NextGen 2024: Refractory SJIA & MAS Session Part 4

NextGen 2024: Refractory SJIA & MAS Session Part 4

• 1. 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

• 2. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, 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) sJIA (2016 – 2024) n= 176 • Mean age : 7 Years • Gender, boys (%) : 108 (61%) • Mean delay in diagnosis : 18.5 months

• 3. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, AIIMS, New Delhi ,India 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: Children with JIA receiving bDMARDs with 3 months follow-up included (Jan 2009- August 2024) Results: • N=115 • 168 patient-years of biologics use Characteristic N=115 Age at symptom onset, months 78.8 (43.3) Age at Diagnosis, months 104.5 (45.9) Delay in diagnosis, months 12 (6-36) Symptoms at initiation Fever Rash Uveitis Macrophage activation syndrome (among SOJIA n=35) 45 (39.1) 24 (20.8) 9 (7.8) 4 (11.4) Active joints 6 (4, 8) Limited joints 2 (0, 4) Sacroiliitis at Initiation 31 (26.9) 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

• 4. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, AIIMS, New Delhi ,India Characteristic N=115 Pre-existent TB Infection requiring prophylaxis Reactive Mantoux CXR abnormality IGRA assay suggestive of TB infection (n=47) Patients who could afford IGRA 15 (13) 12 (10.4) 3 (2.6) 3 (6.38) 68 (59.1) Delay in receiving bDMARDs, months Range, months 2(0-6) 0-66 Remission frequency on bDMARD initiation 106 (92.1) Time to achieve remission, weeks 6.5 (4-12) Reduction in active joints at follow-up -5 (-2 to -8) Reduction in restricted joints at follow-up 0 (0 to -2) Characteristic N=115 bDMARDs stopped 65(56.5) Flares after stopping bDMARDs (n=65) 32 (49.2) Time to flare after stopping bDMARDs, months (n=28) 7 (5-14) Adverse events Proportion of adverse events while on bDMARDs 42 (36.5) Serious infection episodes 13 (11.3) Reactivation of tuberculosis 4 (3.4) Transaminitis 6 (5.2) Anaphylactic reaction 3 (2.6) Leukopenia 7 (6.0) Thrombocytopenia 4 (3.4) Anaemia 4 (3.4) Neuropsychiatric adverse events 2 (1.7) Mortality 1 (0.8) Primary bDMARD failure 7 (6.0) bDMARD interruption or premature cessation 72 (62.6) Reasons for interruption or premature cessation Adverse events Financial constraints 31/72 (44.9) 29/72 (42.3) New-onset autoimmune disease or uveitis on therapy 0 Course complicated by malignancy 0 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). 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

• 5. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, AIIMS, New Delhi ,India Predictors of outcomes

• 6. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, AIIMS, New Delhi ,India 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% Courtesy: Prof Pranay Tanwar

• 7. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, AIIMS, New Delhi ,India Indian Pediatr. 2021 Mar 26:8.PMID: 33772536.

• 8. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, AIIMS, New Delhi ,India 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

• 9. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, AIIMS, New Delhi ,India Total leukocyte count(TLC): 10,600/mm3 Differential leukocyte count: N80%/L7% Hemoglobin: 11g/dL Platelet count : 2.87 lakh/mm3 • ECHO: minimal pericardial effusion • HRCT: consolidation left lower lobe

• 10. Week 1 2 3 4 Ferritin (ng/mL) Cell counts TLC (/ mm3) Platelet count (lakhs/mm3) Tachypnea & O2 support Fever & arthralgia Observation/intervention • Antibiotics • Stress dose steroids • IVIG • IVMP f/b oral steroids • Tocilizumab • Cyclosporine • Antibiotics upgraded Shock MAS 10,600 2.87L 3258 6712 18,140 > 1 L 69,219 11,533 3317 12,310 4.27L 29,520 8.7L 2400 40,000 3880 2.4L Discharged @ 29 On Oral Cycloporine Biweekly TCZ

• 11. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, AIIMS, New Delhi ,India Key concerns • Trend of clinical and lab parameters … • Erratic total leucocytes in MAS ?? •IL-6 as 1st line agent (in settings where Anakinra is not widely available) • Controversies ; IL-6 predisposes to MAS

• 12. Case vigette 14-yr-old girl Symptomatic since 10 years of age History of multiple blood transfusions Anemia and hepatosplenomegaly Asymptomatic for 4 years Symptomatic from past 5 months Fever Oral ulcers Joint pains Rash Presented to AIIMS with persistent symptoms • DCT4+, ICT 1+ • Autoimmune hemolytic anemia • On oral steroids for 6 months • ANA 3+ • Low C3 and C4 • High dsDNA levels • Haematological and skin involvement • Diagnosed as SLE • On steroids, Danazol, HCQ

