Reduced corticosteroid‐binding globulin cleavage in active rheumatoid arthritis
Abstract
Summary: Objective: Corticosteroid‐binding globulin (CBG), the cortisol transport protein, is cleaved from high‐affinity (ha CBG) to low‐affinity (la CBG) CBG at sites of inflammation releasing bioavailable, anti‐inflammatory cortisol. Rheumatoid arthritis (RA) is a glucocorticoid‐responsive disorder, with paradoxically normal cortisol levels despite elevated inflammatory mediators. Our objective was to determine whether CBG cleavage relates to RA disease activity. We hypothesized that impaired CBG cleavage may limit delivery of free cortisol to inflamed joints in RA. Design: Prospective, cross‐sectional observational study. Setting and Participants: Fifty‐three patients with RA recruited from a Rheumatology outpatient clinic at a tertiary referral centre in Adelaide, Australia, and 73 healthy controls. Measurements: Total CBG, ha CBG and la CBG, total, free and salivary cortisol, inflammatory markers including interleukin‐6 soluble receptor (IL‐6sR) and macrophage migration inhibitory factor and clinical measures of disease activity. Results: Among patients with RA, a wide range of disease activity scores was observed (DAS 28: range 1·2–6·4). la CBG was lower in patients with RA (mean ± SEM); 153 ± 9, compared with healthy controls; 191 ± 8 nmol/l, P = 0·003. Levels of total and ha CBG were higher in patients with more severe RA disease activity. Free and total cortisol, free cortisol:IL‐6sR ratio and total cortisol:IL‐6sR ratio correlated negatively with disease activity. Conclusions: These results suggest that patients with RA have reduced CBG cleavage compared to healthy controls and that cleavage is reduced further with higher RA disease activity. Hence, impaired CBG‐mediated delivery of endogenous cortisol may perpetuate chronic inflammation in RA.
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The lack of association between morning serum cortisol and next-morning saliva cortisol in rheumatoid arthritis probably reflects significant alterations in cortisol-binding protein cleavage in patients with rheumatoid arthritis.
“probably reflecting the significant alterations in the cortisol-binding protein cleavage in patients with RA, as previously described by Nenke et al.38”
From Diurnal production of cortisol and prediction of treatment response in rheumatoid arthritis: a 6-month, real-life prospective cohort study (2024) · cites this paper as Nenke et al.38
Cites
Arnett, F. C., Edworthy, S. M., Bloch, D. A., McShane, D. J., Fries, J. F., Cooper, N. S., Healey, L. A., Kaplan, S. R., Liang, M. H., Luthra, H. S., et al. (1988) · Arthritis & Rheumatism · doi:10.1002/art.1780310302 · Cited by 19,753 · see citing works
The Pathogenesis of Rheumatoid Arthritis
McInnes, I. B., & Schett, G. (2011) · New England Journal of Medicine · doi:10.1056/nejmra1004965 · Cited by 5,514 · see citing works
The Hypothalamic–Pituitary–Adrenal Axis and Immune-Mediated Inflammation
Chrousos, G. P. (1995) · New England Journal of Medicine · doi:10.1056/nejm199505183322008 · Cited by 2,579 · see citing works
The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders
Heim, C., Ehlert, U., & Hellhammer, D. H. (2000) · Psychoneuroendocrinology · doi:10.1016/s0306-4530(99)00035-9 · Cited by 1,688 · see citing works
Cortisol awakening response and psychosocial factors: a systematic review and meta-analysis
Chida, Y., & Steptoe, A. (2009) · Biological Psychology · doi:10.1016/j.biopsycho.2008.10.004 · Cited by 1,032 · see citing works
Sternberg, E. M., Hill, J. M., Chrousos, G. P., Kamilaris, T., Listwak, S. J., Gold, P. W., & Wilder, R. L. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.7.2374 · Cited by 723 · see citing works
The soluble interleukin 6 receptor: mechanisms of production and implications in disease
Jones, S. A., Horiuchi, S., Topley, N., Yamamoto, N., & Fuller, G. M. (2001) · The FASEB Journal · doi:10.1096/fj.99-1003rev · Cited by 684 · see citing works
Hormone binding globulins undergo serpin conformational change in inflammation
Pemberton, P. A., Stein, P. E., Pepys, M. B., Potter, J. M., & Carrell, R. W. (1988) · Nature · doi:10.1038/336257a0 · Cited by 422 · see citing works
