Adult-onset Still's disease pathophysiology

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Template:Adult-onset Still's disease Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

Pathophysiology

Adult-onset Still's disease is an automminue 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 largerly idiopathic. Triggers of ASOD 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 (ASOD):[1][2][3][4][5][6][7][8]

Pathogen-associated molecular patterns (PAMPs)

  • Bacteria
    • Yersinia enterocolitica
    • Chlamydophila pneumoniae
    • Brucella abortus
    • Borrelia burgdorferi
  • Viruses
    • Rubella
    • Echovirus 7
    • Mumps
    • Cytomegalovirus (CMV)
  • Fungi

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

  • Natural killer cells have been found to be decreased in patients with ASOD. The mechanism underlying dysfunctional NK cells is a defect in IL-18 receptor β phosphorylation.[9]
  • Neutrophil and macrophage activation lie at the heart of pathogenesis of ASOD due to the effects of the proinflammatory interleukin-18 (IL-18) signalling.
  • CD64, a marker of neutrophil activation has been found to be upregulated in active ASOD.[10]
  • Macrophage colony stimulating factor (MCSF), intercellular adhesion molecule-1 (ICAM-1) and calprotectin are elevated and act as markers of active disease.[11][12]

Changes in the adaptive immunity

  • T cell activation has also been shown to play role in the pathogenesis of ASOD with Th1 (cytotoxic) subset prevailing over Th2 CD4+ T cells.
  • Increased number of Th17 cells derived from the differentiation of naieve CD4+ T cells due to to activation by interleukin-1 beta, transforming growth factor-beta and interleukin- 6 is also seen in active ASOD. [13][14]

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

Interleukin-i 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 ASOD:

(a) Hypothalamic-pituitary axis influence

Activation of the hypothalmic-pitutary axis by interleukin-1 beta lead to the following changes:

Hormonal

  • An increased secretion of adenocorticotrophic hormone (ACTH) and anti-diuretic hormone (ADH).
  • A decreased secretion of growth hormone (GH) and somatostatin.[16]

Systemic

  • Disturbance of the thalmic temperature regulating centres leading to fever.[17]
  • Fatigue[18]
  • Anorexia[19] 

(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 ASOD. The following acute phase reactant proteins are elevated in ASOD as a result of increased liver production:[20][21]

  • C-reactive protein (CRP)
  • Ferritin  
  • Serum amyloid protein (SAA)

(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 ASOD.[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 ASOD:

  • Inducible nitric oxide synthase (iNOS)[24]
  • Innter leukin 1, 6 and TNF-alpha induced cyclo-oxygenase 2 (COX2)[25]
  • Phospholipase A2
  • Adhesion molecules
  • Colony-stimulating factors (CSF). 

Role of interleukin-18

Role of interleukin-17

Role of interferon gamma

Role of tumor necrosis factor-alpha (TNF-alpha)

