Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross-sectional study.
Journal: 2007/May - Annals of the Rheumatic Diseases
ISSN: 0003-4967
Abstract:
BACKGROUND
Juvenile idiopathic arthritis (JIA) consists of a heterogeneous group of disorders with, for the most part, an unknown immunopathogenesis. Although onset and disease course differ, the subtypes of JIA share the occurrence of chronic inflammation of the joints, with infiltrations of immunocompetent cells that secrete inflammatory mediators.
OBJECTIVE
To identify a panel of cytokines specifically related to the inflammatory process in JIA.
METHODS
Using a new technology, the multiplex immunoassay, 30 cytokines were measured in plasma of 65 patients with JIA, of which 34 were paired with synovial fluid. These data were compared with plasma of 20 healthy controls and 9 patients with type I diabetes, a chronic inflammatory disease.
RESULTS
Patients with JIA had, irrespective of their subclassification, significantly higher levels of tumour necrosis factor alpha, macrophage inhibitory factor (MIF), CCL2, CCL3, CCL11, CCL22 and CXCL9 in plasma than controls. In paired plasma and synovial fluid samples of patients with JIA, significantly higher levels of interleukin (IL)6, IL15, CCL2, CCL3, CXCL8, CXCL9 and CXCL10 were present in synovial fluid. Cluster analysis in all patients with JIA revealed a predominant pro-inflammatory cytokine cluster during active disease and a regulatory/anti-inflammatory-related cytokine cluster during remission. Whether a discrimination profile of various cytokines could help in the determination of disease classification was tested.
CONCLUSIONS
It is suggested that several cytokines (IL18, MIF, CCL2, CCL3, CCL11, CXCL9 and CXCL10) may correspond to the activation status during inflammation in JIA and could be instrumental in monitoring disease activity and outcomes of (new) immunotherapies.
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Ann Rheum Dis 66(5): 589-598

Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross‐sectional study

Wilco de Jager, Nico M Wulffraat, Wietse Kuis, Berent J Prakken, Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; IACOPO Institute for Translational Medicine, Utrecht, The Netherlands; San Diego, California, USA
Esther P A H Hoppenreijs, Department of Pediatrics, University Medical Center Nijmegen, Nijmegen, The Netherlands
Lucy R Wedderburn, Rheumatology Unit, Institute of Child Health, University College, London, UK
Correspondence to: Professor B J Prakken
Department of Pediatric Immunology (KC010690), University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands; bprakken@umcutrecht.nl
Wilco de Jager, Nico M Wulffraat, Wietse Kuis, Berent J Prakken, Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; IACOPO Institute for Translational Medicine, Utrecht, The Netherlands; San Diego, California, USAEsther P A H Hoppenreijs, Department of Pediatrics, University Medical Center Nijmegen, Nijmegen, The NetherlandsLucy R Wedderburn, Rheumatology Unit, Institute of Child Health, University College, London, UKCorrespondence to: Professor B J Prakken
Department of Pediatric Immunology (KC010690), University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands; bprakken@umcutrecht.nl
Accepted 2006 Dec 2.

Abstract

Background

Juvenile idiopathic arthritis (JIA) consists of a heterogeneous group of disorders with, for the most part, an unknown immunopathogenesis. Although onset and disease course differ, the subtypes of JIA share the occurrence of chronic inflammation of the joints, with infiltrations of immunocompetent cells that secrete inflammatory mediators.

Objective

To identify a panel of cytokines specifically related to the inflammatory process in JIA.

Methods

Using a new technology, the multiplex immunoassay, 30 cytokines were measured in plasma of 65 patients with JIA , of which 34 were paired with synovial fluid. These data were compared with plasma of 20 healthy controls and 9 patients with type I diabetes, a chronic inflammatory disease.

Results

Patients with JIA had, irrespective of their subclassification, significantly higher levels of tumour necrosis factor α, macrophage inhibitory factor (MIF), CCL2, CCL3, CCL11, CCL22 and CXCL9 in plasma than controls. In paired plasma and synovial fluid samples of patients with JIA, significantly higher levels of interleukin (IL)6, IL15, CCL2, CCL3, CXCL8, CXCL9 and CXCL10 were present in synovial fluid. Cluster analysis in all patients with JIA revealed a predominant pro‐inflammatory cytokine cluster during active disease and a regulatory/anti‐inflammatory‐related cytokine cluster during remission. Whether a discrimination profile of various cytokines could help in the determination of disease classification was tested.

