International Multidisciplinary Consensus (2025): Definition and Clinical‑Approach for Monogenic Inflammatory Immune‑Dysregulation Disorders（MIIDDs）PubMed

Journal: Pediatric Rheumatology, 2025；PMID: 40369629 Delphi‑based modified‑consensus process; 15 experts from 12 countries; 8 overarching‑principles + 10 formal‑consensus‑statements; ≥80 %‑voting‑agreement threshold for consensus‑approval梅斯医学

Abstract

Objective To establish unified‑terminology and standardized‑clinical‑workflow for Monogenic Inflammatory Immune‑Dysregulation Disorders (MIIDDs), a heterogeneous group of rare‑inborn‑errors‑of‑immunity characterised by sterile‑inflammation, multi‑axis immune‑dysregulation and increased‑infection‑susceptibility. Only pathogenic / likely‑pathogenic gene‑variants (ACMG‑classified) are included; variants‑of‑unknown‑significance (VUS) are explicitly excluded from diagnostic‑criteria.

Methods

1. Systematic‑literature‑review up to 31 Dec 2024 (Cochrane‑Library, Web‑of‑Science, Scopus, MEDLINE‑PubMed).
2. Pre‑Delphi‑global‑survey among 95 adult‑paediatric‑immunologists‑rheumatologists.
3. Two‑round modified‑Delphi‑voting by international‑expert‑panel, iteratively refining statements until consensus‑threshold reached梅斯医学.

Results Final outputs cover five‑core‑domains:

1. Definition & conceptual‑framework
2. Diagnostic‑work‑up & longitudinal‑monitoring
3. Therapeutic‑strategies
4. Multidisciplinary‑collaborative‑care‑model
5. Patient‑education, psychosocial‑support & genetic‑counsellingPubMed

Conclusion This consensus introduces the umbrella‑term MIIDDs, delivers actionable‑clinical‑pathway, harmonises phenotyping‑practice and facilitates cross‑centre‑research‑registries for these rare‑inborn‑immune‑conditions.

Keywords: monogenic‑immune‑disease; autoinflammation; autoimmunity; immune‑dysregulation; inborn‑errors‑of‑immunity; genetic‑diagnosis; Delphi‑consensus

Domain A ‑ Definition and conceptual‑framework

Umbrella‑term MIIDDs: patients must satisfy all three criteria simultaneously

1. Presence of pathogenic / likely‑pathogenic germline‑variant affecting genes governing innate‑and‑adaptive‑immune‑pathways (ACMG criteria; functional‑assay‑validation preferred). VUS cannot establish diagnosis.
2. Clinical‑evidence of immune‑system‑dysregulation: may present as autoinflammation, autoimmunity, immunodeficiency‑phenotype, or mixed‑overlap‑features.
3. Evident sterile‑inflammatory‑manifestations; clinical‑phenotypes are dynamic and may evolve across age‑time‑course.

MIIDD unifies previously‑fragmented‑entities: interferonopathies, monogenic‑lupus, inflammasomopathies, STAT‑/NF‑κB‑pathway‑gain‑or‑loss‑of‑function‑disorders, immune‑regulatory‑gene‑defects and related mixed‑phenotype‑inborn‑errors‑of‑immunity.

Distinction reminder:

• Autoinflammation‑predominant: mainly innate‑immune hyperactivation.
• Autoimmunity‑predominant: breakdown of adaptive‑immune‑tolerance (auto‑antibodies, autoreactive‑lymphocytes).
• Many MIIDD patients show mixed‑auto‑inflammatory‑and‑auto‑immune‑overlap‑phenotypes.

