Macrophage Activation Syndrome in Children with Systemic Juvenile Rheumatoid Arthritis

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2 Macrophage Activation Syndrome in Children with Systemic Juvenile Rheumatoid Arthritis Adel wahadneh MD Consultant Pediatric Immunologist and Rheumatologist QRCH-KHMC-JORDAN 2

3 A 7 year male patient Diagnosis of systemic onset JIA was made 3 years ago Controlled on: Prednisolne 5 mg/day, Methotrexate 20 mg/week, Etanercept 20 mg/week 12 months ago, admitted with unremitting fever, petechial rash, nasal epistaxis, hepatosplenomegaly Patient s data as follow 3

4 W1 W2 W3 W4 M1 M2 M3 M4 W21 W22 W23 W FEVER WBC 150 ESR

5 CRP FERRITTEN FIBRINOGEN PLATLETS

6 AST ALT TG Extensive work up for infection was inconclusive 6

7 Diagnosis : Macrophage Activation Syndrome Clinical and laboratory improvement were observed during with corticosteroid and cyclosporine therapy 7

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11 Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis (Behrens EM et al. J Rheumatol 2007;34:1133-8) Retrospective review of 15 patients with syst JIA who underwent BM aspiration within initial diagnostic workup Eight of 15 (53%) patients had BM aspirate suggestive of MAS Two patients were diagnosed clinically with MAS Three patients had frank hemophagocytosis, only 1 of whom was diagnosed with MAS clinically Suggestion: MAS may be an integral part of the spectrum of syst JIA, ranging from its most severe, life-threatening form to its mild, occult form manifest only by biochemical abnormalities and BM hemophagocytosis 11

12 Preliminary diagnostic guidelines for MAS complicating systemic JIA clinical discriminators Hemorrhages 67 Laboratory criteria Decreased PLT ( 262 x 10 9) Elevated GOT/AST (> 59 mu/l) Hypofibrinogenemia ( 2.5 g/l) Decreased WBC ( 4.0 x 10 9 /L) Clinical criteria central nervous system dysfunction 63 laboratory discriminators Hemorrhages (purpura, easy bruising, mucosal bleeding) CNS dysfunction (irritability, disorientation, lethargy, headache, seizures, coma) Hepatomegaly ( 3 cm below the costal Diagnostic rule: The diagnosis of macrophage activation syndrome requires the respectively presence of any 2 or more the following laboratory criteria or 2 or more of the following clinical criteria: A BM aspirate for the demonstration of macrophage hemophagocytosis may be required only in doubtful cases arch) DOR DOR Decreased platelet count 1092 increased aspartate aminotransferase 247 leukopenia 70 hypofibrinogenemia 165 The best separation between patients and control subjects occurred when any 2 or more laboratory criteria were Histopathologic criterion simultaneously present The second best Hemophagocytosis performance was provided in the bone by the marrow presence of any 2, 3, or more clinical and/or laboratory criteria and 743 Ravelli A et al. J Pediatr 2005;146:

13 application of the HLH-2004 protocol to MAS/HLH secondary to sjia may be imperfect. 13

14 NO. OF MAS CASES IN DIFFERENT RHEUMATIC DISEASES No,cases Incidence and prevalence unknown, Probably more common than previously though(7 of 103 diagnosed with sojra developed MAS at some point in their illness.) 2. Approximately 100 cases reported in the literature 3. Most commonly an early complication of active disease 14

