“Neuroimmunoendocrinology” in Children with Rheumatic Diseases: How Glucocorticoids Are the Orchestra Director

The neural, the endocrine, and the immune systems are studied as distinct districts in physiological and pathological settings. However, these systems must be investigated with an integrative approach, while also considering that therapeutic agents, such as glucocorticoids, can induce a reversible or irreversible change of this homeostasis. Children and adolescents affected by rheumatic diseases frequently need treatment with corticosteroids, and the treatment must sometimes be continued for a long time. In the biological era, the treat-to-target strategy allowed a real revolution in treatment, with significant steroid dose sparing or, in many patients, steroid treatment withdrawal. In this review, the impact of glucocorticoids on endocrine, immune, and neurologic targets is analyzed, and the crosstalk between these systems is highlighted. In this narrative review, we explore the reasoning as to why glucocorticoids can disrupt this homeostasis, we summarize some of the key results supporting the impact of glucocorticoids treatment on endocrine, immune, and neurologic systems, and we discuss the data reported in the international literature.

[1]  S. Loche,et al.  Appropriate management of growth hormone deficiency during the age of transition: an Italian Delphi consensus statement , 2022, Journal of Endocrinological Investigation.

[2]  J. Stone,et al.  Optimising both disease control and glucocorticoid dosing is essential for bone protection in patients with rheumatic disease , 2022, Annals of the Rheumatic Diseases.

[3]  F. Chiarelli,et al.  Bone Health in Children with Rheumatic Disorders: Focus on Molecular Mechanisms, Diagnosis, and Management , 2022, International journal of molecular sciences.

[4]  G. Lal,et al.  Role of adrenergic receptor signalling in neuroimmune communication , 2021, Current research in immunology.

[5]  E. Stein,et al.  Glucocorticoid‐induced osteonecrosis in systemic lupus erythematosus patients , 2021, Clinical and translational medicine.

[6]  J. Jaremko,et al.  Osteoporotic Fractures and Vertebral Body Reshaping in Children with Glucocorticoid-Treated Rheumatic Disorders. , 2021, The Journal of clinical endocrinology and metabolism.

[7]  R. Consolini,et al.  Musculoskeletal manifestations of childhood cancer and differential diagnosis with juvenile idiopathic arthritis (ONCOREUM): a multicentre, cross-sectional study , 2021 .

[8]  C. Suh,et al.  Anti-Inflammatory Effects of Low-Dose Glucocorticoids Compensate for Their Detrimental Effects on Bone Mineral Density in Patients with Rheumatoid Arthritis , 2021, Journal of clinical medicine.

[9]  F. Chiarelli,et al.  Growth and puberty in children with juvenile idiopathic arthritis , 2021, Pediatric Rheumatology.

[10]  L. Ramseier,et al.  The Assessment of Steroid Injections as a Potential Risk Factor for Osteochondral Lesions in Children with Juvenile Idiopathic Arthritis , 2020, Cartilage.

[11]  E. Alexeeva,et al.  Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis. , 2020, Rheumatology.

[12]  G. Messina,et al.  Upper and Lower Limb Strength and Body Posture in Children with Congenital Hypothyroidism: An Observational Case-Control Study , 2020, International journal of environmental research and public health.

[13]  S. Kamphuis,et al.  Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adjudication Committee , 2020, Arthritis Research & Therapy.

[14]  S. Lightman,et al.  Dynamics of ACTH and Cortisol Secretion and Implications for Disease , 2020, Endocrine reviews.

[15]  G. Corsello,et al.  FMF is not always “fever”: from clinical presentation to “treat to target” , 2020, Italian journal of pediatrics.

[16]  Z. Stojić-Vukanić,et al.  Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis , 2020, Frontiers in Endocrinology.

[17]  R. Manna,et al.  Anakinra Drug Retention Rate and Predictive Factors of Long-Term Response in Systemic Juvenile Idiopathic Arthritis and Adult Onset Still Disease , 2019, Front. Pharmacol..

