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familial-mediterranean-fever

README.md

Familial Mediterranean Fever (FMF) — QSP Model

Mechanistic Map

Disease Overview

Familial Mediterranean Fever (FMF) is the most common hereditary autoinflammatory disease, caused by gain-of-function mutations in the MEFV gene encoding PYRIN (marenostrin). It is characterized by episodic self-limited attacks of fever and serositis (peritonitis, pleuritis, synovitis), and carries a major long-term risk of AA amyloidosis leading to renal failure.

Feature Details
Gene MEFV (chromosome 16p13.3)
Protein PYRIN / Marenostrin
Inheritance Autosomal recessive (AR); some AD-like phenotypes
Prevalence 1:200–1:1000 in Mediterranean populations
Key mutations M694V, M680I, V726A, E148Q, M694I
Onset Usually < 20 years
Episodes Fever 38–40°C + serositis, 12–72h duration
Major complication AA amyloidosis → CKD/ESRD

Molecular Pathophysiology

MEFV mutation (M694V/M680I)
    │
    ▼
PYRIN protein: impaired RhoA/PKN1-PKN2–mediated phosphorylation
    │         → cannot be inactivated → constitutively active
    ▼
ASC speck assembly (Ser208/Ser242 phosphorylation blocked)
    │
    ▼
Caspase-1 activation
    │
    ├──► Pro-IL-1β cleavage → mature IL-1β (17 kDa) secretion
    ├──► Pro-IL-18 cleavage → IL-18 secretion
    └──► Gasdermin D (GSDMD) cleavage → pyroptosis pores → sterile inflammation
    
IL-1β / IL-18 ──► fever, acute phase response (SAA↑, CRP↑), serositis, neutrophil influx
SAA excess ──► AA amyloid fibril deposition in kidney, liver, spleen
AA amyloidosis ──► nephrotic syndrome → CKD → ESRD

Model Architecture

Mechanistic Map (fmf_qsp_model.dot/.svg/.png)

10 subgraph clusters:

  1. Genetic Basis — MEFV alleles, mutation severity scores
  2. PYRIN Inflammasome — RhoA-GTP, phospho-PYRIN, ASC speck, Caspase-1, GSDMD
  3. Innate Immunity — neutrophil recruitment, NF-κB, NLRP3 crosstalk
  4. Cytokines & Acute Phase — IL-1β, IL-18, IL-6, TNF-α, SAA, CRP
  5. Acute Attack Manifestations — peritonitis, pleuritis, synovitis, fever, erythema
  6. Long-term Complications — AA amyloidosis, renal amyloidosis, CKD, ESRD
  7. Biomarkers & Clinical Endpoints — AIDAI, PGA, SAA, CRP, eGFR
  8. Colchicine PK — oral absorption, 2-compartment, leukocyte accumulation
  9. IL-1 Inhibitor PK — Anakinra SC, Canakinumab 2-compartment SC
  10. Drug PD — colchicine tubulin/PYRIN inhibition, anakinra IL-1R blockade, canakinumab IL-1β neutralization

mrgsolve ODE Model (fmf_mrgsolve_model.R)

22 ODE compartments:

Module Compartments
Colchicine PK GUT → CENTRAL → PERIPHERAL + LEUKOCYTE (4)
Anakinra PK SC depot → CENTRAL (2)
Canakinumab PK SC depot → CENTRAL → PERIPHERAL (3)
PYRIN inflammasome RhoA, Pyrin_phospho, ASC_speck, Caspase1 (4)
Cytokines IL-1β_pro, IL-1β_mature, IL-18, SAA, CRP (5)
Neutrophils Circulating ANC, tissue neutrophils (2)
Attack dynamics Trigger signal, severity score (2)
Amyloidosis AA deposits, eGFR (2)

5 Treatment scenarios:

  1. No treatment (untreated M694V phenotype)
  2. Colchicine 0.5 mg BID (standard first-line)
  3. Colchicine 1.0 mg QD (alternative dosing)
  4. Anakinra 100 mg SC QD (IL-1Ra, colchicine-resistant)
  5. Canakinumab 150 mg SC Q8W (anti-IL-1β mAb, CLUSTER trial)

Key PK parameters (colchicine):

  • F = 45%; Vd ~5 L/kg; t½ ~30h; leukocyte:plasma ratio ~10:1
  • Mechanism: tubulin polymerization inhibition → neutrophil immobility; PYRIN/NLRP3 inhibition

Shiny Dashboard (fmf_shiny_app.R)

8 interactive tabs:

Tab Content
1. Patient Profile MEFV genotype, labs, drug selection, disease classification
2. Drug PK Colchicine plasma/leukocyte, Anakinra, Canakinumab PK curves
3. Inflammasome Dynamics PYRIN, ASC, Caspase-1, IL-1β under drug effect
4. Attack Simulation Attack frequency/severity time series, statistics
5. Clinical Endpoints SAA, CRP, AIDAI, eGFR, outcome boxes
6. Scenario Comparison Multi-arm comparison table + bar chart
7. Amyloidosis Risk Long-term SAA, AA deposits, eGFR projection (≤20 years)
8. Sensitivity Analysis One-at-a-time parameter sensitivity

Key Clinical Trials Informing Parameters

Trial Drug N Key Finding
Zemer et al. 1986 NEJM Colchicine 470 75% attack reduction; amyloidosis prevention
De Benedetti et al. 2018 NEJM (CLUSTER) Canakinumab 63 (FMF) Attack-free 61% vs 6% placebo; SAA normalization
Georgin-Lavialle et al. 2020 Anakinra 67 Rapid attack resolution; SAA reduction
Varan et al. 2019 IL-1 inhibitors 72 Amyloidosis regression with IL-1 blockade

Drug Mechanisms

Drug Target Mechanism Route Dosing
Colchicine Tubulin / PYRIN Blocks neutrophil microtubule polymerization; reduces PYRIN activity Oral 0.5–1 mg QD/BID
Anakinra IL-1 receptor (IL-1R1) Competitive antagonist; blocks both IL-1α and IL-1β SC daily 100 mg/day
Canakinumab IL-1β (free) Neutralizing anti-IL-1β monoclonal antibody; t½ ~26d SC Q8W 150 mg
Rilonacept IL-1α + IL-1β Dimeric IL-1 trap (ILRAP-Fc) SC weekly 160 mg

Files

File Description
fmf_qsp_model.dot Graphviz source (fdp layout, 100+ nodes, 10 clusters)
fmf_qsp_model.svg Vector mechanistic map
fmf_qsp_model.png Raster thumbnail (150 dpi)
fmf_mrgsolve_model.R mrgsolve ODE model (22 compartments, 5 scenarios)
fmf_shiny_app.R Shiny dashboard (8 tabs)
fmf_references.md 50 curated PubMed references

Quick Start

# Install dependencies (first time)
install.packages(c("mrgsolve", "dplyr", "tidyr", "ggplot2", "patchwork",
                   "shiny", "DT"))

# Run mrgsolve simulation
source("fmf_mrgsolve_model.R")
print(summary_metrics)
combined_plot

# Launch Shiny app
shiny::runApp("fmf_shiny_app.R")

References

See fmf_references.md — 50 citations organized by topic: genetics · PYRIN inflammasome · IL-1β biology · colchicine · IL-1 inhibitors · amyloidosis · classification criteria · QSP modeling

Added 2026-06-25 | Claude Code Routine (CCR) | QSP Model Library