 Reactive hemophagocytic lymphohistiocytosis 

Genetics

Associated Conditions

Gross Pathology

Microscopic Pathology

References

  1. ↑ Perez C, Artola V (March 2001). "Adult Still's disease associated with Mycoplasma pneumoniae infection". Clin. Infect. Dis. 32 (6): E105–6. doi:10.1086/319342. PMID 11247732.
  2. ↑ Dua J, Nandagudi A, Sutcliffe N (December 2012). "Mycoplasma pneumoniae infection associated with urticarial vasculitis mimicking adult-onset Still's disease". Rheumatol. Int. 32 (12): 4053–6. doi:10.1007/s00296-011-2107-4. PMID 21918897.
  3. ↑ Escudero FJ, Len O, Falcó V, de Sevilla TF, Sellas A (June 2000). "Rubella infection in adult onset Still's disease". Ann. Rheum. Dis. 59 (6): 493. PMC 1753159. PMID 10885978.
  4. ↑ Efthimiou P, Georgy S (December 2006). "Pathogenesis and management of adult-onset Still's disease". Semin. Arthritis Rheum. 36 (3): 144–52. doi:10.1016/j.semarthrit.2006.07.001. PMID 16949136.
  5. ↑ Wouters JM, van der Veen J, van de Putte LB, de Rooij DJ (September 1988). "Adult onset Still's disease and viral infections". Ann. Rheum. Dis. 47 (9): 764–7. PMC 1003594. PMID 3178317.
  6. ↑ Ogra PL, Chiba Y, Ogra SS, Dzierba JL, Herd JK (May 1975). "Rubella-virus infection in juvenile rheumatoid arthritis". Lancet. 1 (7917): 1157–61. PMID 48775.
  7. ↑ Linnemann CC, Levinson JE, Buncher CR, Schiff GM (August 1975). "Rubella antibody levels in juvenile rheumatoid arthritis". Ann. Rheum. Dis. 34 (4): 354–8. PMC 1006427. PMID 1081377.
  8. ↑ Blotzer JW, Myers AR (1978). "Echovirus-associated polyarthritis. Report of a case with synovial fluid and synovial histologic characterization". Arthritis Rheum. 21 (8): 978–81. PMID 737022.
  9. ↑ de Jager, Wilco; Vastert, Sebastiaan J.; Beekman, Jeffrey M.; Wulffraat, Nico M.; Kuis, Wietse; Coffer, Paul J.; Prakken, Berent J. (2009). "Defective phosphorylation of interleukin-18 receptor β causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis". Arthritis & Rheumatism. 60 (9): 2782–2793. doi:10.1002/art.24750. ISSN 0004-3591.
  10. ↑ Komiya A, Matsui T, Nogi S, Iwata K, Futami H, Takaoka H, Arinuma Y, Hashimoto A, Shimada K, Ikenaka T, Nakayama H, Furukawa H, Tohma S (March 2012). "Neutrophil CD64 is upregulated in patients with active adult-onset Still's disease". Scand. J. Rheumatol. 41 (2): 156–8. doi:10.3109/03009742.2011.644325. PMID 22420333.
  11. ↑ Chen DY, Lan JL, Lin FJ, Hsieh TY (June 2005). "Association of intercellular adhesion molecule-1 with clinical manifestations and interleukin-18 in patients with active, untreated adult-onset Still's disease". Arthritis Rheum. 53 (3): 320–7. doi:10.1002/art.21164. PMID 15934126.
  12. ↑ Matsui K, Tsuchida T, Hiroishi K, Tominaga K, Hayashi N, Hada T, Higashino K (May 1999). "High serum level of macrophage-colony stimulating factor (M-CSF) in adult-onset Still's disease". Rheumatology (Oxford). 38 (5): 477–8. PMID 10371293.
  13. ↑ Chen DY, Chen YM, Lan JL, Lin CC, Chen HH, Hsieh CW (December 2010). "Potential role of Th17 cells in the pathogenesis of adult-onset Still's disease". Rheumatology (Oxford). 49 (12): 2305–12. doi:10.1093/rheumatology/keq284. PMID 20837500.
  14. ↑ Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (November 2005). "A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17". Nat. Immunol. 6 (11): 1133–41. doi:10.1038/ni1261. PMC 1618871. PMID 16200068.
  15. ↑ Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J (May 2005). "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. 201 (9): 1479–86. doi:10.1084/jem.20050473. PMC 2213182. PMID 15851489.
  16. ↑ Ward DJ, Hartog M, Ansell BM (September 1966). "Corticosteroid-induced dwarfism in Still's disease treated with human growth hormone. Clinical and metabolic effects including hydroxyproline excretion in two cases". Ann. Rheum. Dis. 25 (5): 416–21. PMC 2453455. PMID 5915585.
  17. ↑ "onlinelibrary.wiley.com".
  18. ↑ Rossi-Semerano L, Koné-Paut I (2012). "Is Still's Disease an Autoinflammatory Syndrome?". Int J Inflam. 2012: 480373. doi:10.1155/2012/480373. PMC 3350968. PMID 22611516.
  19. ↑ Rossi-Semerano L, Koné-Paut I (2012). "Is Still's Disease an Autoinflammatory Syndrome?". Int J Inflam. 2012: 480373. doi:10.1155/2012/480373. PMC 3350968. PMID 22611516.
  20. ↑ Fautrel B (June 2002). "Ferritin levels in adult Still's disease: any sugar?". Joint Bone Spine. 69 (4): 355–7. PMID 12184429.
  21. ↑ Stam TC, Swaak AJ, Kruit WH, Eggermont AM (March 2002). "Regulation of ferritin: a specific role for interferon-alpha (IFN-alpha)? The acute phase response in patients treated with IFN-alpha-2b". Eur. J. Clin. Invest. 32 Suppl 1: 79–83. PMID 11886436.
  22. ↑ Wehling, N.; Palmer, G. D.; Pilapil, C.; Liu, F.; Wells, J. W.; Müller, P. E.; Evans, C. H.; Porter, R. M. (2009). "Interleukin-1β and tumor necrosis factor α inhibit chondrogenesis by human mesenchymal stem cells through NF-κB-dependent pathways". Arthritis & Rheumatism. 60 (3): 801–812. doi:10.1002/art.24352. ISSN 0004-3591.
  23. ↑ Seo JY, Suh CH, Jung JY, Kim AR, Yang JW, Kim HA (July 2017). "The neutrophil-to-lymphocyte ratio could be a good diagnostic marker and predictor of relapse in patients with adult-onset Still's disease: A STROBE-compliant retrospective observational analysis". Medicine (Baltimore). 96 (29): e7546. doi:10.1097/MD.0000000000007546. PMC 5521915. PMID 28723775.
  24. ↑ Zamora R, Vodovotz Y, Billiar TR (May 2000). "Inducible nitric oxide synthase and inflammatory diseases". Mol. Med. 6 (5): 347–73. PMC 1949959. PMID 10952018.
  25. ↑ García JE, López AM, de Cabo MR, Rodríguez FM, Losada JP, Sarmiento RG, López AJ, Arellano JL (1999). "Cyclosporin A decreases human macrophage interleukin-6 synthesis at post-transcriptional level". Mediators Inflamm. 8 (4–5): 253–9. doi:10.1080/09629359990423. PMC 1781800. PMID 10704080.

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