiencies\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIUIS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Union of Immunological Societies\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIEIs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInborn Errors of Immunity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMIIDDs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMonogenic Inflammatory Immune Dysregulation Disorders\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSLR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSystematic Literature Review\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePRISMA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePreferred Reporting Items for Systematic Reviews and Meta-Analyses\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRAC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eResearch Advisory Council\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eSupplementary Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe attached document contains the supplementary material.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design of study: SMA,\u0026nbsp;HMA. Data analysis and/ or interpretation of data: HMA, SMA, LOM, IAA, All authors made substantial contributions to the interpretation of data for the work. SE, HA, SJ, HM, MO, AA, TA, WC, GE, MF, AG, DH, NM, HW contributed to data interpretation, manuscript drafting, or critical revision for intellectual content. All authors reviewed and approved the final manuscript. All authors are accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo specific funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations and Competing Interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have neither competing financial nor non-financial interests in relation to this work. Also, no potential conflict of interest is relevant to this article. LOM and MLF received a grant from the USP-COFECUB programme (AuBraFra-autoinflmmation Brazil-France) reference 49906-YC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research protocol was approved by the Research Advisory Council (RAC) at King Faisal Specialist Hospital and Research Center (RAC2231314). The study was carried out in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFudenberg HH, Good RA, Hitzig W, Kunkel HG, Roitt IM, Rosen FS, et al. Classification of the primary immune deficiencies: WHO recommendation. N Engl J Med. 1970 Sep 17;283(12):656-7. doi: 10.1056/NEJM197009172831211. \u003c/li\u003e\n\u003cli\u003ePicard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova JL, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. J Clin Immunol. 2018 Jan;38(1):96-128. doi: 10.1007/s10875-017-0464-9.\u003c/li\u003e\n\u003cli\u003eThalhammer J, Kindle G, Nieters A, Rusch S, Sepp\u0026auml;nen MRJ, Fischer A, et al; European Society for Immunodeficiencies Registry Working Party. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations. J Allergy Clin Immunol. 2021 Nov;148(5):1332-1341.e5. doi: 10.1016/j.jaci.2021.04.015.\u003c/li\u003e\n\u003cli\u003eNotarangelo LD, Bacchetta R, Casanova JL, Su HC. Human inborn errors of immunity: An expanding universe. Sci Immunol. 2020 Jul 10;5(49): eabb1662. doi: 10.1126/sciimmunol. abb1662. \u003c/li\u003e\n\u003cli\u003eTangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al I. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022 Oct;42(7):1473-1507. doi: 10.1007/s10875-022-01289-3.\u003c/li\u003e\n\u003cli\u003eSogkas G, Witte T. The link between rheumatic disorders and inborn errors of immunity. EBioMedicine. 2023 Apr; 90:104501. doi: 10.1016/j.ebiom.2023.104501. \u003c/li\u003e\n\u003cli\u003eBranch A, Modi B, Bahrani B, Hildebrand KJ, Cameron SB, Junker AK, et al. Diverse clinical features and diagnostic delay in monogenic inborn errors of immunity: A call for access to genetic testing. Pediatr Allergy Immunol. 2021 Nov;32(8):1796-1803. doi: 10.1111/pai.13571.\u003c/li\u003e\n\u003cli\u003eMcInnes IB, Gravallese EM. Immune-mediated inflammatory disease therapeutics: past, present and future. Nat Rev Immunol. 2021 Oct;21(10):680-686. doi: 10.1038/s41577-021-00603-1. \u003c/li\u003e\n\u003cli\u003ePinto MV, Neves JF. Precision medicine: The use of tailored therapy in primary immunodeficiencies. Front Immunol. 2022 Dec 8; 13:1029560. doi: 10.3389/fimmu.2022.1029560. \u003c/li\u003e\n\u003cli\u003eBigley TM, Cooper MA. Monogenic autoimmunity and infectious diseases: the double-edged sword of immune dysregulation. Curr Opin Immunol. 2021 Oct; 72:230-238. doi: 10.1016/j.coi.2021.06.013.\u003c/li\u003e\n\u003cli\u003eGoyal R, Bulua AC, Nikolov NP, Schwartzberg PL, Siegel RM. Rheumatologic and autoimmune manifestations of primary immunodeficiency disorders. Curr Opin Rheumatol. 2009 Jan;21(1):78-84. doi: 10.1097/BOR.0b013e32831cb939. \u003c/li\u003e\n\u003cli\u003eArakelyan A, Nersisyan L, Poghosyan D, Khondkaryan L, Hakobyan A, L\u0026ouml;ffler-Wirth H, et al. Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles. PLoS One. 2017 Nov 3;12(11): e0187572. doi: 10.1371/journal.pone.0187572.\u003c/li\u003e\n\u003cli\u003eChan AY, Torgerson TR. Primary immune regulatory disorders: a growing universe of immune dysregulation. Curr Opin Allergy Clin Immunol. 