Bicytopenia, triggered by infection, in 3 patients with Systemic onset juvenile idiopathic arthritis
Systemic onset juvenile idiopathic arthritis
Patient 1 m Age at onset Clinical signs at onset Neutrophilic granulocytes: CRP: Ferritine: Initial treatment 2 years Fever Rash Arthralgia 25 000 310 5000 AB + NSAID Corticost. 60mg/m2 Every 2 - 4 months Patient 2 f 6 1/2 years Fever, Rash Lymphadenopathy Myalgia 15 330 368 2350 AB + NSAID Patient 3 m 10 months Fever Rash Pericarditis 9 900 139 AB + NSAID Corticost. 2m/kg
Disease course (relapses):
Every 6 months
After 23 months
Infection with Cytopenia
Patient 1 m Time after onset of SoJIA (age) Clinical signs Cultures 6 months (2 1/2 years) Fever Catheter infection (S. aureus) Patient 2 f 6 months (7 years) Fever Pyelonephritis (E. coli) Patient 3 m 19 months (3 years) Fever arthritis Relapse of SoJIA Cyclophosphamide Pneumonia (C. albicans) 8.5 21 000 → 500 63 0.85 1.4
Hemoglobin: Neutrophils: Thrombocytes: Ferritine: Fibrinogen: Triglycerides:
10.9 50 000 → 27 000 50 5000 1.8 4.4
11.4 11 100 → 1500 72 28 000 2.0 -
Macrophage activation / Hemophagocytosis?
• None of the patients had an enlarged spleen • In 1 patient: bone marrow examination was performed: no hemophagocytosis Ergo: there were not enough criteria to make the diagnosis of hemophagocytosis (according to HLH 2004)
Treatment / Outcome
Patient 1 m treatment AB + Prednisolone maintained (1.5 mg/kg/d) Patient 2 f AB + Prednisolone increased: 1 → 1.5 mg/kg/d 2 weeks later: +Cyclosporine outcome No relapse of cytopenia No relapse of cytopenia 4 months later: Again fever, ↓ Hb, ↓ANC, ↓ Tc, ↓Fibrinogen Renal insufficiency Methylprednisolon Cyclosporine Patient 3 m Amphotericin B
Outcome
Patient 1 m
Patient 2 f
Patient 3 m Polyarthritis
frequent relapses of SoJIA frequent relapses of SoJIA with with fever + arthralgias fever + arthritis (in spite of steroids, MTX, (actually: anti-IL1) Thalidomide, anti-IL1, antiTNFα) Side effects of steroids
Conclusion I
3 patients with severe + relapsing forms of Systemic-onset juvenile idiopathic arthritis We hypothesize that all 3 patients experienced incomplete forms of macrophage activation syndrome
Diagnostic criteria of Hemophagocytosis
Fever Splenomegaly Hemophagocytosis Cytopenia (2/3): Hb <90 g/l, ANC <1.0 x 109/l, Tc <100 x 109/l Ferritine ≥500 mg/l Triglycerides ≥3.0 mmol/l sCD25 ≥2400 U/ml Cell cytotoxicity or Fibrinogen ≤1.5 g/l
5/8
ia t er cr i
according to HLH 2004
Conclusion II
Difficulties in diagnosis of macrophage activation syndrome (MAS) in patients with Systemic-onset juvenile idiopathic arthritis (SoJIA) may arise from: SoJIA Neutrophils Thrombocytes Fibrinogen ↑ ↑ ↑ MAS ↓ ↓ ↓
Discussion
Treatment of macrophage activation syndorme in these patients? Antiinfectious therapy + no immunosuppression? + immunosuppression? Corticosteroids Ciclosporine anti-TNFα? Corticosteroids Ciclosporine (+ Antithymoglobulins) (+ Etoposide)
Impairment of granule-dependent cytotoxicity is the hallmark of inherited HLH
Cytotoxic T cell CTL
IFN γ Antigen presenting cell APC
TCR