Advertisement

Autoinflammatory Granulomatous Disease: Blau Syndrome

  • Carlos D. RoseEmail author
  • Carine H. Wouters
Chapter

Abstract

Blau syndrome (BS) is a monogenic granulomatous polyarthritis associated with rather severe uveitis resulting from mutations at or near the nucleotide-binding oligomerization domain (NOD) domain of NOD2. It encompasses early-onset sarcoidosis (EOS), a form of granulomatous arthritis affecting children before the age of 5 years and known since the mid-1970s, and a familial form described separately by Blau and Jabs in 1985. Once the mutation was identified it was clear that BS and EOS were the same disease and both are now covered under the eponym Blau syndrome. This chapter covers the spectrum of clinical manifestations of and diagnostic strategies for the investigation of patients with Blau syndrome, provides an update on pathogenesis and highlights several management recommendations. These developed as knowledge of the natural history improved with the creation of multicenter cross-sectional studies and an ongoing multicenter cohort study.

Keywords

NOD2 Sarcoidosis Blau syndrome Granulomatous diseases 

Abbreviations

ACE

Angiotensin converting enzyme

BS

Blau Syndrome

CARD

Caspase recruitment domain

CD

Crohn disease

CRP

C-reactive protein

EOS

Early-onset sarcoidosis

IL

Interleukin

JIA

Juvenile idiopathic arthritis

LRRs

Leucine-rich-repeats

MAP

Mitogen-activated protein

MDP

Muramyl dipeptide

MGC

Multinucleated giant cell

NF-ĸB

Nuclear factor-ĸB

NOD2/CARD15

Nucleotide-binding oligomerization domain 2/caspase activation recruitment domain 15

