SJIA and MAS; experience from apex tertiary care referral Institution of India

Narendra Bagri Additional Professor Division of Rheumatology Department of Pediatrics

All India Institute of Medical Sciences(AIIMS), New Delhi, India

Our data (2015- September 2024):

• · n=1022 (63% boys)
• · Age at diagnosis (years), median(IQR): 10.6 (8, 12)
• · Duration of symptoms(months), median (IQR): 9.5 (4-24)
• · ERA in India and Southeast Asia: 32.8-37.4% (Hegde, et al. Indian Journal of Rheumatology,2020;volume 15; issue 4)


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sJIA (2016 - 2024) n= 176

• ·
• Mean age : 7 Years
• ·
• Gender, boys (%) : 108 (61%)
• ·
• Mean delay in diagnosis : 18.5 months

Outcomes in children with JIA receiving bDMARDs : Real-world experience from a resource-limited setting

(IECPG-596/20/09.2023, RT-02/21.02.2024)

Background: Limited data from the LMICs regarding the real-world experience with bDMARDs in JIA

Methods: C hildren with JIA receiving bDMARDs with 3 months follow-up included (Jan 2009August 2024)

Results:

• · N=115
• · 168 patient-years of biologics use

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In all tables, categorical data is presented as proportions, normal continuous data as mean (with standard deviation) and skewed continuous data as median (with interquartile range). LMIC: low & middle-income countries



Key Observations:

• · N=106 (92.1%) achieved remission
• · Serious infections requiring hospitalisation (n=13, 11.3%)
• · Reactivation of tuberculosis in n=4 (3.4%), all on TNFi's

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In all tables, categorical data is presented as proportions, normal continuous data as mean (with standard deviation) and skewed continuous data as median (with interquartile range).


Predictors of outcomes


Macrophage activation syndrome

Retrospective chart review of our unit

Jan 2018- March 2023 n=39 children ( 22 girls) with 43 episodes of MAS

Underlying rheumatic disorder:

• • sJIA 22/43 (51.16%)
• • Others: Lupus, MCTD, JDM

Key observations:

Fever: 41,95.35%)

CNS : (10,23.26%)

Shock : (19,44.18%)

Mortality

In our series: 30%


Macrophage Activation Syndrome in Children: Diagnosis and Management


Case vignette

R.K., a 7-yr-old boy with SJIA since March 2018 presented :

• •

Fever x 7 days

• • Joint pain x 7 days
• • Chest pain x 3 days
• •

Rash x 1 day

On examination:

RR= 38/min, febrile

• · Arthritis of knee joint and
• · Evanescent rash noted during febrile episodes.
• · Pericardial rub was auscultated.
• · Possibilities:

Disease flare vs MAS vs Infection


Total leukocyte count(TLC): 10,600/mm Differential leukocyte count: N80%/L7% Hemoglobin: 11g/dL Platelet count : 2.87 lakh/mm 3

3

• · ECHO: minimal pericardial effusion
• · HRCT: consolidation left lower lobe

Ferritin

(ng/mL)

Cell counts

TLC (/ mm

3

)

Platelet count

(lakhs/mm

3

)

Tachypnea & O2 support

Fever & arthralgia

Observation/intervention

3258

10,600

2.87L

·

Antibiotics

·

Stress dose

steroids

·

IVIG

·

IVMP f/b oral

steroids

69,219

2400

40,000

·

Tocilizumab

• · Cyclosporine

·

Antibiotics upgraded

Week 1 2 3 4

6712

12,310

4.27L

18,140

29,520

8.7L

> 1 L

Shock

MAS

11,533

3317

3880

2.4L

Discharged @ 29

On Oral Cycloporine

Biweekly TCZ

Key concerns


• • Trend of clinical and lab parameters …
• • Erratic total leucocytes in MAS ??
• • IL-6 as 1 st line agent (in settings where Anakinra is not widely available)
• • Controversies ; IL-6 predisposes to MAS
Case vigette

14-yr-old girl Symptomatic since 10 years of age History of multiple blood transfusions

Presented to AIIMS with persistent symptoms

Symptomatic from past 5 months Fever Oral ulcers Joint pains Rash

Anemia and hepatosplenomegaly

Asymptomatic for 4 years

• · ANA 3+
• · Low C3 and C4
• · High dsDNA levels
• · Haematological and skin involvement
• · Diagnosed as SLE
• · On steroids, Danazol, HCQ
• · DCT4+, ICT 1+
• · Autoimmune hemolytic anemia
• · On oral steroids for 6 months
Course


20/10

Course in HDU



80%

NPO



Piperacillin tazobactam/teicoplanin/septran/valganciclovir/lipo amphotericin B

Received IVIG Methylprednisolone pulse

HHHFNC

Respiratory distress

NIV

Cyclosporin started at 3mg/kg HCQ and steroids were continued

PC BIPAP Requiring high peep 12

Fever

Hemodynamic

PLEX one session

22/10

Managemen t Symptomatolog y

Piptaz/teIcoplanin Septran Valganciclovir Lipo amphotericin B

VC SIMV

Bradycardia ?hypokalemia

Adrenaline 0.1 Noradrenaline 0.1

Fever

Respiratory distress

Hemodynamic

22/10 (10:30 pm)

