Macrophage activation syndrome secondary to Rheumatic diseases

A.V. RamananProfessor of Paediatric Rheumatology

Bristol Royal Hospital for Children & Royal National Hospital for Rheumatic Diseases, Bath

Case report

13 year old with fever, rash and breathlessnessSudden worsening of repiratory symptomsIVIG x1 dose – no responseIntubated, HFO ventilationIn ITU for 45 days

Laboratory Values at Different Time Points

Case - 2

• 14 year old girl• 2 week h/o fever, rash• subtle knee effusion

Treatment given None. Methylpred.- 2 doses

Methylpred.Cyclosporin,IgG, Prednisolone

Methylpred.Cyclosporin,IgG, Prednisolone, IL-1 Blockade - one month after starting

Variable(Normal value) At Admission One week after

admission3 weeks after admission

2 months after admission

Haemoglobin g/dl 8.0 9.9 7.0 12

White cell count *103 9.2 9.2 25.0 5.5

Neutrophils *103 7.8 7.8 23.0 4.5

Platelets *103 396 201 391 233

ESR (1-15 ) mm/hr 120 - 155 50

Fibrinogen (150-450) mg/dl - 553 683 309

D-dimer - positive - positive

Ferritin ng/ml 44366 132206 29082 236

AST (15-41) IU/L 52 86 35 -

Prothrombin time (10.5-13) secs 13.7 17 17 13

APPT (24-35) secs 31.3 24 25 24

Outline

NomenclatureClassification of Histiocyte disordersRheumatic diseases associated with HLHEtiopathogenesisDiagnostic criteriaTreatment

Nomenclature

“MAS”, hemophagocytic syndrome, HLHMAS is secondary HLH!Important for - diagnostic, prognostic and therapeutic

reasons

Genetic, primary HLH• FHLH - Chromosome 9 linkage - PRF1 mutations - UNC13d mutations - Unknown mutations

• Immune deficiency syndromes - CHS - Griscelli syndrome - XLP

Acquired, secondary HLH• Exogenous agents - infectious organisms, toxins (VAHS, IAHS)

• Endogenous products - tissue damage - radical stress - metabolic

• Rheumatic diseases (MAS)

• Malignancies

HLH

Genotype-phenotype correlations in primary HLH

Normal Setting

HLH Setting

Threshold model of the HLH spectrum

Rheumatic Diseases Associated with MAS/HLH

SoJIA Systemic SclerosisPolyarticular JIA MCTDERA Rheumatoid arthritisCINCA SarcoidosisAOSD Sjogren’s syndromeSLE Polyarteritis nodosaJuvenile dermatomyositisKawasaki disease

Potential Triggers of MAS/HLH in Rheumatic Diseases

Drugs:

Aspirin Non steroidal anti-inflammatory drugsMethotrexateGold salts (particularly second dose of IM gold)EtanerceptSulfasalazineMorniflumateASCT

Potential Triggers of MAS/HLH in Rheumatic Diseases

Viruses: EBV Varicella zoster virusCoxsackie virusParvovirus B19Hepatitis A virusSalmonella enteritidisPneumocystis cariniiEnterococcal sepsis

Release of proinflammatory cytokines activates effector cells

Antigen presentation drives activation of cytotoxic T cells

Ineffective cytotoxicity leads to persistent viral infectionEffector cells amplify

inflammation leading to systemic hypercytokinemia

Continuous activation of PRRs synergizes with the

inflammatory cytokine milieu to activate innate immune cells

Chronic viral infection drives potent antigen

presenting cell activation

Pattern recognition receptors

Autoinflammatory Trigger Infectious

Trigger

Comparison of Clinical and Laboratory Features of SoJIA and MAS

Comparison of Clinical and Laboratory Features of SoJIA and MAS

SLE and HLH

80 adult patients with SLE73/80 had elevated liver enzymes7/73 –hemophagocytic syndromeCytopenia, fever, elevated liver enzymes – part

of “disease activity” in SLE

JSLE and MAS

38 pts with definite or possible lupus ferritinLDHtriglyceridesfibrinogen

Ravelli et al, A&R 2009 Nov

Prognostic factors of early death in a cohort of 162 adult haemophagocytic syndrome: impact of triggering

disease and early treatment with etoposide Arca et al, BJH, 2014

• 162 patients with HLH• 33 deaths within 30 days

Clinical characteristics of patients on diagnosis according to outcome.

