SJIA

Weaning Therapy

Fatma Dedeoglu, MD

Boston Children's Hospital

Harvard Medical School 11/15/2024

Disclosures

UpToDate (Royalties) SOBI (Honorarium)


PATTERNS

• glyph Recurrent/Episodic with long off medication
• glyph Persistent but with medication free periods
• glyph Persistent with need for continuous therapy

• · 18 yo M
• · Dx Still's
• · Very high ESR (130), CRP (25 mg/dl)
• · High WBC, plt
• · IL-18 9000 range, CXCL9 nl
• · Anakinra with wean to QOD in 4 months
• · Flare in 1 week back to daily anakinra


Patient 1


• · 13 yo F

Patient 2

• · Presented at age 4
• · Multiple MAS episodes, evolving into autoimmunity (Sjogren's)
• · Anakinra, canakinumab, tocilizumab
• · Prolonged and intermittent steroids (no use for 2 ½ years)
• · Tacrolimus
• · Jakinibs ( ruxolitinib)
• · Elevated persistent IL-18 during remission
• · IL-18/ CXCL9: 300000 in 2018 (ferritin: 1600)

Ferritin: Normal-300

71000/ 254- in 2019

28000 - in 2020 -> 15000 in 2020

67000/ 3290 in 2021 -> 23000/1742 in 2021;

38000/3267; 42000/1950 in 2022 ……

• · 2024: MAS flare during switch to jakinib & viral illness

Patient 3

• · 22 yo F- Still Disease /MAS
• · Age 19 y fever, rash, cytopenia, pancreatitis, liver disease- intermittent for 4-5 months then persistent
• · 1 st episode self resolve
• · 2 nd episode,1 month later: steroids, anakinra
• · 3 rd episode, 2 months later (prolonged hospital stay): add jakinib (tofacitinib), stopped anakinra before d/c
• · Weaning tofacitinib after 2 years slowly (BID->QD->QOD) successful so far
• · IL-18/CXCL9/ferritin
• - 318000/5000/30000
• - 48000/360/1900
• - 7000/1200/800

• · Age 3 y

Patient 4 & 5

• · Age 5 y
• · 7 mo: fever, rash
• · ESR:70, CRP:15, high WBC, plt
• · Anakinra
• · Wean over 18m (QOD, Q3d->stop)
• · IL-18/CXCL9/ferritin - 12000/600/600

• · 20 mo: fever, rash, anemia, low plt
• · ESR 13-35, CRP 2-7
• · Steroids (2 ½ m),anakinra (daily for 5 m)
• · Wean (QOD/4m->Q3d/2m ->stop)
• · IL-18/CXCL9/ferritin - 250000/600/1600

Patient 6

• · Age 1

• · Started on anakinra (1year)
• · flare 18 m later; brief anakinra -> canakinumab (weaned off in 1 y)
• · MAS flare after 3 years (3 days pulse steroids, 1 dose of canakinumab & anakinra BID -> in 1 month to QD
• · Switched to canakinumab after 2 months
• · No flares since
• · All labs normalized (IL-18 fluctuates 700-27000)



GAPS

• ❖ Need to improve interpretation of genetic test results


❖


• Need to understand influence of epigenetics better

• ❖ Need to solve decreasing drug efficacy issue

Example

• · This sequence change replaces serine with arginine at codon 1419 of the FAT4 protein (p.Ser1419Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine.
• · This variant is present in population databases (rs377613970, ExAC 0.004%).
• · This variant has not been reported in the literature in individuals with FAT4-related conditions. ClinVar contains an entry for this variant (Variation ID: 452815).
• · Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FAT4 protein function.
• · In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.


• ❖


GAPS

Need to improve delivery of care

• ❖ Need to improve preventive care, vaccinations
• ❖ Need to understand, monitor damage better

• ❖ Need more precise outcome measures

Summary

• 🧿 Follow clues

• glyph Clinical (similarities to other diseases, patient you see, medication response)
• glyph Labs (usual, unusual, unique)
• glyph Genetic and biologic (does it fit?)


MANAGEMENT



SHARED DECISION MAKING



The Key



Collaboration



THANK YOU



Our patients and families



connecting the dots to find a cure



Pui Lee Peter Nigrovic



Boston Children's Hospital (BCH) Rheumatology Program and Autoinflammatory Clinic staff



Lauren Henderson Holly Wobma