Pathogenesis and Management of Adult-Onset Still’s Disease

https://doi.org/10.1016/j.semarthrit.2006.07.001Get rights and content

Objective

To review recent literature regarding the pathogenesis and treatment of adult-onset Still’s disease (AOSD).

Methods

We searched MEDLINE and PUBMED from 1971 to present using the following terms: adult-onset Still’s disease, AOSD, or adult Still’s disease. In addition we manually retrieved relevant abstracts from recent American College of Rheumatology and European League Against Rheumatism meetings.

Results

The etiology of AOSD, a rare, immune-mediated, multisystem inflammatory disorder characterized by quotidian spiking fevers, evanescent rash, and arthritis, remains unknown. An infectious etiology has been postulated, although a definitive agent has yet to be identified. Cytokines, such as interleukin (IL)-1, IL-6, interferon (IFN)-γ, and tumor necrosis factor-α, are elevated in patients with AOSD. IL-18 and macrophage-colony stimulating factor also seem to play a role.

Treatment historically consisted of nonsteroidal antiinflammatory drugs, often in combination with low-dose corticosteroids. Immunosuppressants (mainly methotrexate, but also intramuscular gold, azathioprine, cyclosporine A, leflunomide, and cyclophosphamide) and intravenous gamma-globulin are efficacious and have been used as steroid-sparing drugs. The recently reported use of anticytokine (anti-TNF-α, anti-IL-1, and anti-IL-6) agents in refractory cases has opened new horizons in the treatment of AOSD and provided important clues for its pathophysiology.

Conclusions

Advances in immunology have enhanced our understanding of the role of cytokines in AOSD pathogenesis. Early, promising studies of anticytokine agents in AOSD may provide further insight into the pathogenetic mechanisms of this complex disease.

Section snippets

Methods

We searched OVID/MEDLINE and PUBMED from 1971 to present using the terms adult-onset Still’s disease, AOSD, or Still’s disease. Full-text articles in the English language were selected for relevance. Then the following co-indexing terms were used: “pathogenesis,” “pathophysiology,” “treatment,” or “therapy.” While the majority of the articles retrieved pertained to the adult disease, information from a few selected articles from the pediatric literature pertaining to pathophysiologic mechanisms

Pathogenesis

The etiology of AOSD is currently unknown, but several studies have suggested various etiologic components. An infectious etiology may be implicated due to the resemblance of the clinical presentation of AOSD with established viral syndromes that also present with high fever, lymphadenopathy, and splenomegaly (6). Several isolated reports suggest the role of an infectious trigger in the pathogenesis of AOSD, attempting to incriminate viruses (mumps, parainfluenza, rubella, coxsackie B4,

Discussion

AOSD is a rare, poorly understood, systemic inflammatory disease. Advances in immunology have enhanced our understanding of the role of cytokines in its pathogenesis. In particular, it has emphasized the role of TNF-α, IL-1, and IL-6. This knowledge has led to the off-label use of anticytokine therapy with biologic agents originally developed for RA. This new approach has shown some promise in small, uncontrolled studies and may provide further insight of the pathogenetic mechanisms behind this

References (86)

  • P. Efthimiou et al.

    Diagnosis and management of adult onset Still’s disease

    Ann Rheum Dis

    (2006)
  • E.G. Bywaters

    Still’s disease in the adult

    Ann Rheum Dis

    (1971)
  • A. Ohta et al.

    Adult Still’s disease: review of 228 cases from the literature

    J Rheumatol

    (1987)
  • J. Pouchot et al.

    Adult Still’s disease: manifestations, disease course, and outcome in 62 patients

    Medicine (Baltimore)

    (1991)
  • A. Ohta et al.

    Adult Still’s disease: a multicenter survey of Japanese patients

    J Rheumatol

    (1990)
  • F.J. Escudero et al.

    Rubella infection in adult onset Still’s disease

    Ann Rheum Dis

    (2000)
  • C. Perez et al.

    Adult Still’s disease associated with Mycoplasma pneumoniae infection

    Clin Infect Dis

    (2001)
  • J.M. Wouters et al.

    Adult-onset Still’s diseaseDisease course and HLA associations

    Arthritis Rheum

    (1986)
  • R. Terkeltaub et al.