Conclusion

It is suggested that several cytokines (IL18, MIF, CCL2, CCL3, CCL11, CXCL9 and CXCL10) may correspond to the activation status during inflammation in JIA and could be instrumental in monitoring disease activity and outcomes of (new) immunotherapies.

Abstract

Juvenile idiopathic arthritis (JIA) consists of a heterogeneous group of disorders with unknown aetiology. This autoimmune disorder is a major cause of chronic disability in children. The underlying factors influencing susceptibility are thought to include a combination of environmental interactions and genes.1 Although onset and disease course may differ, the subtypes of JIA share the occurrence of chronic inflammation of the joints. Monocytes, macrophages, fibroblasts and T cells within the inflamed microenvironment secrete many mediators that interact directly with the surrounding tissue and tend to have a pro‐inflammatory character.23 The produced interleukins (ILs) regulate the production of inflammatory mediators from the surrounding tissue, whereas secreted chemotactic cytokines (chemokines) function as regulatory molecules that attract and direct the differentiation of new potent inflammatory cells to the site of inflammation.4567

Cytokine profiles in both plasma and synovial fluid are no more than a reflection of the local inflammatory process. However, detection of these mediators might serve as biomarkers for disease diagnosis, prognosis and treatment outcome. Indeed, analysis of individual mediators with ELISA and mRNA detection has contributed to our understanding of the immune and inflammatory reactions in JIA. Increased levels of pro‐inflammatory cytokines and decreased production of the regulatory cytokine IL10 have been reported as biomarkers for disease.89101112 Through the characterisation of cytokine pathways, new treatments have been developed using monoclonal antibodies that block specific components of the immune system, and, consequently, modulate the inflammatory process. An immune intervention based on blocking the biological effects of tumour necrosis factor (TNF)α and IL1 is effective for the treatment of JIA, whereas an antibody that blocks IL6 as well as several chemokine‐based interventions are under investigation.13141516171819

Owing to systemic intervention of the immune system, major changes will occur in the cytokine milieu downstream of these pro‐inflammatory pathways. Circulating cytokines correspond to the activation status of immunocompetent cells, and it could be instrumental to monitor changes in this profile during treatment. Intervention with monoclonal antibodies is not without risk, as illustrated by the occurrence of serious side effects such as drug‐induced autoimmunity by accumulation of cytokines (interferon (IFN)α) in blood after anti‐TNFα treatment,2021 as well as the dramatic side effects observed in healthy volunteers after administration of a monoclonal antibody directed against CD28.2223 These severe side effects after administration of this antibody are partly due to an evolving cytokine storm.24 Evaluating circulating cytokines and chemokines in plasma might help in identifying surrogate parameters for disease activity, disease severity, risk of side effects and treatment outcome.

Innovation in the technology for detection of proteins has led to the development of particle‐based multiplex immunoassays (MIAs). This new technology allows individual and multiplex analysis of up to a hundred different mediators in a single sample volume of 50 µl.252627 We have developed an MIA to detect 30 human soluble mediators, all related to chronic inflammation, in plasma and in synovial fluid.27 Using this technology, we measured a panel of ILs, chemokines and soluble adhesion molecule profiles in plasma and synovial fluid of patients with oligoarticular, polyarticular and systemic JIA as well as in plasma of healthy controls. We correlated plasma cytokine levels with disease activity and used a mathematical approach to assess the predictive value of cytokines and chemokines for the diagnosis of JIA.

Acknowledgements

We thank CS Uiterwaal, the Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, and EP Martens, the Center for Biostatistics, Utrecht University, for advice with statistical and data analysis.

Acknowledgements

Abbreviations

CRP - C reactive protein

ESR - erythrocyte sedimentation rate

IFN - interferon

IL - interleukin

JIA - juvenile idiopathic arthritis

MIA - multiplex immunoassay

MIF - macrophage inhibitory factor

NK - natural killer

OSM - oncostatin M

RANKL - receptor activator of nuclear factor κ B ligand

Th - T helper (cell)

TNF - tumour necrosis factor

Abbreviations

Footnotes

Funding: WdJ and BJP are financially supported by the Dutch Rheumatoid Arthritis Foundation (Nationaal Reumafonds) and by the Immune Tolerance Network (ITN). Furthermore, BJP is supported by a VIDI innovation grant from the Dutch Organization for Scientific Research (NWO). LRW is supported by grants from SPARKS UK and the Arthritis Research Campaign.

Competing interests: None.

