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Volume 3 Number 2 |
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EDITORIAL The paradox of macrophage activation
syndrome triggered by biologic medications. Antonella
Buoncompagni, Anna Loy, Ilaria Sala, Angelo Ravelli Macrophage activation syndrome (MAS) is a
life-threatening complication of childhood rheumatic diseases, particularly
systemic juvenile idiopathic arthritis (S-JIA), which is characterized by
fever, hepatosplenomegaly, lymphoadenopathy, profound depression of all three
blood cell lines, deranged liver function, intravascular coagulation, and
central nervous system dysfunction. [1] The diagnostic hallmark of the
syndrome is found in the bone marrow aspiration, which reveals widespread
signs of macrophage hemophagocytosis. The clinical and pathologic manifestations of MAS
are thought to result from the activation and uncontrolled proliferation of
T-lymphocytes and well-differentiated macrophages, which leads to an
unrestricted release of inflammatory cytokines, such as TNF-α,
interleukin-1 and interleukin-6. The cause of the immunologic derangement in
MAS is unknown. Recently, markedly decreased natural killer cell function
and, in some cases, depressed perforin expression have been identified in
patients with S-JIA and it has been suggested that these abnormalities may
explain the distinctive susceptibility of these patients to the development
of MAS. [2-3] MAS is a serious condition that is associated with
considerable morbidity and high risk of fatal outcome. Early diagnosis and
immediate therapeutic intervention are, therefore, critical. The treatment of
MAS has traditionally been based on the administration of high-dose
corticosteroids and, more recently, cyclosporine A. [1] The demonstration
that TNF-α may play a central role in the pathogenesis of the clinical
and laboratory manifestations of the syndrome and the observation that
increased serum levels of this cytokine occurs in the acute phase of MAS have
provided the rationale for proposing inhibition of TNF-α as a way to
reduce the consequences of the excessive activation of macrophages. [1]
Prahalad et al reported a dramatic clinical response to etanercept in a
7-year-old boy with a S-JIA-like syndrome and MAS who responded to high-dose
corticosteroid therapy, but experienced two episodes of acute clinical
deterioration after the reduction of the dose of corticosteroids. [4] The
favorable outcome in this patient led to suggest that TNF antagonists
represent an effective adjunctive therapeutic agent in MAS. This important therapeutic achievement has been
subsequently challenged by the description of a case of MAS apparently
triggered by an anti-TNF agent. Ramanan and Schneider reported a 4.5-year-old
girls with S-JIA who developed, after 4 doses of etanercept, a mildly
pruritic giant urticarial rash adjacent to the injection sites and, 4 days
later, a diffuse urticarial rash associated with improvement in arthritis
symptoms, but laboratory evidence of MAS. [5] In the absence of a flare of
systemic disease, an identifiable infection, or any other recent change in
medication, etanercept was considered the most likely inciting factor. In
this issue of the Pediatric Rheumatology Online Journal, Lurati et al
describe an 18-year-old girl with S-JIA who developed MAS during therapy with
another biologic medication, the recombinant interleukin-1 receptor
antagonist anakinra. [6] The syndrome occurred after the 10th dose of the
drug and no evidence of other triggering factors, notably infection, was
found. While writing this commentary, we have also admitted a 15-year-old boy
with S-JIA who developed a full-blown MAS episode during treatment with
anakinra. These observations contrast with the recent anecdotal
evidence regarding the excellent response of resistant S-JIA patients to
anakinra therapy. [7-10] In addition, one of these resistant S-JIA patients
had an episode of MAS which responded partially to corticosteroids,
cyclosporine A, and VP-16. [9] This episode occurred before the start of
anakinra. Interestingly, anakinra treatment appeared to lead to improvement
not only in the systemic and joint symptoms of the underlying disease, but
also in the residual laboratory abnormalities of MAS. How does one explain the paradoxical occurrence of
MAS during treatment with medications that are designed to antagonize the
cytokines believed to be responsible for its development? Because MAS may
represent the severe end of the spectrum of a very active systemic disease,
one possible explanation is that the biologic agent was unable to control the
disease activity and, thus, to prevent MAS. Systemic JIA is one of the more
difficult forms of JIA to manage and it is known that a number of patients
may not respond adequately to biologic therapies. [11] Alternatively, the
syndrome might have been triggered by a drug-related toxic effect, similarly
to what has been observed for other antirheumatic medications, including nonsteroidal antiinflammatory drugs,
parenteral gold salts, sulfasalazine, and methotrexate. [1] A further
hypothesis is that MAS was induced by an undetected infection. It is known
that biologic therapies may increase the susceptibility to infection,
including those that may trigger MAS. Notably, instances of MAS in patients
on biologics in whom a viral infection, rather than the drug, was found to be
the inciting factor have been described. [12-13] In conclusion, the reported
instances of MAS during treatment with biologic medications suggest that the
administration of these agents may occasionally induce (or be associated
with) this complication in patients with S-JIA. It is, however, important not
to generate undue alarm about the safety of these drugs in this subset of JIA
patients. The introduction of biologics holds great promise in the management
of this often aggressive and challenging form of JIA. [10,14] Simply, these
observations should serve as a reminder that patients with S-JIA are uniquely
susceptible to the development of this potentially serious complication and
that, therefore, they deserve very careful clinical monitoring for MAS. The
recently published preliminary diagnostic guidelines for the syndrome
represent a valuable clinical tool to facilitate timely diagnosis and prompt
therapeutic intervention. [15] References 1.