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16 In 20 cases HLH might have been triggered by immunosuppressive treatment of the rheumatic condition, including adalimumab/, infliximab,etanercept, leflunomide, sulfasalazine, azathioprine, methotrexate 26) STERBA G, STERBA Y, STEMPEL C, BLANK J, AZOR E, GOMEZ L. Macrophage activation syndrome induced by etanercept in a patient with systemic sclerosis. Isr Med Assoc J 2010; 12: ) CUSINI A, GUNTHARD HF, STUSSI G, SCHWARZ U, FEHR T, GRUETER E, MEERBACH A, BOSSART W, SCHAER DJ, RUDIGER A. Hemophagocytic syndrome caused by primary herpes simplex virus 1 infection: report of a first case. Infection 2010; 38: ) PEREZ-DE PEDRO I, MIRANDA-CANDON I, CAMPS-GARCIA MT, GOMEZ-HUELGAS R. [Hemophagocytic syndrome in adult Still disease after initiation of sulfasalazine]. Rev Clin Esp 2010; 210: ) ARLET JB, It LE TH, is MARINHO possible A, AMOURA Z, WECHSLER that B, PAPO immunosuppression T, PIETTE JC. Reactive haemophagocytic syndrome in adult-onset Still's disease: a report of six patients and a review of the literature. Ann Rheum Dis 2006; 65: ) GIANELLA induced S, SCHAER DJ, SCHWARZ by U, KURRER anti-tnf-á M, HEPPNER FL, FEHR J, SEEBACH treatment JD. Retinal microangiopathy may and favor rapidly fatal cerebral edema in a patient with adult-onset Still's disease and concurrent macrophage activation syndrome. Am J Hematol 2008; 83: ) STERN A, RILEY R, BUCKLEY L. Worsening of macrophage activation syndrome in a patient with adult onset the Still's occurrence disease after initiation of Etanercept of therapy. serious J Clin Rheumatol 2001; infections 7: leading, 73) AGARWAL S, MOODLEY J, AJANI GOEL G, THEIL KS,MAHMOOD SS, LANG RS. A rare trigger for macrophage activation syndrome. Rheumatol Int 2011; 31: in turn, to HLH. 74) ODA Y, URUSHIDANI Y, OOI S, ENDOH A, NAKAMURA R,ADACHI K, FUKUSHIMA H. Hemophagocytic lymphohistiocytosis in a rheumatoid arthritis patient treated with infliximab. Intern Med 2012; 51: ) AOUBA A, DE BANDT M, ASLANGUL E, ATKHEN N, PATRIB. Haemophagocytic syndrome in a rheumatoid arthritis patient treated with infliximab. Rheumatology (Oxford) 2003; 42: ) SANDHU C, CHESNEY A, PILIOTIS E, BUCKSTEIN R, KOREN S. Macrophage activation syndrome after Etanercept treatment. J Rheumatol 2007; 34: ) TSUBOI H, IWATA H, NAMPEI A, MATSUSHITA M, SHI K. Hemophagocytic syndrome in a patient with rheumatoid arthritis. Mod Rheumatol 2011; 21: ) ARAKI D, FUJII H, MATSUMURA M, YAMAGISHI M, YACHIE A, KAWANO M. Etanercept-induced lupus accompanied by hemophagocytic syndrome. Intern Med 2011; 50: ) SAWAR H, ESPINOZA LR, GEDALIA A. Macrophage activation syndrome and etanercept in children with systemic juvenile rheumatoid arthritis. J Rheumatol 2004; 31: 623; author reply ) NADIA EA, CARVALHO JF, BONFA E, LOTITO AP, SILVA CA. Macrophage activation syndrome associated with etanercept in a child with systemic onset juvenile idiopathic arthritis. Isr Med Assoc J 2009;11: ) RAMANAN AV, SCHNEIDER R. Macrophage activation syndrome following initiation of etanercept in a child with systemic onset juvenile rheumatoid arthritis. J Rheumatol 2003; 30: ) TRONCOSO MARINO A, CAMPELO SANCHEZ E, MARTINEZ LOPEZ DE CASTRO N, INARAJA BOBO MT. Haemophagocytic syndrome and paradoxical reaction to tuberculostatics after treatment with infliximab. Pharm World Sci 2010; 32:

17 Pathogenesis Central question: is there an underlying abnormality of the immune response that contributes to lack of control of an exaggerated immune response? Starting point: strong clinical similarities with hemophagocytic lymphohistiocytosis (HLH) Familial HLH: decreased NK and cytotoxic cell function often secondary to mutations in the gene encoding perforin (PRF1), a protein that mediates cytotoxic activity of NK and T cells. The number of NK cells is usually normal Virus-associated HLH: very low or absent cytolitic NK cell activity related to profoundly decreased number of NK cells rather than impaired perforin expression. NK function may completely recover after resolution of acute phase 17

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20 Role of Perforin in the Cytotoxic Response The Mechanism of Action of Perforin - N Engl J Med 335 (22): 1651,

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22 Pathogenesis of Hemophagocytic Syndromes Decreased Perforin Expression + / - Trigger (Drug or infection) Excessive Macrophage Activation Hypercytokinemia End organ damage 22

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26 15/24 MAS patients improved within 5-15 days of steroid initiation. IVIG: Occasional anecdotal responses, Rarely used in isolation CYCLOSPORIN-A: 5 cases of successful treatment with CsA alone VP 16 (Etoposide): Used in unresponsive or very severe patients with MAS, Evidence in MAS is anecdotal 26

27 Med Sci Monit Mar;14(3):RA Macrophage activation syndrome: a frequent but under-diagnosed complication associated with rheumatic diseases. Tristano AG Treatment of MAS in patients with rheumatic diseases has not been standardized yet, but it commonly includes a variety of agents such as high-dose corticosteroids, cyclosporine, cyclophosphamide, etoposide, and intravenous immunoglobulin (IVIG). Pediatr Blood Cancer Feb;48(2): HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Henter JI,et al. HLH-2004 chemo-immunotherapy includes etoposide, dexamethasone, cyclosporine A upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids. Subsequent hematopoietic stem cell transplantation (HSCT) is recommended for patients with familial disease or molecular diagnosis, and patients with severe and persistent, or reactivated, disease. 27

28 Rheumatology (Oxford) Nov;40(11): Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Stéphan JL immediate withdrawal of potentially triggering medications, anti-infective therapy when relevant, and urgent immunosuppressive treatment, measures that are very often effective. Cyclosporin A may be the drug of choice. J Pediatr Nov;129(5): Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: report of five cases. Mouy R, These observations underline the usefulness of cyclosporine A in this complication. The use of this drug may circumvent the need for increased doses of corticosteroids in some patients. The mechanism of action of cyclosporine A remains speculative, but these results indicate indirectly that T-helper lymphocytes may play a role in the pathogenesis of MAS. 28