Patients characteristics (N = 162)

Survivors(N =129)

Non-survivors(N =33)

P-value

Age (years) 47 (44-49) 56 (50-61) 0.004

Platelet count (x109/l) 75.8 (66.3-85.4) 40.6 (31.1-50) 0.0005

Aspartate aminotransferase (iu/l) 159 (105-213) 529 (183-1241) 0.04

Lactate dehydrogenase (iu/l) 1607 (1288-1927) 2550 (161-3938) 0.04

Underlying immunodeficiency (HIV infection) 54 7 0.029

Main triggering condition

Lymphoma 52 22

Infection or other condition* 36 4 0.04†

Multicentric Castleman disease 17 0

Arca et al, A&R, 2014

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Clinical Characteristics and Treatment Outcomes of Autoimmune-Associated Hemophagocytic Syndrome in

Adults Kumukura et al, A&R, Aug 2014

• 116 patients• SLE – 61, AOSD – 31• Normal or low CRP in SLE patients with HLH• Mortality of 12.9%• Male sex, anaemia and DM – poor prognosis

Clinical characteristics and treatment outcomes

Patients still living(n=101)

Patients deceased(n-15)

Age, mean ± SD years 40.9 ± 17.7 45.8 ± 24.9

Male sex, no. (%) 19 (18.8) 9 (60.0)

Physical findings

Fever, no./total no.(%) ‡ 85/99 (85.9) 14/15 (93.3)

Lymphadenopathy, no./total no.(%) 27/69 (39.1) 5/9 (55.6)

Hepatomegaly, no./total no.(%) 20/55 (36.4) 8/12 (66.7)

Splenomegaly, no./total no.(%) 34/77 (44.2) 6/11 (54.5)

Laboratory findings

WBC count 3.7 ± 5 7.2 ± 11.8

Hgb 9 ± 2 8.8 ± 2.3

Platelet count 130.6 ± 131.7 83.3 ± 104

Coagulopathy 33/69 (47.8) 7/10 (70)

AST 224.8 ± 448.2 571.2 ± 1034

ALT 164.1 ± 318.9 302.7 ± 514.9

LDH 1,196 ± 1,571 1,714 ± 1,784

CRP 7.5 ± 10.4 9.3 ± 8.1

Ferritin 12,963 ± 27,982 32,133 ± 66,866

Kumakura et al, A&R, 2014

Clinical characteristics of the adults with AAHS

Total

(n=116)Underlying SLE

(n=61)Underlying AOSD

(n=31)P

Age, mean 41.6 ± 18.7 34.4 ± 14.2 43.5 ± 17.4 0.014Male:Female ratio 1:3 1:4.1 1:4.2