Effects of glucocorticoids on radiological progression in rheumatoid arthritis
Kirwan, J., Bijlsma, J. W. J., Boers, M., & Shea, B. (2007) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd006356 · Cited by 346 · see citing works
Septic Shock and Sepsis: A Comparison of Total and Free Plasma Cortisol Levels
Ho, J. T., Al-Musalhi, H., Chapman, M. J., Quach, T., Thomas, P. D., Bagley, C. J., Lewis, J. G., & Torpy, D. J. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0265 · Cited by 312 · see citing works
Self-citationHammond, G. L., Smith, C. S., Goping, I. S., Underhill, D. A., Harley, M. J., Reventós, J., Musto, N. A., Gunsalus, G. L., & Bardin, C. W. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.15.5153 · Cited by 266 · see citing works
A Role for Corticosteroid-Binding Globulin in Delivery of Cortisol to Activated Neutrophils*
Hammond, G. L., Smith, C. S., Paterson, N. A. M., & Sibbald, W. J. (1990) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-71-1-34 · Cited by 265 · see citing works
Plasma free cortisol fraction reflects levels of functioning corticosteroid-binding globulin
Lewis, J. G., Bagley, C. J., Elder, P. A., Bachmann, A. W., & Torpy, D. J. (2005) · Clinica Chimica Acta · doi:10.1016/j.cccn.2005.03.044 · Cited by 214 · see citing works
Self-citationThe Disease Activity Score and the EULAR Response Criteria
Fransen, J., & van Riel, P. L. C. M. (2009) · Rheumatic Disease Clinics of North America · doi:10.1016/j.rdc.2009.10.001 · Cited by 207 · see citing works
Current view of glucocorticoid co-therapy with DMARDs in rheumatoid arthritis
Hoes, J. N., Jacobs, J. W. G., Buttgereit, F., & Bijlsma, J. W. J. (2010) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2010.179 · Cited by 157 · see citing works
McCarthy, C., Saldova, R., Wormald, M. R., Rudd, P. M., McElvaney, N. G., & Reeves, E. P. (2014) · Journal of Proteome Research · doi:10.1021/pr500146y · Cited by 148 · see citing works
Klieber, M. A., Underhill, C., Hammond, G. L., & Muller, Y. A. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705014200 · Cited by 128 · see citing works
N-Glycans Modulate the Function of Human Corticosteroid-Binding Globulin
Sumer‐Bayraktar, Z., Kolarich, D., Campbell, M. P., Ali, S. O., Packer, N. H., & Thaysen‐Andersen, M. (2011) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m111.009100 · Cited by 87 · see citing works
Mechanisms of Disease: macrophage migration inhibitory factor in SLE, RA and atherosclerosis
Ayoub, S., Hickey, M. J., & Morand, E. F. (2008) · Nature Clinical Practice Rheumatology · doi:10.1038/ncprheum0701 · Cited by 84 · see citing works
How Changes in Affinity of Corticosteroid-binding Globulin Modulate Free Cortisol Concentration
Chan, W., Carrell, R., Zhou, A., & Read, R. J. (2013) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2012-4280 · Cited by 82 · see citing works
The S-to-R Transition of Corticosteroid-Binding Globulin and the Mechanism of Hormone Release
Zhou, A., Wei, Z., Stanley, P. L. D., Read, R. J., Stein, P. E., & Carrell, R. W. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.05.012 · Cited by 77 · see citing works
Proudman, S., Keen, H. I., Stamp, L. K., Lee, A. T. Y., Goldblatt, F., Ayres, O. C., Rischmueller, M., James, M. J., Hill, C. L., Caughey, G. E., et al. (2007) · Seminars in Arthritis and Rheumatism · doi:10.1016/j.semarthrit.2007.02.001 · Cited by 76 · see citing works
Self-citationEmptoz-Bonneton, A., Crave, J. C., Lejeune, H., Brébant, C., & Pugeat, M. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.11.4362 · Cited by 68 · see citing works
Corticosteroid-Binding Globulin: Structure-Function Implications from Species Differences
Gardill, B. R., Vogl, M. R., Lin, H., Hammond, G. L., & Muller, Y. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0052759 · Cited by 67 · see citing works
Holliday, K. L., Nicholl, B. I., Macfarlane, G. J., Thomson, W., Davies, K. A., & McBeth, J. (2009) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2009.116137 · Cited by 67 · see citing works
Hypothalamic-pituitary-adrenal axis activity in patients with rheumatoid arthritis.