29 J Pediatr Feb;128(2): Macrophage activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine. Ravelli A, A macrophage activation syndrome, possibly related to methotrexate toxicity, developed in a boy with systemic juvenile rheumatoid arthritis. Corticosteroid administration was ineffective, whereas a prompt response to cyclosporine was observed. Two months later, Pneumocystis carinii pneumonia developed. 29

30 In 18 cases biologicals were used for HLH treatment including infliximab in three cases etanercept in 13 cases, and Anakinra in two cases 51) KIKUCHI H, YAMAMOTO T, ASAKO K, TAKAYAMA M, SHIRASAKI R, ONO Y. Etanercept for the treatment of intractable hemophagocytic syndrome with systemic lupus erythematosus. Mod Rheumatol 2011; 22: ) TAKAHASHI N, NANIWA T, BANNO S. Successful use of etanercept in the treatment of acute lupus hemophagocytic syndrome. Mod Rheumatol 2008; 18: ) IDEGUCHI H, OHNO S, TAKASE K, HATTORI H, KIRINO Y,TAKENO M, ISHIGATSUBO Y. Successful treatment of refractory lupus-associated haemophagocytic lymphohistiocytosis with infliximab. Rheumatology (Oxford) 2007; 46: ) HENZAN T, NAGAFUJI K, TSUKAMOTO H, MIYAMOTO T, GONDO H, IMASHUKU S, HARADA M. Success with infliximab in treating refractory hemophagocytic lymphohistiocytosis. Am J Hematol 2006; 81: ) MAESHIMA K, ISHII K, IWAKURA M, AKAMINE M, HAMASAKI H, ABE I, HARANAKA M, TATSUKAWA H, YOSHIMATSU H. Adult-onset Still's disease with macrophage activation syndrome successfully treated with a combination of methotrexate and etanercept. Mod Rheumatol 2012; 22: ) CORTIS E, INSALACO A. Macrophage activation syndrome in juvenile idiopathic arthritis. Acta Paediatr Suppl 2006; 95: ) PRAHALAD S, BOVE KE, DICKENS D, LOVELL DJ, GROM AA. Etanercept in the treatment of macrophage activation syndrome. J Rheumatol 2001; 28: ) BRUCK N, SUTTORP M, KABUS M, HEUBNER G, GAHR M, PESSLER F. Rapid and sustained remission of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome through treatment with anakinra and corticosteroids. J Clin Rheumatol 2011; 17: ) KELLY A, RAMANAN AV. A case of macrophage activation syndrome successfully treated with anakinra. Nat Clin Pract Rheumatol 2008; 4:

31 Anakinra & MAS Lurati A et al. MAS during anakinra therapy in a child with systemic JIA. Pediatr Rheumatol Oline J 2005 Commentary: The paradox of macrophage activation syndrome triggered by biologic medications. Pediatr Rheumatol Oline J 2005 On day 13 of treatment 2 patients presented laboratory features consistent with MAS Both patients discontinued anakinra and were treated with oral corticosteroids and Cyclosporin A, with rapid control of MAS Six months later, one patient was re-treated with anakinra for a relapse of his underlying disease and no signs of MAS were observed after 6 mo of follow-up 31

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33 EVOLUTION OF MAS IN REPORTED CASES NUMBER OF PATIENTS 100 TOTAL FAVOURABLE DEATH NR OUTCOME MAS mortality estimated 8-22% 33

34 Hematopoietic stem cell transplantation as a curative treatment for primary Hemophagocytic Lymphohistiocytosis in children: Immunology group at Queen Rania Children s Hospital Experience: Primary diagnosis Fulfill criteria of HLH Initial treatment Engraftment and chimerism Immunreconstitution Chediak COMPLETE HLH % DONOR CURED/FULL Higashi Syndrome Chediak COMPLETE HLH % DONOR CURED/FULL Higashi Syndrome Chediak COMPLETE HLH % DONOR CURED/FULL Higashi Syndrome Griscelli COMPLETE HLH % DONOR CURED/FULL Syndrome type II Griscelli Syndrome type II COMPLETE HLH % DONOR CURED/FULL 34

35 Key messages 1. MAS is a rare complication of childhood rheumatic disease 2. It is a potentially fulminant disorder, which may occur as part of the initial presentation of the rheumatic disease 3. An infective trigger may herald the onset of this complication in predisposed patients 4. Differentiation from a disease flare may be difficult, but is critical to ensure optimal outcome 5. An early and dramatic fall in platelet count is characteristic, with changes in WBC and haemoglobin being more variable early and common 6. Elevation in transaminases and coagulation abnormalities may not be present at onset of MAS 7. Bone marrow examination is supportive, but false negative reports occur as a result of sampling errors or the subtle nature of the disease 8. Multisystem involvement is a poor prognostic sign 35

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