PBMC

Peripheral blood mononuclear cells

PIP

Proximal interphalangeal

RIP2

Receptor-interacting protein kinase 2

TAK

Transforming growth factor β-activated kinase

TB

Tuberculosis

References

  1. 1.
    Blau EB. Familial granulomatous arthritis, iritis, and rash. J Pediatr. 1985;107:689–93.CrossRefGoogle Scholar
  2. 2.
    Miceli-Richard C, Lesage S, Rybojad M, et al. CARD15 mutations in Blau syndrome. Nat Genet. 2001;29:19–20.CrossRefGoogle Scholar
  3. 3.
    Rose CD, Pans S, Casteels I, et al. Blau syndrome: baseline data from a prospective multicenter cohort study of clinical, radiological and functional outcomes. Rheumatology (Oxford). 2015;54:1008–16.CrossRefGoogle Scholar
  4. 4.
    Rose CD, Arostegui JI, Martin TM, et al. NOD2-associated pediatric granulomatous arthritis, an expanding phenotype: study of an international registry and a national cohort in Spain. Arthritis Rheum. 2009;60:1797–803.CrossRefGoogle Scholar
  5. 5.
    Byg KE, Milman N, Hansen S. Sarcoidosis in Denmark 1980-1994. A registry-based incidence study comprising 5536 patients. Sarcoidosis Vasc Diffuse Lung Dis. 2003;20:46–52.PubMedGoogle Scholar
  6. 6.
    Lindsley CB, Petty RE. Overview and report on international registry of sarcoid arthritis in childhood. Curr Rheumatol Rep. 2000;2:343–8.CrossRefGoogle Scholar
  7. 7.
    Rose CD, Wouters CH, Meiorin S, et al. Pediatric granulomatous arthritis: an international registry. Arthritis Rheum. 2006;54:3337–44.CrossRefGoogle Scholar
  8. 8.
    Cavanaugh J. International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. Am J Hum Genet. 2001;68:1165–71.CrossRefGoogle Scholar
  9. 9.
    Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599–603.CrossRefGoogle Scholar
  10. 10.
    Tromp G, Kuivaniemi H, Raphael S, et al. Genetic linkage of familial granulomatous inflammatory arthritis, skin rash, and uveitis to chromosome 16. Am J Hum Genet. 1996;59:1097–107.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Wang X, Kuivaniemi H, Bonavita G, et al. CARD15 mutations in familial granulomatosis syndromes: a study of the original Blau syndrome kindred and other families with large-vessel arteritis and cranial neuropathy. Arthritis Rheum. 2002;46:3041–5.CrossRefGoogle Scholar
  12. 12.
    North AF Jr, Fink CW, Gibson WM, et al. Sarcoid arthritis in children. Am J Med. 1970;48:449–55.CrossRefGoogle Scholar
  13. 13.
    Kanazawa N, Matsushima S, Kambe N, Tachibana T, Nagai S, Miyachi Y. Presence of a sporadic case of systemic granulomatosis syndrome with a CARD15 mutation. J Invest Dermatol. 2004;122:851–2.CrossRefGoogle Scholar
  14. 14.
    Rose CD, Doyle TM, McIlvain-Simpson G, et al. Blau syndrome mutation of CARD15/NOD2 in sporadic early onset granulomatous arthritis. J Rheumatol. 2005;32:373–5.PubMedGoogle Scholar
  15. 15.
    Infevers: an online database for autoinflammatory mutations. http://fmf.igh.cnrs.fr/ISSAID/infevers/. Last updated 10/29/2014. Accessed 1 May 2017.
  16. 16.
    De Inocencio J, Mensa-Vilaro A, Tejada-Palacios P, et al. Somatic NOD2 mosaicism in Blau syndrome. J Allergy Clin Immunol. 2015;136:484.CrossRefGoogle Scholar
  17. 17.
    Saulsbury FT, Wouters CH, Martin TM, et al. Incomplete penetrance of the NOD2 E383K substitution among members of a pediatric granulomatous arthritis pedigree. Arthritis Rheum. 2009;60:1804–6.CrossRefGoogle Scholar
  18. 18.
    Harada J, Nakajima T, Kanazawa N. A case of Blau syndrome with NOD2 E383K mutation. Pediatr Dermatol. 2016;33:e385–7.CrossRefGoogle Scholar
  19. 19.
    Okafuji I, Nishikomori R, Kanazawa N, et al. Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis. Arthritis Rheum. 2009;60:242–50.CrossRefGoogle Scholar
  20. 20.
    Sarens IL, Casteels I, Anton J, et al. Blau syndrome-associated uveitis: preliminary results from an international prospective interventional case series. Am J Ophthalmol. 2018;187:158–66.CrossRefGoogle Scholar
  21. 21.
    Inohara N, Nunez G. NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol. 2003;3:371–82.CrossRefGoogle Scholar
  22. 22.
    Inohara, Chamaillard, McDonald C, Nunez G. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem. 2005;74:355–83.CrossRefGoogle Scholar
  23. 23.
    Maekawa S, Ohto U, Shibata T, Miyake K, Shimizu T. Crystal structure of NOD2 and its implications in human disease. Nat Commun. 2016;7:11813.CrossRefGoogle Scholar
  24. 24.
    Kanazawa N, Okafuji I, Kambe N, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. Blood. 2005;105:1195–7.CrossRefGoogle Scholar
  25. 25.
    Foley K, Desai B, Vossenkämper A, et al. RIP2 kinase is activated in Blau syndrome and IBD. Pediatr Rheumatol Online J. 2013;11(Suppl 1):A3.CrossRefGoogle Scholar
  26. 26.
    Martin TM, Zhang Z, Kurz P, et al. The NOD2 defect in Blau syndrome does not result in excess interleukin-1 activity. Arthritis Rheum. 2009;60:611–8.CrossRefGoogle Scholar
  27. 27.
    Dugan J, Griffiths E, Snow P, et al. Blau syndrome-associated Nod2 mutation alters expression of full-length NOD2 and limits responses to muramyl dipeptide in knock-in mice. J Immunol. 2015;194:349–57.CrossRefGoogle Scholar