[18]  Ayla Güven Different Potent Glucocorticoids, Different Routes of Exposure but the Same Result: Iatrogenic Cushing’s Syndrome and Adrenal Insufficiency , 2019, Journal of clinical research in pediatric endocrinology.

[19]  F. Bagnasco,et al.  Disease activity and damage in juvenile idiopathic arthritis: methotrexate era versus biologic era , 2019, Arthritis Research & Therapy.

[20]  D. Origgi,et al.  National guidelines for dental diagnostic imaging in the developmental age , 2019, La radiologia medica.

[21]  R. Cimaz,et al.  Drug Retention Rate and Predictive Factors of Drug Survival for Interleukin-1 Inhibitors in Systemic Juvenile Idiopathic Arthritis , 2019, Front. Pharmacol..

[22]  T. Oranges,et al.  Clinical Use and Molecular Action of Corticosteroids in the Pediatric Age , 2019, International journal of molecular sciences.

[23]  R. Xavier,et al.  Height and sexual maturation in girls with juvenile idiopathic arthritis , 2018, Jornal de pediatria.

[24]  Stefan Boehringer,et al.  Treat to target (drug-free) inactive disease in DMARD-naive juvenile idiopathic arthritis: 24-month clinical outcomes of a three-armed randomised trial , 2018, Annals of the rheumatic diseases.

[25]  M. Cooper,et al.  11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis , 2018, Journal of autoimmunity.

[26]  T. Nickolas,et al.  KDOQI US Commentary on the 2017 KDIGO Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). , 2017, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[27]  W. Thomson,et al.  Growth patterns in early juvenile idiopathic arthritis: Results from the Childhood Arthritis Prospective Study (CAPS) , 2017, Seminars in arthritis and rheumatism.

[28]  G. Messina,et al.  Evaluation of Fitness and the Balance Levels of Children with a Diagnosis of Juvenile Idiopathic Arthritis: A Pilot Study , 2017, International journal of environmental research and public health.

[29]  A. Berdal,et al.  Disruption of Steroid Axis, a New Paradigm for Molar Incisor Hypomineralization (MIH) , 2017, Front. Physiol..

[30]  G. Manukyan,et al.  Differential modulation of innate immune response by epinephrine and estradiol , 2017, Hormone molecular biology and clinical investigation.

[31]  Yujuan Zhang,et al.  Protecting Bone Health in Pediatric Rheumatic Diseases: Pharmacological Considerations , 2017, Pediatric Drugs.

[32]  A. Martini,et al.  Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial , 2017, The Lancet.

[33]  C. Weber,et al.  Neutrophils as protagonists and targets in chronic inflammation , 2017 .

[34]  E. Zoratti,et al.  CD14++ CD16− monocytes are the main source of 11&bgr;‐HSD type 1 after IL‐4 stimulation , 2017, International immunopharmacology.

[35]  A. Berdal,et al.  Expression of Steroid Receptors in Ameloblasts during Amelogenesis in Rat Incisors , 2016, Front. Physiol..

[36]  J. Cidlowski,et al.  Corticosteroids: Mechanisms of Action in Health and Disease. , 2016, Rheumatic diseases clinics of North America.

[37]  C. Farquharson,et al.  Growth and the Growth Hormone-Insulin Like Growth Factor 1 Axis in Children With Chronic Inflammation: Current Evidence, Gaps in Knowledge, and Future Directions. , 2016, Endocrine reviews.

[38]  J. Kratzsch,et al.  Corticosteroid-binding globulin: modulating mechanisms of bioavailability of cortisol and its clinical implications. , 2015, Best practice & research. Clinical endocrinology & metabolism.

[39]  D. Heijde,et al.  Frequency of joint involvement in juvenile idiopathic arthritis during a 5-year follow-up of newly diagnosed patients: implications for MR imaging as outcome measure , 2015, Rheumatology International.

[40]  M. Matucci Cerinic,et al.  Comparison of bone mass and quality determinants in adolescents and young adults with juvenile systemic lupus erythematosus (JSLE) and juvenile idiopathic arthritis (JIA) , 2014, Pediatric Rheumatology.