Physical findings

Fever 99/114 56/60 30/31 NS

Lymphadenopathy 32/78 16/40 13/24 NS

Hepatomegaly 28/67 12/29 10/20 NS

Splenomegaly 40/88 15/43 16/25 NS

Laboratory findings

WBC count 4.1 ± 6.08 2.2 ± 1.2 6.8 ± 6.6 0.002Hgb 8.9 ± 2 8.7 ± 1.8 9.6 ± 1.9 NS

Platelet count 98.1 ± 96.8 81.9 ± 52.2 141.9 ± 142 NS

Coagulopathy 40/79 24/35 12/27 NS

AST 264.2 ± 548 211.3 ± 341 423.4 ± 757.9 NS

ALT 183 ± 351 96.1 ± 117 315.9 ± 402 0.029LDH 1,251 ± 1,592 1,012 ± 974 1,923.1 ± 1,721 NS

CRP 7.7 ± 10.2 2.8 ± 4.0 14.9 ± 12.6 0.00002

Ferritin 15,334.1 ± 35,181 5,849.5 ± 10,47240,136.4 ± 64,069.7

0.003

Kumakura et al, A&R, 2014

Diagnostic Criteria for HLH

Familial disease/known genetic defectClinical and laboratory criteria (five of eight criteria)• Fever• Splenomegaly• Cytopenia 2 cell lines Haemoglobin <90 g/l (below 4 weeks <120 g/l) Platelets <100 X 109/l Neutrophils <1 X 109/l• Hypertriglyceridemia and/or hypofibrinogenemia Fasting triglycerides 3 mmol/l Fibrinogen <1.5 g/l• Ferritin 500 µg/l• sCD252 2400 U/ml• Decreased or absent NK-cell activity• Haemophagocytosis in bone marrow CSF or lymphnodes

Date of prep: September 2016 NP-1338

Patient samples evaluated in the study and results of web-based expert evaluations.

Angelo Ravelli et al. Ann Rheum Dis 2016;75:481-489

©2016 by BMJ Publishing Group Ltd and European League Against Rheumatism

Criteria for the classification of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis.

Angelo Ravelli et al. Ann Rheum Dis 2016;75:481-489

©2016 by BMJ Publishing Group Ltd and European League Against Rheumatism

Development and validation of a score for the diagnosis of reactive hemophagocytic syndrome (HScore)

Fardet et al, A & R, Sept 2014

• Consensus by experts• 312 patients• 116 with HS• Median H score for HS patients is 230• H score for non HS patients 125

The HScore

Parameter No. of points (criteria for scoring)

Known underlying immunosuppression* 0 (no) or 18 (yes)

Temperature (°C) 0 (<38.4), 33 (38.4–39.4), or 49 (>39.4)

Organomegaly0 (no), 23 (hepatomegaly or splenomegaly), or 38 (hepatomegaly and splenomegaly)

No. of cytopenias† 0 (1 lineage), 24 (2 lineages), or 34 (3 lineages)

Ferritin (ng/ml) 0 (<2,000), 35 (2,000–6,000), or 50 (>6,000)

Triglyceride (mmol/l) 0 (<1.5), 44 (1.5–4), or 64 (>4)

Fibrinogen (gm/l) 0 (<2.5) or 30 (≤2.5)

Serum glutamic oxaloacetic transaminase (IU/l) 0 (<30) or 19 (≥30)

Hemophagocytosis features on bone marrow aspirate

0 (no) or 35 (yes)

* The best cut off value for HScore was 169, corresponding to a sensitivity of 93%, a specificity of 86%, and accurate classification of 90% of the patients.

Date of prep: September 2016 NP-1338

HLH and Sepsis/MODS/SIRS

Part of same spectrumSIRS/MODS non specificImportance of terminology is in managementImmunosuppression for HLH/SIRS/MODS seen in

sepsis

Ferritin and HLH

Ferritin in trauma – with ARDS (638ng/ml), without ARDS (185ng/ml)

Pneumococcal sepsis – under 75 yrs of age (653), >75 yrs of age (312)

Ferritin and HLH

Allen et al; Peditr Blood Cancer; 2008330 Pts >500Ferritin>10,000 – 90% sensitive and 96% specific

for HLH10 patients with PUO

Ferritin distributions over the major 11 disease categories

HLH in PICU – Chennai data

• 2007-2008• 33 children diagnosed with HLH• 18(55%) required PICU admission• PICU admission – severe sepsis or

respiratory distress• 7 required ventilatory support

Ramachandran et al, Indian Pediatrics, Aug 2010 (e pub)

