1. بسم الله الرحمن الرحیم

2. Pediatirc Rheumatologist TUMS Bahrami children,s Hospital
Dr. Mahdie Mousavi
Pediatirc Rheumatologist
TUMS
Bahrami children,s Hospital

3. HLH or MAS ??? Disease Monitoring

4. HLH classification
Hemophagocytic lymphohistiocytosis (reproduced with permission from Janka and Zur Stadt, 2005)

5. Genetic HLH Familial HLH (Farquhar Disease)
Known Genetic Defects (Perforin, Munc 13-4, Syntaxin 11)
Unknown Gene Defects
Immune Deficiency Syndromes:
Che`diak-higashi Syndrome
Griscelli Syndrome X-linked Lymphoproliferative Syndrome (Xlp)
Acquired HLH Exogenous Agents (Infections, Toxins)
Infection-associated Hemophagocytic Syndrome (IAHS)
Endogenous Products
Tissue Damage
Inborn Error Of Metabolism Such As Lysinuric Protein Intolerance And Multiple Sulfates Deficiency)
Rheumatic Diseases (Macrophage Activation Syndrome (MAS))
Malignant Diseases (Especially Lymphoma-associated Hs Or LAHS)

6. MAS is a challenging diagnosis
1st presentation or complication of rheumatic dis.
Uncommon
No definite criteria
Similar signs and symptoms with:
Active diaease ( SLE, SOJIA )
Infections
DIC
Drug toxicity

7. Rheumatic diseases: SLE S.O.JIA Kawasaki disease
Some of periodic fever syndromes
Epidemiology: 10% in SOJIA ( clinical )
30% – 40% ( subclinical )
Iran: 7%
Mortality: 8%

8. MAS typically occurs within the first few days or weeks of the onset of systemic JIA, although it can occur at any point over the course of the disease.
Some patients have recurrent episodes of MAS. Triggers may include viral or bacterial infections or new medications, but often no inciting event is identified.

10. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis
In a febrile patient with known or suspected S.O.JIA
Ferritin > 684 ng/ml
and any 2 of the followings:
PLT <
AST> 48
TG > 156 mg/dl
fibrinogen < 360 mg/dl

11. Differentiation primary HLH from MAS

12. J Pediatr. 2017 Oct;189:72-78. e3. doi: 10. 1016/j. jpeds. 2017. 06
J Pediatr Oct;189:72-78.e3. doi: /j.jpeds Epub 2017 Aug 12.
362 patients with MAS and 258 patients with pHLH
The MAS/HLH (MH) score was made up with the individual scores of selected variables.
Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin
The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile ) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from <1% for a score of <11 to >99% for a score of  ≥123. A cutoff value of ≥60 revealed the best performance in discriminating pHLH from MAS.

13. 27 MAS, SOJIA & 90 FHLH & 42 VA-HLH
J Pediatr Jun;162(6): doi: /j.jpeds Epub 2013 Jan 17. Differentiating macrophage activation syndrome in systemic juvenile idiopathic arthritis from other forms of hemophagocytic lymphohistiocytosis.
27 MAS, SOJIA & 90 FHLH & 42 VA-HLH
Neutrophil count and C-reactive protein were significantly higher in patients with MAS/sJIA compared with patients with FHL and patients with VA-HLH, with 1.8×10(9)/L neutrophils (sensitivity 85%, specificity 83%) and 90 mg/L C-reactive protein (74%, 89%) as cutoff values.

14. Disease Monitoring

15. Pre- therapy testing: HLA typing and search for an HCT donor ( HLH )
Cardiac function ( ECG & ECHO )
Disease markers: The distinction between chemotherapy toxicity and worsening disease may be difficult to make clinically.
Baseline immunologic studies (eg, soluble IL-2 receptor alpha [sCD25], soluble hemoglobin-haptoglobin scavenger receptor [sCD163])
Other markers of disease activity (eg, complete blood count, ferritin, fibrinogen, D-dimer, liver function tests)

16. Thank You For Your Attension