2020 Dec;20(6):582-590. doi: 10.1097/ACI.0000000000000689. PMID: \u003c/li\u003e\n\u003cli\u003eJamee M, Azizi G, Baris S, Karakoc-Aydiner E, Ozen A, Kili\u0026ccedil; SŞ, et al. Clinical, immunological, molecular and therapeutic findings in monogenic immune dysregulation diseases: Middle East and North Africa registry. Clin Immunol. 2022 Nov; 244:109131. doi: 10.1016/j.clim.2022.109131.\u003c/li\u003e\n\u003cli\u003eL\u0026oacute;pez-Nevado M, Gonz\u0026aacute;lez-Granado LI, Ruiz-Garc\u0026iacute;a R, Pleguezuelo D, Cabrera-Marante O, Salm\u0026oacute;n N, et al. Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management. Front Immunol. 2021 Aug 10; 12:671755. doi: 10.3389/fimmu.2021.671755.\u003c/li\u003e\n\u003cli\u003ePascual V, Chaussabel D, Banchereau J. A genomic approach to human autoimmune diseases. Annu Rev Immunol. 2010; 28:535-71. doi: 10.1146/annurev-immunol-030409-101221.\u003c/li\u003e\n\u003cli\u003eDelmonte OM, Castagnoli R, Calzoni E, Notarangelo LD. Inborn Errors of Immunity With Immune Dysregulation: From Bench to Bedside. Front Pediatr. 2019 Aug 27; 7:353. doi: 10.3389/fped.2019.00353.\u003c/li\u003e\n\u003cli\u003eKaracan İ, Balamir A, Uğurlu S, Aydın AK, Everest E, Zor S, \u0026Ouml;nen M\u0026Ouml;, et al. Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study. Rheumatol Int. 2019 May;39(5):911-919. doi: 10.1007/s00296-019-04252-5.\u003c/li\u003e\n\u003cli\u003eMerlo Pich LM, Ziogas A, Netea MG. Genetic and epigenetic dysregulation of innate immune mechanisms in autoinflammatory diseases. FEBS J. 2024 Oct;291(20):4414-4432. doi: 10.1111/febs.17116.\u003c/li\u003e\n\u003cli\u003evon Hardenberg S, Klefenz I, Steinemann D, Di Donato N, Baumann U, Auber B, Klemann C. Current genetic diagnostics in inborn errors of immunity. Front Pediatr. 2024 Apr 10; 12:1279112. doi: 10.3389/fped.2024.1279112. \u003c/li\u003e\n\u003cli\u003eSeidel MG, Tesch VK, Yang L, Hauck F, Horn AL, Smolle MA, et al. The Immune Deficiency and Dysregulation Activity (IDDA2.1 \u0026apos;Kaleidoscope\u0026apos;) Score and Other Clinical Measures in Inborn Errors of Immunity. J Clin Immunol. 2022 Apr;42(3):484-498. doi: 10.1007/s10875-021-01177-2.\u003c/li\u003e\n\u003cli\u003eKon\u0026eacute;-Paut I, Piram M, Benseler S, Kuemmerle-Deschner JB, Jansson A, Rosner I, et al. Use of the Auto-inflammatory Disease Activity Index to monitor disease activity in patients with colchicine-resistant Familial Mediterranean Fever, Mevalonate Kinase Deficiency, and TRAPS treated with canakinumab. Joint Bone Spine. 2022 Nov;89(6):105448. doi: 10.1016/j.jbspin.2022.105448.\u003c/li\u003e\n\u003cli\u003eTouitou I, J\u0026eacute;ziorski E, Al-Saleh A, Carbasse A, Piram M. Quality of life in monogenic autoinflammatory diseases. A review. Joint Bone Spine. 2023 Mar;90(2):105475. doi: 10.1016/j.jbspin.2022.105475.\u003c/li\u003e\n\u003cli\u003eMcInnes IB, Gravallese EM. Immune-mediated inflammatory disease therapeutics: past, present and future. Nat Rev Immunol. 2021 Oct;21(10):680-686. doi: 10.1038/s41577-021-00603-1.\u003c/li\u003e\n\u003cli\u003eMcBride DA, Jones RM, Bottini N, Shah NJ. The therapeutic potential of immunoengineering for systemic autoimmunity. Nat Rev Rheumatol. 2024 Apr;20(4):203-215. doi: 10.1038/s41584-024-01084-x.\u003c/li\u003e\n\u003cli\u003eKaegi C, Wuest B, Crowley C, Boyman O. Systematic Review of Safety and Efficacy of Second- and Third-Generation CD20-Targeting Biologics in Treating Immune-Mediated Disorders. Front Immunol. 2022 Feb 2; 12:788830. doi: 10.3389/fimmu.2021.\u003c/li\u003e\n\u003cli\u003eArnold DD, Yalamanoglu A, Boyman O. Systematic Review of Safety and Efficacy of IL-1-Targeted Biologics in Treating Immune-Mediated Disorders. Front Immunol. 2022 Jul 6; 13:888392. doi: 10.3389/fimmu.2022.888392.\u003c/li\u003e\n\u003cli\u003eRomano M, Arici ZS, Piskin D, Alehashemi S, Aletaha D, Barron KS, Benseler S, et al. The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist. Ann Rheum Dis. 2022 Jul;81(7):907-921. doi: 10.1136/annrheumdis-2021-221801\u003c/li\u003e\n\u003cli\u003eSlatter M, Lum SH. Personalized hematopoietic stem cell transplantation for inborn errors of immunity. Front Immunol. 2023 Apr 5; 14:1162605. doi: 10.3389/fimmu.2023.1162605. \u003c/li\u003e\n\u003cli\u003eMudde A, Booth C. Gene therapy for inborn error of immunity - current status and future perspectives. Curr Opin Allergy Clin Immunol. 2023 Feb 1;23(1):51-62. doi: 10.1097/ACI.0000000000000876.\u003c/li\u003e\n\u003cli\u003eNicholson B, Goodman R, Day J, Worth A, Carpenter B, Sandford K, et al. Quality of Life and Social and Psychological Outcomes in Adulthood Following Allogeneic HSCT in Childhood for Inborn Errors of Immunity. J Clin Immunol. 2022 Oct;42(7):1451-1460. doi: 10.1007/s10875-022-01286-6.