Domain B ‑ Diagnostic & monitoring considerations

1. Red‑flag‑clinical‑clues prompting MIIDD‑genetic‑work‑up
   • Early‑onset recurrent‑or‑persistent sterile‑inflammation; multi‑organ‑involvement.
   • Combined features: autoimmunity + autoinflammation + recurrent‑infections.
   • Positive‑family‑history of early‑onset immune‑mediated‑disease; consanguineous‑pedigree.
   • Poor‑or‑partial‑response to conventional‑immunosuppression.
2. Step‑wise‑diagnostic‑algorithm
   1. Comprehensive‑phenotyping: full history‑taking, physical‑examination, inflammatory‑markers, auto‑antibody‑panel, immunological‑phenotyping (lymphocyte‑subsets, cytokine‑profile).
   2. Exclude secondary‑acquired‑causes (infection, malignancy, drug‑induced‑immune‑activation).
   3. Genetic‑testing strategy: start with targeted‑gene‑panel; if negative proceed to WES / WGS. Interpret variants strictly using ACMG‑classification; functional‑validation improves confidence.
3. Longitudinal‑monitoring‑principles
   • Clinical‑outcome: organ‑damage‑burden, flare‑frequency, growth‑development (paediatric cohort).
   • Laboratory: inflammatory‑markers, immunological‑read‑outs, infection‑surveillance, drug‑safety‑biochemistry.
   • Genetic‑counselling should run in parallel throughout follow‑up.

Domain C ‑ Treatment‑therapeutic‑strategies

1. Core‑principle: Therapy is phenotype‑driven, not purely‑genotype‑driven; one‑gene‑variant can produce variable‑clinical‑expressivity among individuals.
2. General‑treatment‑hierarchy
   • Supportive‑care: infection‑prophylaxis, vaccination‑optimisation, organ‑protective‑measures.
   • Broad‑immunosuppression: conventional‑DMARDs, glucocorticoids (minimise long‑term steroid‑exposure).
   • Targeted‑cytokine‑or‑pathway‑biologics (IL‑1‑blockade, JAK‑inhibitors, IFN‑blockade, anti‑TNF‑agents etc), selected based on dominant‑inflammatory‑signature.
   • Curative‑options: haematopoietic‑stem‑cell‑transplant‑HSCT for severe‑refractory‑life‑threatening‑MIIDD cases.
3. Avoid over‑treatment: VUS‑carriers without convincing‑clinical‑phenotype should not receive empirical‑immunosuppressive‑therapy.

Domain D ‑ Multidisciplinary‑collaborative‑care

• Recommended‑core‑team‑members: clinical‑immunologist, paediatric‑adult‑rheumatologist, geneticist‑genetic‑counsellor; as‑needed: nephrology‑neurology‑dermatology‑haematology subspecialists, psychologist‑social‑worker.
• Transition‑care plan: structured‑paediatric‑to‑adult‑health‑care‑transfer is mandatory for adolescent‑patients.
• International‑patient‑registries are encouraged for real‑world‑outcome‑data‑collection.

Domain E ‑ Patient‑education & support

1. Families receive plain‑language‑explanation of genotype‑phenotype‑correlation, disease‑natural‑history, treatment‑risk‑benefit‑profile.
2. Genetic‑counselling covers recurrence‑risk for‑offspring and extended‑family‑members.
3. Address psychosocial‑burden, quality‑of‑life‑assessment; connect with rare‑disease‑patient‑advocacy‑groups.

Key‑take‑aways / Highlights compared with prior‑frameworks

1. New‑unifying‑nosology term MIIDDs for mixed‑auto‑inflammatory‑auto‑immune monogenic‑conditions.
2. Strict‑separation: only pathogenic/likely‑pathogenic‑variants count for diagnosis; VUS alone cannot confirm‑disease.
3. Emphasise frequent‑overlap‑between auto‑inflammatory‑and‑auto‑immune‑phenotypes in monogenic‑immune‑defects (old‑binary‑classification is insufficient).
4. Treatment guided by clinical‑phenotype‑and‑molecular‑pathway, not genotype‑alone.
5. Formal‑requirement for multidisciplinary‑team‑model, genetic‑counselling and adolescent‑transition‑program.

Executive‑summary‑abstract (short‑version for‑PPT‑slide)

2025‑International‑Multidisciplinary‑Consensus‑on‑MIIDDs MIIDDs is an umbrella‑term for rare monogenic‑immune‑disorders caused by pathogenic‑germline‑variants, combining sterile‑inflammation, immune‑dysregulation and infection‑susceptibility. Diagnosis requires integration of clinical‑phenotype, immunology‑work‑up and validated‑genetic‑findings; VUS are insufficient for diagnosis. Management adopts phenotype‑driven‑targeted‑therapy plus multidisciplinary‑care‑model including genetic‑counselling and structured transition‑care.