[41]  S. Bechtold,et al.  Growth abnormalities in children and adolescents with juvenile idiopathic arthritis , 2014, Rheumatology International.

[42]  A. Bianco,et al.  Evaluation of fitness levels of children with a diagnosis of acute leukemia and lymphoma after completion of chemotherapy and autologous hematopoietic stem cell transplantation , 2014, Cancer medicine.

[43]  S. Okret,et al.  Extra-adrenal glucocorticoid synthesis: Immune regulation and aspects on local organ homeostasis , 2013, Molecular and Cellular Endocrinology.

[44]  J. Seckl,et al.  11β-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. , 2013, Physiological reviews.

[45]  C. Rodd,et al.  Long-Term Bone Health in Glucocorticoid-Treated Children with Rheumatic Diseases , 2013, Current Rheumatology Reports.

[46]  L. Mazzanti,et al.  Impaired GH Secretion in Patients with SHOX Deficiency and Efficacy of Recombinant Human GH Therapy , 2012, Hormone Research in Paediatrics.

[47]  P. Cattini,et al.  The hidden but positive role for glucocorticoids in the regulation of growth hormone-producing cells , 2012, Molecular and Cellular Endocrinology.

[48]  F. Dhabhar,et al.  Stress-induced redistribution of immune cells—From barracks to boulevards to battlefields: A tale of three hormones – Curt Richter Award Winner , 2012, Psychoneuroendocrinology.

[49]  G. Klein,et al.  Overview of pediatric bone problems and related osteoporosis. , 2012, Journal of musculoskeletal & neuronal interactions.

[50]  A. Martini,et al.  Toward a treat-to-target approach in the management of juvenile idiopathic arthritis. , 2012, Clinical and experimental rheumatology.

[51]  K. Chapman,et al.  The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights , 2011, Molecular and Cellular Endocrinology.

[52]  M. Matucci-Cerinic,et al.  Cross-sectional and Longitudinal Evaluation of Bone Mass in Children and Young Adults with Juvenile Idiopathic Arthritis: The Role of Bone Mass Determinants in a Large Cohort of Patients , 2010, The Journal of Rheumatology.

[53]  C. Wouters,et al.  Etanercept improves linear growth and bone mass acquisition in MTX-resistant polyarticular-course juvenile idiopathic arthritis. , 2010, Rheumatology.

[54]  D. Dragoș,et al.  The effect of stress on the defense systems , 2010, Journal of medicine and life.

[55]  Kazuhisa Takahashi,et al.  Age at time of corticosteroid administration is a risk factor for osteonecrosis in pediatric patients with systemic lupus erythematosus: a prospective magnetic resonance imaging study. , 2010, Arthritis and rheumatism.

[56]  Ty C. Voss,et al.  Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription , 2009, Nature Cell Biology.

[57]  Stoyan Dimitrov,et al.  Cortisol and epinephrine control opposing circadian rhythms in T cell subsets. , 2009, Blood.

[58]  Thomas Korn,et al.  IL-17 and Th17 Cells. , 2009, Annual review of immunology.

[59]  N. Maalouf,et al.  The Role of Receptor Activator of Nuclear Factor-κB (RANK)/RANK Ligand/Osteoprotegerin: Clinical Implications , 2007 .

[60]  V. Lilleby Review: Bone status in juvenile systemic lupus erythematosus , 2007 .

[61]  J. Bilezikian,et al.  Glucocorticoid-induced osteoporosis: pathophysiology and therapy , 2007, Osteoporosis International.

[62]  J. Monson,et al.  Modulation of glucocorticoid metabolism by the growth hormone – IGF‐1 axis , 2007, Clinical endocrinology.

[63]  K. Zacharowski,et al.  The Role of Toll‐like Receptors in the Immune–Adrenal Crosstalk , 2006, Annals of the New York Academy of Sciences.