Eijsbouts, A. M. M., van den Hoogen, F. H. J., Laan, R. F. J. M., Hermus, A. R. M. M., Sweep, F. C. G. J., & van de Putte, L. B. A. (2005) · PubMed · Cited by 62 · see citing works
Mastrángelo, A., Colasanti, T., Barbati, C., Pecani, A., Sabatinelli, D., Pendolino, M., Truglia, S., Massaro, L., Mancini, R., Miranda, F., et al. (2015) · Journal of Immunology Research · doi:10.1155/2015/712490 · Cited by 55 · see citing works
Fifty Years of Experience with Cortisone Therapy in the Study and Treatment of Rheumatoid Arthritis
Neeck, G. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb04199.x · Cited by 53 · see citing works
Underhill, D. A., & Hammond, G. L. (1989) · Molecular Endocrinology · doi:10.1210/mend-3-9-1448 · Cited by 52 · see citing works
Nenke, M. A., Rankin, W., Chapman, M. J., Stevens, N. E., Diener, K. R., Hayball, J. D., Lewis, J. G., & Torpy, D. J. (2015) · Clinical Endocrinology · doi:10.1111/cen.12680 · Cited by 52 · see citing works
Self-citationEmptoz-Bonneton, A. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.82.11.3758 · Cited by 48 · see citing works
Nishina, N., Kikuchi, J., Hashizume, M., Yoshimoto, K., Kameda, H., & Takeuchi, T. (2013) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2013-204137 · Cited by 43 · see citing works
Naturally occurring mutations of human corticosteroid-binding globulin.
Simard, M., Hill, L., Lewis, J., & Hammond, G. L. (2015) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2014-3130 · Cited by 41 · see citing works
Self-citationLewis, J., & Elder, P. (2013) · Clinica chimica acta; international journal of clinical chemistry · doi:10.1016/j.cca.2012.11.016 · Cited by 36 · see citing works
Self-citationCBG Santiago: a novel CBG mutation.
Torpy, D., Lundgren, B. A., Ho, J., Lewis, J., Scott, H. S., & Mericq, V. (2012) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2011-2022 · Cited by 35 · see citing works
Self-citationSimard, M., Hill, L. A., Underhill, C., Keller, B. O., Villanueva, I., Hancock, R. E. W., & Hammond, G. L. (2014) · Endocrinology · doi:10.1210/en.2014-1055 · Cited by 34 · see citing works
Séralini, G., B�rub�, D., Gagn�, R., & Hammond, G. L. (1990) · Human Genetics · doi:10.1007/bf00205177 · Cited by 34 · see citing works
Pregnancy-associated Corticosteroid-binding Globulin: High Resolution Separation of Glycan Isoforms
Mitchell, E., Torpy, D. J., & Bagley, C. J. (2004) · Hormone and Metabolic Research · doi:10.1055/s-2004-814580 · Cited by 27 · see citing works
Self-citationNenke, M., Holmes, M., Rankin, W., Lewis, J., & Torpy, D. (2016) · Clinica chimica acta; international journal of clinical chemistry · doi:10.1016/j.cca.2015.10.028 · Cited by 23 · see citing works
Self-citationLewis, J., Saunders, K., Dyer, A., & Elder, P. (2015) · Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2015.01.020 · Cited by 15 · see citing works
Self-citation
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1 of the 41 references couldn’t be matched to a known paper.
Cited by
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Sumer‐Bayraktar, Z., Grant, O. C., Venkatakrishnan, V., Woods, R. J., Packer, N. H., & Thaysen‐Andersen, M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.735258 · Cited by 33 · see citing works
Glucocorticoids in rheumatoid arthritis: the silent companion in the therapeutic strategy
Berardicurti, O., Ruscitti, P., Pavlych, V., Conforti, A., Giacomelli, R., & Cipriani, P. (2020) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2020.1772055 · Cited by 24 · see citing works
Corticosteroid-Binding Globulin Deficiency Independently Predicts Mortality in Septic Shock.