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable I. Core Domains Addressed in the Consensus\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eDomain A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 390px;\"\u003e\n \u003cp\u003eDefinitions and Conceptual Framework\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eDomain B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 390px;\"\u003e\n \u003cp\u003eDiagnostic and Monitoring Considerations\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eDomain C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 390px;\"\u003e\n \u003cp\u003eTreatment and Therapeutic Options\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eDomain D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 390px;\"\u003e\n \u003cp\u003eMultidisciplinary and Collaborative Care\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eDomain E\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 390px;\"\u003e\n \u003cp\u003ePatient Education and Support\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable II. Overarching Principles and Final Recommendations for Patients with MIIDDs\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" valign=\"top\" style=\"width: 286px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAgreement\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDescriptive Statistics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePercentage (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStandard deviation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInterquartile range\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverarching Principles\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eA.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eMonogenic Inflammatory Immune-Dysregulation Disorders (MIIDDs) is an umbrella term for a heterogeneous group of disorders.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eA.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eA patient with Monogenic Inflammatory Immune-Dysregulation Disorder (MIIDD) is defined as having a pathogenic gene mutation, immune system dysregulation, and inflammatory manifestations with clinical features that can evolve over time.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eB.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eThe availability, accessibility, and accurate interpretation of genetic testing will enhance patient identification and improve overall care outcomes.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e93.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eB.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eThere is a need for the development of a definition of disease remission in patients with MIIDDs.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eB.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eThere is a need for the development and validation of disease activity and damage indices for patients with MIIDDs.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eC.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eClinical improvement while on treatment is a feasible goal in the management of patients with MIIDDs.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e93.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eC.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eMore effective therapeutic options for the management of patients with MIIDDs should be explored and tested.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eC.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eThere is a need for the development of therapeutic guidelines for the management of patients with MIIDDs.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecommendations\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eB.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eClinical and laboratory improvement should be used to assess the response to treatment.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eC.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eCorticosteroids may serve as a therapeutic option for some patients with MIIDDs, depending on the clinical context and individual patient needs.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e93.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eC.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eBoth conventional and/or biologic disease-modifying antirheumatic drugs may serve as therapeutic options for some patients with MIIDDs, depending on the clinical context and individual patient needs.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eC.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eIntravenous immunoglobulin (IVIG) may serve as a therapeutic option for some patients with MIIDDs, depending on the clinical context and individual patient needs.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eC.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eAntibiotic prophylaxis may be required for some patients with MIIDDs, depending on the clinical context and individual patient needs.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e86.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e3.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eC.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eA hematopoietic stem cell transplant may be needed for some patients with MIIDDs, depending on the clinical context and individual patient needs.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e86.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e3.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eD.