• 13. Course Managemen t Symptomatolog y Room air Orally allowed Ceftriaxone O2 Fever Respiratory distress Maintenance fluids Feeds 14/10 Hemodynamic Piperacillin Teicoplanin H3FNC 20L/min and FIO2 50% Chest xray diffuse infiltrates Septran Valganciclovir Liposomal amphotericin B Chest xray was normal CMV + EBV - Possibilities : ?CMV pneumonitis ?Fungal pneumonia ?ARDS –MAS ?Diffuse alveolar hemorrhage MAS Ferritin – 1,00000 Fibrinogen – 272 Triglycerides -297 LDH-2047 Methylprednisolone Pulse 3 doses at 1g/kg IVIG at 2mg/kg 16/10 17/10 20/10 One bolus at 10ml/kg

• 14. Course in HDU Managemen t Symptomatolog y HHHFNC Piperacillin tazobactam/teicoplanin/septran/valganciclovir/lipo amphotericin B Fever Respiratory distress Hemodynamic PC BIPAP NIV Requiring high peep 12 Received IVIG Methylprednisolone pulse Fluids 80% NPO Parameter Initial PIP 28 PEEP 13 Rate 25 FiO270 20/10 Cyclosporin started at 3mg/kg HCQ and steroids were continued 22/10 PLEX one session

• 15. Managemen t Symptomatolog y VC SIMV Piptaz/teIcoplanin Septran Valganciclovir Lipo amphotericin B Fever Respiratory distress Hemodynamic 22/10 (10:30 pm) 23/10 3 :00 AM 23/10 5:00 am Bradycardia ?hypokalemia Adrenaline 0.1 Noradrenaline 0.1 Parameter Initial VT 240 PEEP 14 Rate 30 FiO2100 VC SIMV PULMONARY BLEED (500ml ) Increase in requirement of setting (peep 18) Adrenaline 0.5 Noradrenaline 0.5 Blood products transfused Ventricular tachycardia amiodarone Synchronised cardioversion (twice) Adenosine POCUS : no pleural effusion Poor aeration with multiple B lines in bilateral lung fields Intermittent AV block Hypotension Vasopressin added 23/10 7:00 am

• 16. Thoughts … •Biomarkers to differentiate infection versus MAS : IL-18 ? •PLEX in MAS

• 17. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, AIIMS, New Delhi ,India Case vignette April 2022 June 22 Nov 2022 Feb 2023 Fever Rash 2 yr- girl Down’s Syndrome (Trisomy 21) MIS-C Joint swelling COVID antibody positive 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 Asymptomatic • Fever • Cough/ cold • Fast breathing • Rash • COVID antibody still positive EBV, CMV Neg Rickettsia Neg HSV-1,2 VZV Neg Adeno Neg WES- No evidence of primary HLH BM Bx- No e/o malignancy

• 18. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, AIIMS, New Delhi ,India Feb 2023 Apr 2023 May 2023 June 2023 Aug 2023 Fever Down’s Syndrome (Trisomy 21) 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 Steroids 2 mg/kg/d Cyclosporine Ruxolitinib 2.5 mg BD Pericardial effusion ?Infective Endocarditis Anaemia TLC high ( 21k) Platelets 5.6 L CRP 32 ESR 127 Ferritin 1200 Fever on and off • Respiratory distress – put on mechanical ventilation • Pulmonary Haemorrhage • VAP- MDR-Klebsiella • Septic shock • Ferritin > 1 lakh Anakinra Cyclosporine I/V MPS X 5 Days, IVIG 2GM/KG Persistent fever

• 19. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, AIIMS, New Delhi ,India • B/L lower lobe dependent atelectasis , in paravertebral location • Possibility of recurrent aspiration related changes

• 20. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, AIIMS, New Delhi ,India 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

• 21. Thoughts ? • Trisomy 21 and SJIA and MAS • Etoposide • JAK -i

• 22. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, AIIMS, New Delhi ,India 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 1st line agent (in settings where Anakinra is not widely available) Controversies ; IL-6 predisposes to MAS ? • Etoposide • JAK -i • PLEX

• 23. Next Gen conference,Washington DC Division of Rheumatology, Department of Pediatrics, AIIMS, New Delhi ,India Thank you All the children and their families in our care