HLH in PICU – Chennai data

• Mean age 46 months (2mo -14 yrs)• CNS symptoms in 36%• HB(<9) – 97%, Plt (<100) – 72%• Hyperferritenemia – 97%• fibrinogen and LDH – 92%• Marrow haemophagocytosis – 82%

Ramachandran et al, Indian Pediatrics, Aug 2010

HLH in PICU – Chennai data

5 Dengue, 3 EBV, 1CMV, 1TB and 5 bacterial infections

Steroids -67%, IVIG – 64%, cyclosporine – 33%, etoposide – 15%

Survival – 76%

Ramachandran et al, Indian Pediatrics, Aug 2010

n Median 25th centile 75th centile

HLH total 123 4,123 1,584 11,210

FHL alone 76 3,624 1,519 11,803

VA-HLH alone 37 5,573 1,740 10,796

Controls 320 1,341 796 2,662

Distribution of ferritin values

Lehmberg et al, A&R, 2014

Dengue Associated Hemophagocytic Lymphohistiocytosis: A Case Series P PAL, P P GIRI AND *AV RAMANAN

Indian Paediatrics, 2014

• Dengue outbreak 2013• 358 Dengue cases• 8 had HLH• All did well with steroids

Figure 4. EBV has high similarity to DENV and inflammatory syndromes.

Dunmire SK, Odumade OA, Porter JL, Reyes-Genere J, et al. (2014) Primary EBV Infection Induces an Expression Profile Distinct from Other Viruses but Similar to Hemophagocytic Syndromes. PLoS ONE 9(1): e85422. doi:10.1371/journal.pone.0085422http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085422

Figure 2. Ferritin levels and fold change are associated with viraemia.

van de Weg CAM, Huits RMHG, Pannuti CS, Brouns RM, et al. (2014) Hyperferritinaemia in Dengue Virus Infected Patients Is Associated with Immune Activation and Coagulation Disturbances. PLoS Negl Trop Dis 8(10): e3214. doi:10.1371/journal.pntd.0003214http://www.plosntd.org/article/info:doi/10.1371/journal.pntd.0003214

Poor Prognostic factors

Renal involvementSevere neutropeniaSevere coagulation abnormalitiesCNS involvement

Ramanan et al, 2005

Treatment of HLH/MAS in rheumatic diseases

Supportive careCorticosteroidsIVIGCyclosporinEtoposideIL-1 BlockadeHLH-94 protocol

IVIG in HLH

Useful alone or in conjunction with steroidsUseful when diagnosis unclear7/20 pts in one study treated with IVIG

(Emmenegger et al)Good response with one group in Switzerland

Cyclosporin in HLH

EffectiveBeware of neurotoxicity when given

parenterallySeveral reports of success, part of HLH-94?DMARD of choice in SoJIA patients at high risk

of HLH

Etoposide in HLH

Very effectivePerhaps not used enough by RheumatologistsConsider outside the context of HLH-94

Recombinant IL-1 receptor antagonist

4 weeks of spiking pyrexias resolved with IL-1 blockade

Prednisolone weaned

Well off all medication for past year.

Benefit of IL-1 Blockade for MAS among sJIA Patients

Suggested Management According to Risk Groupsat Initial Diagnosis

Schematic algorithm of our approach to the diagnosis and treatment of adult HLH.

Alison M. Schram, and Nancy Berliner Blood 2015;125:2908-2914

©2015 by American Society of Hematology

Ebola fever and ferritin as biomarker

• EF outbreak in Sudan 2000-01• Samples analysed for multiple biomarkers• Death and haemorrhage associated with

thrombomodulin and serum ferritin levels

Viremia as a function of clinical outcome.

McElroy A K et al. J Infect Dis. 2014;210:558-566

Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Markers of inflammation associated with a fatal outcome (black bars) or hemorrhagic manifestations (red bars). *P ≤ .05.

McElroy A K et al. J Infect Dis. 2014;210:558-566

HLH-94 protocol

Henter et al, 2002

Questions?