Meyer, E., Nenke, M., Davies, M., Chapman, M., Rankin, W., Rushworth, R., & Torpy, D. (2022) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/clinem/dgac035 · Cited by 17 · see citing works
Self-citationCorticosteroid-binding globulin: acute and chronic inflammation
Meyer, E., Nenke, M., Lewis, J., & Torpy, D. (2017) · Expert Review of Endocrinology & Metabolism · doi:10.1080/17446651.2017.1332991 · Cited by 20 · see citing works
Self-citationMeyer, E. J., Torpy, D. J., Chernykh, A., Thaysen‐Andersen, M., Nenke, M. A., Lewis, J. G., Rajapaksha, H., Rankin, W. A., & Polyak, S. W. (2020) · Protein Science · doi:10.1002/pro.3982 · Cited by 17 · see citing works
Self-citationCiregia, F., Baiwir, D., Cobraiville, G., Dewael, T., Mazzucchelli, G., Badot, V., Romana, S. D., Sidiras, P., Sokolova, T., Durez, P., et al. (2020) · Journal of Translational Medicine · doi:10.1186/s12967-019-02188-9 · Cited by 14 · see citing works
Yavropoulou, M. P., Filippa, M. G., Vlachogiannis, N. I., Fragoulis, G. E., Laskari, K., Mantzou, A., Panopoulos, S., Fanouriakis, A., Bournia, V.-K., Evangelatos, G., et al. (2024) · RMD Open · doi:10.1136/rmdopen-2023-003575 · Cited by 13 · see citing works
“38 Disturbed circadian cortisol rhythm in active RA Next, we examined individual diurnal measurements of saliva cortisol to detect possible disturbed circadian rhythms.”
N-Glycosylation influences human corticosteroid-binding globulin measurements
Hill, L. A., Sumer‐Bayraktar, Z., Lewis, J. G., Morava, É., Thaysen‐Andersen, M., & Hammond, G. L. (2019) · Endocrine Connections · doi:10.1530/ec-19-0242 · Cited by 8 · see citing works
Self-citationNeutrophil elastase-cleaved corticosteroid-binding globulin is absent in human plasma
Hill, L. A., Vassiliadi, D. A., Dimopoulou, I., Anderson, A. J., Boyle, L. D., Kilgour, A. H. M., Stimson, R. H., Machado, Y. J., Overall, C. M., Walker, B. R., et al. (2018) · Journal of Endocrinology · doi:10.1530/joe-18-0479 · Cited by 6 · see citing works
Self-citationBinding for life: corticosteroid binding globulin from vertebrate physiology to human diseases
Rouzic, P. L., & Rousseau, K. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1647096 · Cited by 4 · see citing works
Corticosteroid Binding Globulin
Jirikowski, G. F., Rodewald, A., Sivukhina, E. V., & Caldwell, J. D. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809324-5.03222-3 · Cited by 3 · see citing works
Biodisponibilidad y acción de los glucocorticoides en diversos modelos de inflamación
Ledda, A. (2016) · Tesis Doctorals en Xarxa (Consorci de Serveis Universitaris de Catalunya)
Lee, J. H., Sumer-Bayraktar, Z., Rushworth, R., Chernykh, A., Nenke, M., Thaysen-Andersen, M., Meyer, E. J., & Torpy, D. J. (2026) · Journal of the Endocrine Society · doi:10.1210/jendso/bvag058
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- Authors
- Nenke, M. A., Lewis, J. G., Rankin, W., McWilliams, L., Metcalf, R. G., Proudman, S. M., & Torpy, D. J.
- Affiliations
- Royal Adelaide Hospital (AU)
- Canterbury Health Laboratories (NZ)
- South Australia Pathology (AU)
- Corresponding author
- Nenke, Marni A.
- ORCID
- Venue
- Clinical Endocrinology
- Publisher
- Wiley
- Published
- 2016-05-08
- Volume
- 85
- Issue
- 3
- Pages
- 369-377
- ISSN
- 0300-0664 (ISSN-L)
- 1365-2265
- OpenAlex
- W2333175251
- Cited by
- 13
- References
- 41
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2022: 1 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 2
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- Royal Adelaide Hospital/Institute of Medical and Veterinary Science Research Committee
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- corticosteroid-binding globulin, rheumatoid arthritis, disease activity, free cortisol, glucocorticoid delivery, macrophage migration inhibitory factor, chronic inflammation, salivary cortisol
- MeSH terms
- Adult, Aged, Aged, 80 and over, Arthritis, Rheumatoid, Cross-Sectional Studies, Female, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Inflammation, Male, Middle Aged, Pituitary-Adrenal System, Prospective Studies, Severity of Illness Index, Transcortin, Case-Control Studies, Receptors, Interleukin-6
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