Macrophage activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine

doi:10.1016/S0022-3476(96)70408-0

The Journal of Pediatrics

Volume 128, Issue 2, February 1996, Pages 275-278

https://doi.org/10.1016/S0022-3476(96)70408-0 Get rights and content

Abstract

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. (J PEDIATR 1996;128:275-8)

Section snippets

CASE REPORT

A diagnosis of S-JRA⁵ was made for our patient, a boy, at the age of 12 years. The disease course was marked by persistent activity with corticosteroid-dependent systemic manifestations and severe polyarthritis leading to diffuse joint lesions. One year after onset, treatment with orally administered methotrexate at a dose of 15 mg (7.9 mg/m²) weekly was started. Nonsteroidal antiinflammatory drug therapy consisted of the use of piroxicam. The dose of methotrexate was increased to 30 mg (15.8

DISCUSSION

Macrophage activation syndrome is among the most common causes of death in S-JRA and requires prompt recognition and treatment.1, 2, 6, 7 The mainstay of the management of MAS in JRA is based on high-dose intravenous corticosteroid administration. However, there have been some deaths in the reported series, even among patients treated with massive doses of corticosteroids.³ Therapy with cyclosporine was recently proposed by Stéphan et al.³ as a result of their findings suggesting macrophage

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Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening state of immune hyperactivation that arises in the setting of genetic mutations and infectious, inflammatory, or neoplastic triggers. Sustained, aberrant activation of cytotoxic CD8⁺ T cells and resultant inflammatory cytokine release are core pathogenic mechanisms. Key clinical features include high persistent fever, hepatosplenomegaly, blood cytopenia, elevated aminotransferase and ferritin levels, and coagulopathy. HLH is likely under-recognized, and mortality remains high, especially in adults; thus, prompt diagnosis and treatment are essential. Familial forms of HLH are currently treated with chemotherapy as a bridge to hematopoietic stem cell transplantation. HLH occurring in rheumatic disease (macrophage activation syndrome) is treated with glucocorticoids, IL-1 blockade, or cyclosporine A. In other forms of HLH, addressing the underlying trigger is essential. There remains a pressing need for more sensitive, context-specific diagnostic tools. Safer, more effective therapies will arise with improved understanding of the cellular and molecular mechanisms of HLH.
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Fig. 1A) Clinical and laboratory parameters in the MAS/sHLH phenotype are similar to primary HLH but the latter is invariably autosomal recessive, presenting in childhood, and is typically due to mutations that impair NK and CD8+ cytotoxic T-cell function [9–11], although there are emergent overlaps. As the focus of this perspective is restricted to IL-6 in potential MAS in COVID-19 related pneumonia, the reader is referred to several recent articles on primary and secondary HLH and sJIA with MAS [12–15]. Laboratory parameters including highly elevated CRP and hyperferritinaemia, the latter of which may play a complex role in disease [16–18], are key to the diagnosis of MAS/HLH and are elevated in many severe COVID-19 pneumonia cases.
Severe COVID-19 associated pneumonia patients may exhibit features of systemic hyper-inflammation designated under the umbrella term of macrophage activation syndrome (MAS) or cytokine storm, also known as secondary haemophagocytic lymphohistocytosis (sHLH). This is distinct from HLH associated with immunodeficiency states termed primary HLH -with radically different therapy strategies in both situations. COVID-19 infection with MAS typically occurs in subjects with adult respiratory distress syndrome (ARDS) and historically, non-survival in ARDS was linked to sustained IL-6 and IL-1 elevation. We provide a model for the classification of MAS to stratify the MAS-like presentation in COVID-19 pneumonia and explore the complexities of discerning ARDS from MAS. We discuss the potential impact of timing of anti-cytokine therapy on viral clearance and the impact of such therapy on intra-pulmonary macrophage activation and emergent pulmonary vascular disease.
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A brief literature review of four case series examining MAS reveals that rheumatological diseases are implicated infrequently. In the few cases in which MAS is determined to be of rheumatological aetiology, it is mentioned that a missed infection or even medication could be an occult trigger [35,36]. Here is a brief summary of these case series.
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^☆: From the Clinica Pediatrica dell'Universita' di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico S. Matteo, Pavia, Italy

^☆☆: Supported in part by Istituto di Ricovero e Cura a Carattere Scientifico S. Matteo, Pavia, Italy.

^★: Reprint requests: Alberto Martini, MD, Clinica Pediatrica dell'Università di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico S. Matteo, P.le Golgi (2), 27100 Pavia, Italy.

^★★: 0022-3476/96/$5.00 + 0 9/26/69139

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Macrophage activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine☆,☆☆,★,★★

Abstract

Section snippets

CASE REPORT

DISCUSSION

J Pediatr

J Pediatr

J Pediatr

J Pediatr

Macrophage activation syndrome and rheumatic disease in childhood: a report of four new cases

Clin Exp Rheumatol

Current proposed revision of JRA criteria

Arthritis Rheum (Suppl)