Footnotes

References

  • 1. Prahalad SGenetics of juvenile idiopathic arthritis: an update. Curr Opin Rheumatol 200416588–594. [[PubMed][Google Scholar]
  • 2. Choy E H, Panayi G SCytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001344907–916. [[PubMed][Google Scholar]
  • 3. Woo PCytokines and juvenile idiopathic arthritis. Curr Rheumatol Rep 20024452–457. [[PubMed][Google Scholar]
  • 4. Baggiolini MChemokines and leukocyte traffic. Nature 1998392565–568. [[PubMed][Google Scholar]
  • 5. Luster A DChemokines—chemotactic cytokines that mediate inflammation. N Engl J Med 1998338436–445. [[PubMed][Google Scholar]
  • 6. O'Shea J J, Ma A, Lipsky PCytokines and autoimmunity. Nat Rev Immunol 2002237–45. [[PubMed][Google Scholar]
  • 7. Trautmann AChemokines as immunotransmitters? Nat Immunol 20056427–428. [[PubMed][Google Scholar]
  • 8. De Benedetti F, Pignatti P, Bernasconi S, Gerloni V, Matsushima K, Caporali R. et al Interleukin 8 and monocyte chemoattractant protein‐1 in patients with juvenile rheumatoid arthritis. Relation to onset types, disease activity, and synovial fluid leukocytes. J Rheumatol 199926425–431. [[PubMed]
  • 9. Ozen S, Saatci U, Bakkaloglu A, Ozdemir O, Besbas N, Kirazli S. et al Interleukin‐1, ‐6, and ‐8 levels in juvenile chronic arthritis. Clin Rheumatol 199716173–178. [[PubMed]
  • 10. Yilmaz M, Kendirli S G, Altintas D, Bingol G, Antmen BCytokine levels in serum of patients with juvenile rheumatoid arthritis. Clin Rheumatol 20012030–35. [[PubMed][Google Scholar]
  • 11. Crawley E, Kon S, Woo PHereditary predisposition to low interleukin‐10 production in children with extended oligoarticular juvenile idiopathic arthritis. Rheumatology (Oxford) 200140574–578. [[PubMed][Google Scholar]
  • 12. De Benedetti F, Meazza C, Vivarelli M, Rossi F, Pistorio A, Lamb R. et al Functional and prognostic relevance of the ‐173 polymorphism of the macrophage migration inhibitory factor gene in systemic‐onset juvenile idiopathic arthritis. Arthritis Rheum 2003481398–1407. [[PubMed]
  • 13. Barnes D A, Tse J, Kaufhold M, Owen M, Hesselgesser J, Strieter R. et al Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant‐induced arthritis model. J Clin Invest 19981012910–2919.
  • 14. Lovell D J, Giannini E H, Reiff A, Cawkwell G D, Silverman E D, Nocton J J. et al Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med 2000342763–769. [[PubMed]
  • 15. Yokota SInterleukin 6 as a therapeutic target in systemic‐onset juvenile idiopathic arthritis. Curr Opin Rheumatol 200315581–586. [[PubMed][Google Scholar]
  • 16. Steinman LImmune therapy for autoimmune diseases. Science 2004305212–216. [[PubMed][Google Scholar]
  • 17. Haringman J J, Tak P PChemokine blockade: a new era in the treatment of rheumatoid arthritis? Arthritis Res Ther 2004693–97. [[PubMed][Google Scholar]
  • 18. Pascual V, Allantaz F, Arce E, Punaro M, Banchereau JRole of interleukin‐1 (IL‐1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL‐1 blockade. J Exp Med 20052011479–1486. [Google Scholar]
  • 19. Charo I F, Ransohoff R MThe many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 2006354610–621. [[PubMed][Google Scholar]
  • 20. Blanco P, Palucka A K, Gill M, Pascual V, Banchereau JInduction of dendritic cell differentiation by IFN‐alpha in systemic lupus erythematosus. Science 20012941540–1543. [[PubMed][Google Scholar]
  • 21. Shakoor N, Michalska M, Harris C A, Block J ADrug‐induced systemic lupus erythematosus associated with etanercept therapy. Lancet 2002359579–580. [[PubMed][Google Scholar]
  • 22. Goodyear MLearning from the TGN1412 trial. BMJ 2006332677–678. [Google Scholar]
  • 23. Mayor SSevere adverse reactions prompt call for trial design changes. BMJ 2006332683 [Google Scholar]