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eBased on the predominant clinic picture in patients with MIIDDs, the primary healthcare provider can be a rheumatologist or an immunologist. However, joint rheumatology/immunology care or clinics are advocated to provide optimum care for patients with MIIDDs.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eD.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eCollaboration with other subspecialties as needed is advocated in the care of patients with MIIDDs.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eD.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003ePatients with MIIDDs should be screened for other non-inflammatory autoimmune conditions, such as autoimmune thyroiditis.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e86.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eE.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003ePatients with MIIDDs should be educated regarding their disease and provided with ongoing support.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eMIIDDs: Monogenic Inflammatory Immune-Dysregulation Disorders\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"proj","sideBox":"Learn more about [Pediatric Rheumatology](http://ped-rheum.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/proj/default.aspx","title":"Pediatric Rheumatology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"inborn errors of immunity, genetic, inflammatory, autoimmune, autoinflammatory, immune dysregulation, consensus","lastPublishedDoi":"10.21203/rs.3.rs-5942561/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5942561/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo achieve consensus on the definition and clinical approach of Monogenic Inflammatory Immune Dysregulation Disorders (MIIDDs), a collective term for rare conditions marked by inflammation, immune dysregulation, and infection susceptibility.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e A multi-step, evidence-based, multidisciplinary consensus process was employed, consisting of: 1) a systematic literature review across four electronic databases (Cochrane Library, Web of Science, Scopus, and MEDLINE via PubMed), updated through December 31, 2024; 2) a pre-Delphi electronic survey completed by 95 international adult and pediatric immunologists and rheumatologists; and 3) a modified online Delphi process with an international multidisciplinary expert panel, where statements were iteratively analyzed and refined until achieving consensus (\u0026ge;\u0026thinsp;80% agreement among panelists).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFifteen experts from 12 countries participated in two rounds of the Delphi process, resulting in the development of eight overarching principles and 10 consensus statements. These were categorized into five domains: 1) definitions and conceptual framework, 2) diagnostic and monitoring considerations, 3) treatment and therapeutic strategies, 4) multidisciplinary and collaborative care, and 5) patient education and support.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis consensus defines MIIDDs and provides a structured clinical framework to streamline research efforts and improve patient outcomes.\u003c/p\u003e","manuscriptTitle":"International Multidisciplinary Consensus on the Definition and Clinical Approach for Monogenic Inflammatory Immune Dysregulation Disorders","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-06 06:57:57","doi":"10.21203/rs.3.rs-5942561/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-03-24T02:20:20+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-19T13:20:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"274948017892527446323331333887889153869","date":"2025-02-26T09:33:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-12T10:39:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"82542208589882463777460353188132917448","date":"2025-02-10T07:12:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-02-06T02:57:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-02-05T04:22:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-02-05T04:21:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Rheumatology","date":"2025-02-01T15:34:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"proj","sideBox":"Learn more about [Pediatric Rheumatology](http://ped-rheum.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/proj/default.aspx","title":"Pediatric Rheumatology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a034ad3b-a4b2-48e6-b51e-aff6b3d3d3eb","owner":[],"postedDate":"February 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-19T16:04:10+00:00","versionOfRecord":{"articleIdentity":"rs-5942561","link":"https://doi.org/10.1186/s12969-025-01109-z","journal":{"identity":"pediatric-rheumatology","isVorOnly":false,"title":"Pediatric Rheumatology"},"publishedOn":"2025-05-14 15:57:38","publishedOnDateReadable":"May 14th, 2025"},"versionCreatedAt":"2025-02-06 06:57:57","video":"","vorDoi":"10.1186/s12969-025-01109-z","vorDoiUrl":"https://doi.org/10.1186/s12969-025-01109-z","workflowStages":[]},"version":"v1","identity":"rs-5942561","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5942561","identity":"rs-5942561","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}