[64]  E. Schwarz,et al.  Osteoclast precursors: cytokine-stimulated immunomodulators of inflammatory bone disease , 2006, Current opinion in rheumatology.

[65]  J. Schölmerich,et al.  Increase of sympathetic outflow measured by neuropeptide Y and decrease of the hypothalamic-pituitary-adrenal axis tone in patients with systemic lupus erythematosus and rheumatoid arthritis: another example of uncoupling of response systems , 2005, Annals of the rheumatic diseases.

[66]  J. Cidlowski,et al.  Mechanisms of glucocorticoid receptor signaling during inflammation , 2004, Mechanisms of Ageing and Development.

[67]  A. Foussat,et al.  Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10. , 2003, Blood.

[68]  J. Mullol,et al.  Expression of glucocorticoid receptor alpha- and beta-isoforms in human cells and tissues. , 2002, American journal of physiology. Cell physiology.

[69]  R. Cimaz Osteoporosis in childhood rheumatic diseases: prevention and therapy. , 2002, Best practice & research. Clinical rheumatology.

[70]  P. Czernichow,et al.  Linear growth and final height in patients with systemic juvenile idiopathic arthritis treated with longterm glucocorticoids. , 2002, The Journal of rheumatology.

[71]  J. Krueger,et al.  The Role of Cytokines in Physiological Sleep Regulation , 2001, Annals of the New York Academy of Sciences.

[72]  T. Rosol,et al.  Adrenal Gland: Structure, Function, and Mechanisms of Toxicity , 2001, Toxicologic pathology.

[73]  G. Chrousos,et al.  The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. , 2000, Pharmacological reviews.

[74]  C. Cooper,et al.  Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. , 2000, Rheumatology.

[75]  S. Mccann,et al.  Role of the hypothalamic pituitary adrenal axis in the control of the response to stress and infection. , 2000, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[76]  S. Lightman,et al.  Early-life exposure to endotoxin alters hypothalamic-pituitary-adrenal function and predisposition to inflammation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[77]  J. Veldhuis,et al.  Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. , 1998, Endocrine reviews.

[78]  P. Barnes,et al.  Anti-inflammatory actions of glucocorticoids: molecular mechanisms. , 1998, Clinical science.

[79]  G. Ciliberto,et al.  IL‐6 Mediates the Effects of IL‐1 or TNF, but Not PTHrP or 1,25(OH)2D3, on Osteoclast‐like Cell Formation in Normal Human Bone Marrow Cultures , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[80]  C. Diéguez,et al.  Regulation of hypothalamic somatostatin, growth hormone-releasing hormone, and growth hormone receptor messenger ribonucleic acid by glucocorticoids. , 1996, Endocrinology.

[81]  D. Vercelli,et al.  Hydrocortisone and IL-4 induce IgE isotype switching in human B cells. , 1991, Journal of immunology.

[82]  P. Guerne,et al.  IL-6 production by human articular chondrocytes. Modulation of its synthesis by cytokines, growth factors, and hormones in vitro. , 1990, Journal of immunology.

[83]  R. Evans,et al.  The steroid and thyroid hormone receptor superfamily. , 1988, Science.

[84]  T. Yanase,et al.  In vivo evidence of regulation by pituitary-adrenal axis of urinary epinephrine excretion in men. , 1986, Endocrinologia japonica.

[85]  M. Tesher Pediatric Rheumatology. , 2015, Pediatric annals.

[86]  L. Stojanovich,et al.  Stress as a trigger of autoimmune disease. , 2008, Autoimmunity reviews.

[87]  R. Cimaz,et al.  Bone Mass Change During Methotrexate Treatment in Patients with Juvenile Rheumatoid Arthritis , 1999, Osteoporosis International.

[88]  M. Papale,et al.  Growth retardation in non-steroid treated juvenile rheumatoid arthritis. , 1997, Scandinavian journal of rheumatology.

[89]  B. Burguera,et al.  Dual and selective actions of glucocorticoids upon basal and stimulated growth hormone release in man. , 1990, Neuroendocrinology.