Ravelli A. Macrophage activation syndrome. Curr Opin Rheumatol. 2002;14:
548-52. 2.
Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH, Filipovich A.. Natural
killer cell dysfunction is a distinguishing feature of systemic onset
juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis
Res Ther. 2005;7:R30-R37. 3.
Wulffraat NM, Rijkers GT, Elst E, Brooimans R, Kuis W. Reduced perforin
expression in systemic juvenile idiopathic arthritis is restored by
autologous stem-cell transplantation. Rheumatology. 2003;42:375-9. 4.
Prahalad S, Bove KE, Dickens D, Lovell DJ, Grom A.. Etanercept in the
treatment of macrophage activation syndrome. J Rheumatol. 2001;28:2120-4. 5.
Ramanan AV, Schneider R. Macrophage activation syndrome following initiation
of etanercept in a child with systemic onset juvenile rheumatoid arthritis. J
Rheumatol. 2003;30:401-3. 6.
Lurati A, Teruzzi B, Salmaso A, Demarco G, Pontikaki I, Gattinara M.
Macrophage activation syndrome (MAS) during anti-IL1 receptor therapy
(anakinra) in a patient affected by systemic onset idiopathic juvenile
arthritis (soJIA). Pediatr. Rheumatol Online J. 2005;3(1). 7.
Irigoyen PI, Olsen J, Hom C, Ilowite NT. Treatment of systemic juvenile
rheumatoid arthritis with anakinra [abstract]. Arthritis Rheum. 2004;50
Suppl:S437. 8.
Henrickson M. Efficacy of anakinra in refractory systemic arthritis
[abstract]. Arthritis Rheum. 2004;50 Suppl:S438. 9.
Verbsky JW, White AJ. Effective use of the recombinant interleukin1 receptor
antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid
arthritis. J Rheumatol. 2004;31:2071-5. 10.
Pasqual V, Allantaz F, Arce E, Punaro M, Banchereau J. Role of interleukin-1
(IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis
and clinical response to IL-1 blockade. J Exp Med. 2005;201:1479-86. 11.
Eberhard BA, Ilowite NT. Response of systemic onset juvenile rheumatoid
arthritis to etanercept: is the glass half full or half empty? J Rheumatol.
2005;32;763-5. 12.
Sarwar H, Espinoza LR, Gedalia A. Macrophage activation syndrome and
etanercept in children with systemic juvenile rheumatoid arthritis [letter].
J Rheumatol. 2004;31:623. 13. Skripak JM, Rodgers GL, Martucci C, et al. Disseminated herpes simplex (HSV) infection
precipitating macrophage activation syndrome (MAS) in a child with systemic
juvenile idiopathic arthritis (SJIA) undergoing therapy with infliximab
[abstract]. Pediatr Rheumatol Online J. 2003;vol.1(3):S58. 14.
De Benedetti F, Martini A. Targeting the interleukin-6 receptor: a new
treatment for systemic juvenile idiopathic arthritis? Arthritis Rheum.
2005;52:687-93. 15.
Ravelli A, Magni-Manzoni S, Pistorio A, Basana C, Foti T, Ruperto N et al.
Preliminary diagnostic guidelines for macrophage activation syndrome
complicating systemic juvenile idiopathic arthritis. J Pediatr.
2005;146:598-604. |
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