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

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.
  26. ↑ Woese CR (July 1979). "A proposal concerning the origin of life on the planet earth". J. Mol. Evol. 13 (2): 95–101. PMID 480373.
  27. ↑ 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.
  28. ↑ Takeshita A, Takeuchi T, Nakagawa A, Tsuda Y, Fukuda A, Nariyama K, Shibayama Y (May 2000). "Adult onset Still's disease with hemophagocytic syndrome and severe liver dysfunction". Hepatol. Res. 17 (2): 139–144. PMID 10707007.
  29. ↑ Maeno N, Takei S, Nomura Y, Imanaka H, Hokonohara M, Miyata K (September 2002). "Highly elevated serum levels of interleukin-18 in systemic juvenile idiopathic arthritis but not in other juvenile idiopathic arthritis subtypes or in Kawasaki disease: comment on the article by Kawashima et al". Arthritis Rheum. 46 (9): 2539–41, author reply 2541–2. doi:10.1002/art.10389. PMID 12355506.
  30. ↑ de Jager W, Vastert SJ, Beekman JM, Wulffraat NM, Kuis W, Coffer PJ, Prakken BJ (September 2009). "Defective phosphorylation of interleukin-18 receptor beta causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis". Arthritis Rheum. 60 (9): 2782–93. doi:10.1002/art.24750. PMID 19714583.
  31. ↑ Chen DY, Lin CC, Chen YM, Lan JL, Hung WT, Chen HH, Lai KL, Hsieh CW (March 2013). "Involvement of TLR7 MyD88-dependent signaling pathway in the pathogenesis of adult-onset Still's disease". Arthritis Res. Ther. 15 (2): R39. doi:10.1186/ar4193. PMC 3672755. PMID 23497717.
  32. ↑ 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.
  33. ↑ Canna SW (May 2014). "Editorial: interferon-γ: friend or foe in systemic juvenile idiopathic arthritis and adult-onset Still's Disease?". Arthritis Rheumatol. 66 (5): 1072–6. doi:10.1002/art.38362. PMC 4181835. PMID 24470448.
  34. ↑ Han JH, Suh CH, Jung JY, Ahn MH, Han MH, Kwon JE, Yim H, Kim HA (April 2017). "Elevated circulating levels of the interferon-γ-induced chemokines are associated with disease activity and cutaneous manifestations in adult-onset Still's disease". Sci Rep. 7: 46652. doi:10.1038/srep46652. PMC 5402387. PMID 28436448.
  35. ↑ Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X (April 2014). "Adult haemophagocytic syndrome". Lancet. 383 (9927): 1503–1516. doi:10.1016/S0140-6736(13)61048-X. PMID 24290661.
  36. ↑ Bae CB, Jung JY, Kim HA, Suh CH (January 2015). "Reactive hemophagocytic syndrome in adult-onset Still disease: clinical features, predictive factors, and prognosis in 21 patients". Medicine (Baltimore). 94 (4): e451. doi:10.1097/MD.0000000000000451. PMC 4602979. PMID 25634183.
  37. ↑ Larroche C, Mouthon L (February 2004). "Pathogenesis of hemophagocytic syndrome (HPS)". Autoimmun Rev. 3 (2): 69–75. doi:10.1016/S1568-9972(03)00091-0. PMID 15003190.
  38. ↑ Canna SW, Behrens EM (January 2012). "Not all hemophagocytes are created equally: appreciating the heterogeneity of the hemophagocytic syndromes". Curr Opin Rheumatol. 24 (1): 113–8. doi:10.1097/BOR.0b013e32834dd37e. PMC 3285509. PMID 22089101.
  39. ↑ Wouters, Jacques M. G. W.; Reekers, Paul; van de Putte, Levinus B. A. (1986). "Adult-onset still's disease. Disease course and HLA associations". Arthritis & Rheumatism. 29 (3): 415–418. doi:10.1002/art.1780290316. ISSN 0004-3591.
  40. ↑ Pouchot J, Sampalis JS, Beaudet F, Carette S, Décary F, Salusinsky-Sternbach M, Hill RO, Gutkowski A, Harth M, Myhal D (March 1991). "Adult Still's disease: manifestations, disease course, and outcome in 62 patients". Medicine (Baltimore). 70 (2): 118–36. PMID 2005777.
  41. ↑ Pouchot J, Sampalis JS, Beaudet F, Carette S, Décary F, Salusinsky-Sternbach M, Hill RO, Gutkowski A, Harth M, Myhal D (March 1991). "Adult Still's disease: manifestations, disease course, and outcome in 62 patients". Medicine (Baltimore). 70 (2): 118–36. PMID 2005777.

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