Adult-onset Still's disease pathophysiology

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Adult-onset Still's disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

Adult-onset Still's disease (AOSD) is an autoimmune inflammatory arthritis that typically affects adolescents and adults ranging from age 16-40 years. Major etiological mechanisms behind cause a dysfunction of the innate and cellular immunity (limited) leading to activation of effector cells of the disease. Although the pathogenesis of adult-onset Still's disease is largely knwon to be idiopathic. Triggers of AOSD lead to activation of toll-like receptors (TLR) and activation of immune system. Pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) play an important role in the etiopathogenesis of AOSD. They lead to release of various cytokines in the body such as interleukin-1 beta (IL-1), interleukin-6 (IL-6), interleukin-17, interleukin-18, interferon-alpha (IFN-alpha) and tumor necrosis factor (TNF-alpha). These cytokines play major roles in modifying the normal working of the body and produce the typical clinical pictiure associated with AOSD. Some distinct HLA alleles have been shown to be associated with AOSD such as HLA-DR4, HLA-Bw35 (associated with good prognosis), HLA-DRB1, HLA-DRw6 (joint root involvement), HLA-B17, HLA-B35 and HLA-DR2. On gross examination, the involved joints may exhibit soft tissue swelling, cartilage loss, joint erosions and carpal ankylosis (late during the disease process). On microscopic examination of the joint fluid, typical features associated with inflammatory joint disease may be observed.

Pathophysiology

Adult-onset Still's disease is an autoimmune inflammatory arthritis that typically affects adolescents and adults ranging from age 16-40 years. Major etiological mechanisms behind cause a dysfunction of the innate and cellular immunity (limited) leading to activation of effector cells of the disease.

Putative triggers

Although the pathogenesis of adult-onset Still's disease is largely known to be idiopathic. Triggers of AOSD lead to activation of toll-like receptors (TLR) and activation of immune system. The following triggers may be implicated as factors responsible for generating key pathological processes occurring in adult-onset Still's disease (AOSD):[1][2][3][4][5][6][7][8]

Pathogen-associated molecular patterns (PAMPs)

Danger-associated molecular patterns (DAMPs)

  • Chemicals
  • Toxins
  • Stress

Immune dysfunction

Both innate and adaptive immunity play roles in the pathological evolution of adult-onset Still's disease with the dysfunction occurring in the innate immunity predominating the picture. The following dysfunctions are involved:

Changes in the innate immunity

Changes in the adaptive immunity

Role of interleukin-1 beta (IL-1), interleukin-6 (IL-6), interferon-alpha (IFN-alpha) and tumor necrosis factor (TNF-alpha)

Interleukin-1 beta plays a key role in producing major characteristic features of adult-onset Still's disease. PAMPs and DAMPs lead to stimulation of protein complex nucleotide-binding oligomerization-domain-(NOD-) like receptor family, pyrin domain containing 3 (NLRP3) inflammasome (expressed in myeloid cells). The consequence of all these trigger-stimulated NOD and NLRP increasing interactions is an increased production of interleukin-1 beta.[15]The following processes are affected by an increased production of this key interleukin of AOSD:

(a) Hypothalamic-pituitary axis influence

Activation of the hypothalamic-pituitary axis by interleukin-1 beta lead to the following changes:

Hormonal

Systemic

(b) Liver synthesis and secretion of acute phase proteins

Both interleukin-1 beta, interleukin-6 and interferon-alpha (IFN-alpha) lead to increased production of acute phase reactants by the liver due to inflammatory and oxidative stress occurring during active AOSD. The following acute phase reactant proteins are elevated in AOSD as a result of increased liver production:[20][21]

(c) Osteoclasts activation and matrix metalloproteinases (MMPs) synthesis

Interleukin-1 and TNF-alpha have been shown to inhibit chondrogenesis leading to decreased repair process of bone and cartilage in AOSD.[22]

(d) Innate immune system cells activation

Effector cells of the innate immune system such as macrophages and neutrophils are activated mainly due to interleukin-1. The neutrophil to lymphocyte count ratio is increased due to elevated neutrophils.[23]

(e) Increased gene transcription of proinflammatory molecules

The following proinflammatory factors are produced in an increased concentration in AOSD:

Role of interleukin-18

It is produced by macrophages and monocytes as a consequence of bacterial and viral infections (which are thought to be triggers of AOSD).[29] A defective phosphorylation of IL-18 receptor is though to give rise to this dysfunction.[30]

Role of interleukin-17

Th17 cells lead to an increased production of interleukin-17. The stimulaton of Th17 cells is drived by interleukin-1, transforming growth factor beta (TGF-beta) and interleukin-6.[31][32]

Role of interferon gamma

Imblanced production of interferon-gamma is thought to be associated with AOSD.[33]  Levels of the IFN-γ-induced chemokines, CXCL9, CXCL10 and CXCL11 are increased during active phase of AOSD.[34]

Reactive hemophagocytic lymphohistiocytosis 

Hemophagocytic lymphohistiocytosis (also known as macrophage activation syndrome- MAS) is a severe life-threatening complication that may develop in patients of Still's disease.[35][36] Interleukin 1-beta and interleukin 18 mediated activation of macrophages eventually leads to secretion of interferon-gamma by the NK and CD8+ T cells. There is increased activation of T cells leading to hypersecretion of proinflammatory cytokines, including interferon gamma, interleukin (IL)-1, IL-6, IL-18, and tumor necrosis factor alpha (TNF-alpha).[37][38]

Genetics

Some distinct HLA alleles have been shown to be associated with AOSD. The following are the major HLA alleles:[39][40]

Genetic polymorphisms in genes encoding the following factors are known to be asosicated with AOSDL:

  • IL-6
  • IL-1
  • Macrophage inhibitory factor (MIF), or TNF i

Gross Pathology

On gross examination, the involved joints may exhibit the following features:[41]

Microscopic Pathology

On microscopic examination of the synovial fluid, typical findings of inflammatory arthritis may be observed. The following table outlines the typical findings on synovial fluid examination of joints affected by AOSD:

Test Normal Inflammatory arthritis (AOSD, RA, crystal arthritis, spondyloarthritis)
Appearance Clear Clear to opaque (yellow white)
White blood cell count/mm3 < 200 > 2000
Polymorphonuclear cells < 25% Greater than equal to 50%
Culture Negative Negative
Intracellular crystals Negative Positive only in crystal induced arthritis

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