    HLA-Bw35 and prognosis in adult Still’s disease

    Arthritis Rheum

    (1981)
  • M.L. Miller et al.

    HLA gene frequencies in children and adults with systemic onset juvenile rheumatoid arthritis

    Arthritis Rheum

    (1985)
  • T. Fujii et al.

    Cytokine and immunogenetic profiles in Japanese patients with adult Still’s diseaseAssociation with chronic articular disease

    Rheumatology (Oxford)

    (2001)
  • C.I. Joung et al.

    Association between HLA-DR B1 and clinical features of adult onset Still’s disease in Korea

    Clin Exp Rheumatol

    (2003)
  • T. Hoshino et al.

    Elevated serum interleukin 6, interferon-gamma, and tumor necrosis factor-alpha levels in patients with adult Still’s disease

    J Rheumatol

    (1998)
  • D.Y. Chen et al.

    Predominance of Th1 cytokine in peripheral blood and pathological tissues of patients with active untreated adult onset Still’s disease

    Ann Rheum Dis

    (2004)
  • F. de Benedetti et al.

    Targeting the interleukin-6 receptor: a new treatment for systemic juvenile idiopathic arthritis?

    Arthritis Rheum

    (2005)
  • K. Matsui et al.

    High serum level of macrophage-colony stimulating factor (M-CSF) in adult-onset Still’s disease

    Rheumatology (Oxford)

    (1999)
  • M. Kawashima et al.

    Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still’s disease

    Arthritis Rheum

    (2001)
  • T. Sugiura et al.

    Association between adult-onset Still’s disease and interleukin-18 gene polymorphisms

    Genes Immun

    (2002)
  • H. Okamura et al.

    Cloning of a new cytokine that induces IFN-gamma production by T cells

    Nature

    (1995)
  • J.M. Esdaile et al.

    Hepatic abnormalities in adult onset Still’s disease

    J Rheumatol

    (1979)
  • H. Tsutsui et al.

    Pathophysiological roles of interleukin-18 in inflammatory liver diseases

    Immunol Rev

    (2000)
  • Y. Sakao et al.

    IL-18-deficient mice are resistant to endotoxin-induced liver injury but highly susceptible to endotoxin shock

    Int Immunol

    (1999)
  • N. Maeno et al.

    Increased interleukin-18 expression in bone marrow of a patient with systemic juvenile idiopathic arthritis and unrecognized macrophage-activation syndrome

    Arthritis Rheum

    (2004)
  • D.Y. Chen et al.

    Proinflammatory cytokine profiles in sera and pathological tissues of patients with active untreated adult onset Still’s disease

    J Rheumatol

    (2004)
  • A. Ogata et al.

    Interleukin 18 and hepatocyte growth factor in fulminant hepatic failure of adult onset Still’s disease

    J Rheumatol

    (2003)
  • D.Y. Chen et al.

    Association of intercellular adhesion molecule-1 with clinical manifestations and interleukin-18 in patients with active, untreated adult-onset Still’s disease

    Arthritis Rheum

    (2005)
  • T. Hoshino et al.

    TCR gamma delta + T cells in peripheral blood of patients with adult Still’s disease

    J Rheumatol

    (1996)
  • K.B. Elkon et al.

    Adult-onset Still’s diseaseTwenty-year followup and further studies of patients with active disease

    Arthritis Rheum

    (1982)
  • A.V. Elezoglou et al.

    Cutaneous vasculitis associated with mixed cryoglobulinemia in adult Still’s disease

    Clin Exp Rheumatol

    (2003)
  • Y. Kirino et al.

    Increased serum HO-1 in hemophagocytic syndrome and adult-onset Still’s disease: use in the differential diagnosis of hyperferritinemia

    Arthritis Res Ther

    (2005)
  • V. Pascual et al.

    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)
  • C.A. Dinarello

    Interleukin-1beta

    Crit Care Med

    (2005)
  • C.A. Dinarello

    Blocking IL-1 in systemic inflammation

    J Exp Med

    (2005)

    • Cited by (95)

    View all citing articles on Scopus

    *Assistant Professor of Medicine, Division of Allergy, Immunology, and Rheumatology.

    The authors have no conflicts of interest to report.

    View full text
    Copyright © 2006 Elsevier Inc. All rights reserved.