  • 24. Suntharalingam G, Perry M R, Ward S, Brett S J, Castello‐Cortes A, Brunner M D. et al Cytokine storm in a phase 1 trial of the anti‐CD28 monoclonal antibody TGN1412. N Engl J Med 20063551018–1028. [[PubMed]
  • 25. de Jager W, Te Velthuis H, Prakken B J, Kuis W, Rijkers G TSimultaneous detection of 15 human cytokines in a single sample of stimulated peripheral blood mononuclear cells. Clin Diagn Lab Immunol 200310133–139. [Google Scholar]
  • 26. Vignali D AMultiplexed particle‐based flow cytometric assays. J Immunol Methods 2000243243–255. [[PubMed][Google Scholar]
  • 27. de Jager W, Prakken B J, Bijlsma J W, Kuis W, Rijkers G TImproved multiplex immunoassay performance in human plasma and synovial fluid following removal of interfering heterophilic antibodies. J Immunol Methods 2005300124–135. [[PubMed][Google Scholar]
  • 28. Petty R E, Southwood T R, Baum J, Bhettay E, Glass D N, Manners P. et al Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol 1998251991–1994. [[PubMed]
  • 29. Petty R E, Southwood T R, Manners P, Baum J, Glass D N, Goldenberg J. et al International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 200431390–392. [[PubMed]
  • 30. Kamphuis S, Kuis W, de Jager W, Teklenburg G, Massa M, Gordon G. et al Tolerogenic immune responses to novel T‐cell epitopes from heat‐shock protein 60 in juvenile idiopathic arthritis. Lancet 200536650–56. [[PubMed]
  • 31. Ravelli A, Magni‐Manzoni S, Pistorio A, Besana C, Foti T, Ruperto N. et al Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr 2005146598–604. [[PubMed]
  • 32. Ravelli A, Felici E, Magni‐Manzoni S, Pistorio A, Novarini C, Bozzola E. et al Patients with antinuclear antibody‐positive juvenile idiopathic arthritis constitute a homogeneous subgroup irrespective of the course of joint disease. Arthritis Rheum 200552826–832. [[PubMed]
  • 33. Phelan J D, Thompson S D, Glass D NSusceptibility to JRA/JIA: complementing general autoimmune and arthritis traits. Genes Immun 200671–10. [[PubMed][Google Scholar]
  • 34. Fishman D, Faulds G, Jeffery R, Mohamed‐Ali V, Yudkin J S, Humphries S. et al The effect of novel polymorphisms in the interleukin‐6 (IL‐6) gene on IL‐6 transcription and plasma IL‐6 levels, and an association with systemic‐onset juvenile chronic arthritis. J Clin Invest 19981021369–1376.
  • 35. Ozen S, Alikasifoglu M, Bakkaloglu A, Duzova A, Jarosova K, Nemcova D. et al Tumour necrosis factor alpha G→A ‐238 and G→A ‐308 polymorphisms in juvenile idiopathic arthritis. Rheumatology (Oxford) 200241223–227. [[PubMed]
  • 36. Zeggini E, Thomson W, Kwiatkowski D, Richardson A, Ollier W, Donn RLinkage and association studies of single‐nucleotide polymorphism‐tagged tumor necrosis factor haplotypes in juvenile oligoarthritis. Arthritis Rheum 2002463304–3311. [[PubMed][Google Scholar]
  • 37. Pharoah D S, Varsani H, Tatham R W, Newton K R, de Jager W, Prakken B J. et al Expression of the inflammatory chemokines CCL5, CCL3 and CXCL10 in juvenile idiopathic arthritis, and demonstration of CCL5 production by an atypical subset of CD8+ T cells. Arthritis Res Ther 20068R50
  • 38. Raza K, Falciani F, Curnow S J, Ross E, Lee C Y, Akbar A. et al Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther 20057R784–R795.
  • 39. Ou L S, See L C, Wu C J, Kao C C, Lin Y L, Huang J LAssociation between serum inflammatory cytokines and disease activity in juvenile idiopathic arthritis. Clin Rheumatol 20022152–56. [[PubMed][Google Scholar]
  • 40. Lepore L, Pennesi M, Saletta S, Perticarari S, Presani G, Prodan MStudy of IL‐2, IL‐6, TNF alpha, IFN gamma and beta in the serum and synovial fluid of patients with juvenile chronic arthritis. Clin Exp Rheumatol 199412561–565. [[PubMed][Google Scholar]