23/10 3 :00 AM

23/10 5:00 am

Parameter

Initial

VT

240

PEEP

14

Rate

30

FiO 2

100

VC SIMV PULMONARY BLEED (500ml ) Increase in requirement of setting (peep 18)

Adrenaline 0.5 Noradrenaline 0.5 Blood products transfused

POCUS : no pleural effusion Poor aeration with multiple B lines in bilateral lung fields

Ventricular tachycardia amiodarone Synchronised cardioversion (twice) Adenosine

Intermittent AV block Hypotension Vasopressin added

Managemen

Symptomatolog

y

23/10 7:00 am

t

Thoughts …

• · Biomarkers to differentiate infection versus MAS : IL-18 ?
• · PLEX in MAS


2 yr- girl Down's Syndrome (Trisomy 21)

Fever

Rash

Joint swelling COVID antibody positive

MIS-C

IVIG, Steroids

Bicytopenia, Ferritin- 90 K Raised ESR, CRP, Raised triglycerides, lymphadenopathy

HLH/?ALPS

HLH 2ary to: ? Lymphoma ?Primary

Steroids 2 mg/kg/d

Cyclosporine

EBV, CMV Neg Rickettsia Neg HSV-1,2 VZV Neg Adeno Neg WES- No evidence of primary HLH BM Bx- No e/o malignancy

April 2022 June 22 Nov 2022 Feb 2023



Asymptomatic

• · Fever
• · Cough/ cold
• · Fast breathing
• · Rash
• · COVID antibody still positive
Down's Syndrome (Trisomy 21)

Fever

Fever No LAP/ HSM Hb- 6 ( transfused-10.2) TLC- 17,700 DLC 78/18 Platelet- 2.4 L ESR- 160 CRP 106 Ferritin 14000

Recurrent HLH

Pericardial effusion ?Infective Endocarditis Anaemia TLC high ( 21k) Platelets 5.6 L CRP 32 ESR 127 Ferritin 1200

I/V MPS X 5 Days, IVIG 2GM/KG

Cyclosporine

Anakinra

Persistent fever

• · Respiratory distress put on mechanical ventilation
• · Pulmonary Haemorrhage
• · VAP- MDR-Klebsiella
• · Septic shock
• · Ferritin > 1 lakh

Feb 2023 Apr 2023 May 2023 June 2023 Aug 2023

Steroids 2 mg/kg/d

Cyclosporine

Ruxolitinib 2.5 mg BD

Fever on and off

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• · B/L lower lobe dependent atelectasis , in paravertebral location
• · Possibility of recurrent aspiration related changes

Challenges

• · SJIA recurrent MAS:
• Etoposide
• Biweekly TCZ
• · Respiratory distress /Oxygen dependency :

CECT : Consolidation in posterobasal regions s/o aspiration pneumonitis

• Discharged on home oxygen
• Last follow-up :

Off oxygen , doing well on biweekly TCZ


Thoughts ?


• · Trisomy 21 and SJIA and MAS
• · Etoposide
• · JAK -i

CASE REPORT

Open Access

Hemophagocytic lymphohistocytosis in trisomy 21: successful treatment with interferon inhibition

Allison Guild' Jordan Fritch? , Sachit Patel? , Adam Reinhardt? and Melissa Acquazzino?

Abstract

Background: Hemophagocytic lymphohistiocytosis (HLH) is life-threatening condition of immune dysregula tion primarily driven by the cytokine interferon gamma. It can be either a genetic or acquired disorder associated with infection; malignancy; and rheumatologic disorders. Trisomy 21 can express include immune dysregulation and shares inherent pathophysiology with a group of disorders termed interferonopathies Knowledge of this overlap in seemingly unrelated conditions could provide basis for future research; and most importantly; alternative therapeutic interventions in acute life threatening clinical scenarios. Herein; we describe two cessfully managed with novel interventions targeting the interferon pathway.

Case presentation: We describe 17-month-old male and 15-month-old female with trisomy 21 presenting with with HLH Each had relapsing refractory HLH over time requiring several admissions to the hospital receiving conventional high dose corticosteroids and interleukin-1 inhibition therapy. Successful steroid-free remission was achieved after targeting interferon inhibition with emapalumab induction followed by long-term maintenance on baricitinib.

Conclusion: To our knowledge; these are the first reported cases of relapsed, refractory HLH in patients with trisomy 21 successfully treated with emapalumab and transitioned to steroid-sparing regimen with oral baricitinib for maintenance therapy Trisomy 21 autoimmunity and HLH are both thought to be driven by interferon gamma. Targeting therapy toward interferon signaling in both HLH and autoimmunity in trisomy 21 may have potential therapeutic this common pathway.


Brain storming

• • Erratic total leucocytes in MAS ?
• •
• Biomarkers to differentiate infection versus MAS : IL-18 ?
• • Trisomy 21 and SJIA/MAS

Therapeutics

• · IL-6 blockers as 1 st line agent (in settings where Anakinra is not widely available) Controversies ; IL-6 predisposes to MAS ?
• · Etoposide
• · JAK -i
• · PLEX



All the children and their families in our care

Thank you