  28. 28.
    Takada S, Kambe N, Kawaski Y, et al. Pluripotent stem cell models of Blau syndrome reveal an IFN-γ-dependent inflammatory response in macrophages. J Allergy Clin Immunol. 2018;141:339–49.CrossRefGoogle Scholar
  29. 29.
    Boyle JP, Parkhouse R, Monie TP. Insights into the molecular basis of the NOD2 signaling pathway. Open Biol. 2014;4(12).CrossRefGoogle Scholar
  30. 30.
    Janssen CE, Rose CD, De HG, et al. Morphologic and immunohistochemical characterization of granulomas in the nucleotide oligomerization domain 2-related disorders Blau syndrome and Crohn disease. J Allergy Clin Immunol. 2012;129:1076–84.CrossRefGoogle Scholar
  31. 31.
    Homer CR, Kabi A, Marina-Garcia N, et al. A dual role of receptor-interacting protein kinase 2 (RIP2) kinase activity nucleotide-binding oligomerization domain 2 (NOD2)-dependent autophagy. J Biol Chem. 2012;287:25565–76.CrossRefGoogle Scholar
  32. 32.
    Meiorin SM, Espada G, Costa CE, et al. Granulomatous nephritis associated with R334Q mutation in NOD2. J Rheumatol. 2007;34:1945–7.PubMedGoogle Scholar
  33. 33.
    Wouters C, Rose CD, Prieur AM. Rhumatologie pédiatrique. Paris: Flammarion Médicine-Sciences; 2009.Google Scholar
  34. 34.
    Wouters C, Rose CD. Childhood sarcoidosis. In: Cimaz R, Lehman T, editors. Pediatrics in systemic autoimmune diseaeses, vol. 6. Amsterdam: Elsevier; 2008.Google Scholar
  35. 35.
    Lindsley CB, Godfrey WA. Childhood sarcoidosis manifesting as juvenile rheumatoid arthritis. Pediatrics. 1985;76:765–8.PubMedGoogle Scholar
  36. 36.
    Becker ML, Martin TM, Doyle TM, Rose CD. Interstitial pneumonitis in Blau syndrome with documented mutation in CARD15. Arthritis Rheum. 2007;56:1292–4.CrossRefGoogle Scholar
  37. 37.
    Jabs DA, Houk JL, Bias WB, Arnett FC. Familial granulomatous synovitis, uveitis, and cranial neuropathies. Am J Med. 1985;78:801–4.CrossRefGoogle Scholar
  38. 38.
    Fink CW, Cimaz R. Early onset sarcoidosis: not a benign disease. J Rheumatol. 1997;24:174–7.PubMedGoogle Scholar
  39. 39.
    Saini SK, Rose CD. Liver involvement in familial granulomatous arthritis (Blau syndrome). J Rheumatol. 1996;23:396–9.PubMedGoogle Scholar
  40. 40.
    Arostegui JI, Arnal C, Merino R, et al. NOD2 gene-associated pediatric granulomatous arthritis: clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin-1 blockade in a Spanish cohort. Arthritis Rheum. 2007;56:3805–13.CrossRefGoogle Scholar
  41. 41.
    Ting SS, Ziegler J, Fischer E. Familial granulomatous arthritis (Blau syndrome) with granulomatous renal lesions. J Pediatr. 1998;133:450–2.CrossRefGoogle Scholar
  42. 42.
    Gross KR, Malleson PN, Culham G, Lirenman DS, McCormick AQ, Petty RE. Vasculopathy with renal artery stenosis in a child with sarcoidosis. J Pediatr. 1986;108:724–6.CrossRefGoogle Scholar
  43. 43.
    Gedalia A, Shetty AK, Ward K, Correa H, Venters CL, Loe WA. Abdominal aortic aneurysm associated with childhood sarcoidosis. J Rheumatol. 1996;23:757–9.PubMedGoogle Scholar
  44. 44.
    Khubchandani RP, Hasija R, Touitou I, Khemani C, Wouters CH, Rose CD. Blau arteritis resembling Takayasu disease with a novel NOD2 mutation. J Rheumatol. 2012;39:1888–92.CrossRefGoogle Scholar
  45. 45.
    Rotenstein D, Gibbas DL, Majmudar B, Chastain EA. Familial granulomatous arteritis with polyarthritis of juvenile onset. N Engl J Med. 1982;306:86–90.CrossRefGoogle Scholar
  46. 46.
    Mourad F, Tang A. Sinus of valsalva aneurysm in Blau syndrome. J Thorac Cardiovasc Surg. 2010;5:16.Google Scholar
  47. 47.
    Wang L, Rosé CD, Foley KP, et al. S100A12 and S100A8/9 proteins are biomarkers of articular disease activity in Blau syndrome. Rheumatology. 2018;57:1299–304.CrossRefGoogle Scholar
  48. 48.
    Mensa-Vilaro A, Cham WT, Tang SP, et al. Brief report: first identification of intrafamilial recurrence of Blau syndrome due to gonosomal NOD2 mosaicism. Arthritis Rheumatol. 2016;68:1039–44.CrossRefGoogle Scholar
  49. 49.
    Rose CD, Neven B, Wouters CH. Granulomatous inflammation: the overlap of immunodeficiencies and inflammation. Best Pract Res Clin Rheumatol. 2014;28:191–212.CrossRefGoogle Scholar
  50. 50.
    Brescia A, Mcllvain-Simpson G, Rose CD . Infliximab therapy for steroid-dependent early onset sarcoid arthritis and Blau syndrome. Arthritis Rheum. 2014;46:S313.Google Scholar
  51. 51.
    Milman N, Andersen CB, Hansen A, et al. Favourable effect of TNF-alpha inhibitor (infliximab) on Blau syndrome in monozygotic twins with a de novo CARD15 mutation. APMIS. 2006;114:912–9.CrossRefGoogle Scholar
  52. 52.
    Simonini G, Xu Z, Caputo R, et al. Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis. Arthritis Rheum. 2013;65:513–8.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.duPont Children’s Hospital, Thomas Jefferson UniversityPhiladelphiaUSA
  2. 2.Department of Microbiology and ImmunologyKU Leuven-University of LeuvenLeuvenBelgium
  3. 3.Pediatric RheumatologyUniversity Hospitals LeuvenLeuvenBelgium

Personalised recommendations