  • 41. De Benedetti F, Ravelli A, Martini ACytokines in juvenile rheumatoid arthritis. Curr Opin Rheumatol 19979428–433. [[PubMed][Google Scholar]
  • 42. Gattorno M, Picco P, Vignola S, Stalla F, Buoncompagni A, Pistoia VSerum interleukin 12 concentration in juvenile chronic arthritis. Ann Rheum Dis 199857425–428. [Google Scholar]
  • 43. De Benedetti F, Vivarelli M, Pignatti P, Oliveri M, Massa M, Pistorio A. et al Circulating levels of soluble E‐selectin, P‐selectin and intercellular adhesion molecule‐1 in patients with juvenile idiopathic arthritis. J Rheumatol 2000272246–2250. [[PubMed]
  • 44. Charo I F, Ransohoff R MThe many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 2006354610–621. [[PubMed][Google Scholar]
  • 45. Iellem A, Mariani M, Lang R, Recalde H, Panina‐Bordignon P, Sinigaglia F. et al Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med 2001194847–853.
  • 46. Harrington L E, Hatton R D, Mangan P R, Turner H, Murphy T L, Murphy K M. et al Interleukin 17‐producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 200561123–1132. [[PubMed]
  • 47. Park H, Li Z, Yang X O, Chang S H, Nurieva R, Wang Y H. et al A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 200561133–1141.
  • 48. Wulffraat N M, Rijkers G T, Elst E, Brooimans R, Kuis WReduced perforin expression in systemic juvenile idiopathic arthritis is restored by autologous stem‐cell transplantation. Rheumatology (Oxford) 200342375–379. [[PubMed][Google Scholar]
  • 49. Maeno N, Takei S, Nomura Y, Imanaka H, Hokonohara M, Miyata KHighly 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 2002462539–2541. [[PubMed][Google Scholar]
  • 50. Andoniou C E, van Dommelen S L, Voigt V, Andrews D M, Brizard G, Asselin‐Paturel C. et al Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity. Nat Immunol 200561011–1019. [[PubMed]
  • 51. De Benedetti F, Massa M, Pignatti P, Albani S, Novick D, Martini ASerum soluble interleukin 6 (IL‐6) receptor and IL‐6/soluble IL‐6 receptor complex in systemic juvenile rheumatoid arthritis. J Clin Invest 1994932114–2119. [Google Scholar]
  • 52. Kutukculer N, Caglayan S, Aydogdu FStudy of pro‐inflammatory (TNF‐alpha, IL‐1alpha, IL‐6) and T‐cell‐derived (IL‐2, IL‐4) cytokines in plasma and synovial fluid of patients with juvenile chronic arthritis: correlations with clinical and laboratory parameters. Clin Rheumatol 199817288–292. [[PubMed][Google Scholar]
  • 53. Pignatti P, Ciapponi L, Galle P, Hansen M B, Massa M, Meazza C. et al High circulating levels of biologically inactive IL‐6/SIL‐6 receptor complexes in systemic juvenile idiopathic arthritis: evidence for serum factors interfering with the binding to gp130. Clin Exp Immunol 2003131355–363.
  • 54. Svenson M, Hansen M B, Heegaard P, Abell K, Bendtzen K. Specific binding of interleukin 1 (IL‐1) beta and IL‐1 receptor antagonist (IL‐1ra) to human serum. High‐affinity binding of IL‐1ra to soluble IL‐1 receptor type I. Cytokine 19935427–435. [[PubMed]
  • 55. de Jager W, Rijkers G TSolid‐phase and bead‐based cytokine immunoassay: a comparison. Methods 2006 [[PubMed][Google Scholar]
  • 56. Petrovsky N, McNair P, Harrison L CDiurnal rhythms of pro‐inflammatory cytokines: regulation by plasma cortisol and therapeutic implications. Cytokine 199810307–312. [[PubMed][Google Scholar]
  • 57. Petrovsky N, Harrison L CThe chronobiology of human cytokine production. Int Rev Immunol 199816635–649. [[PubMed][Google Scholar]
  • 58. Gudewill S, Pollmacher T, Vedder H, Schreiber W, Fassbender K, Holsboer FNocturnal plasma levels of cytokines in healthy men. Eur Arch Psychiatry Clin Neurosci 199224253–56. [[PubMed][Google Scholar]
  • 59. Cutolo M, Seriolo B, Craviotto C, Pizzorni C, Sulli ACircadian rhythms in RA. Ann Rheum Dis 200362593–596. [Google Scholar]
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