Glucocorticoid-targeted therapies for the treatment of rheumatoid arthritis

ABSTRACT Introduction: The beneficial effects of glucocorticoids are highly regarded in the treatment of inflammatory diseases. In rheumatoid arthritis, these drugs are widely used because they effectively reduce signs and symptoms of the disease, and exert disease-modifying effects. However, both patients and physicians frequently associate glucocorticoids with a variety of adverse effects which hamper adherence. Due to this ambivalent nature of these drugs, several new glucocorticoids or glucocorticoid receptor ligands are being developed, aiming at improving their benefit-risk balance. Areas covered: Focussing on rheumatoid arthritis, we discuss current approaches to achieve this goal, including an optimized application of conventional glucocorticoids and the development of novel formulations aiming at minimizing adverse effects while keeping or even enhancing the anti-inflammatory efficacy. Expert opinion: Glucocorticoids – be it conventional or modified/delayed-release formulations – have so far been convincing in clinical practice, and their widespread use will therefore continue. They are not likely to be replaced by novel drugs in the near future although some investigational preparations are promising, and results obtained from currently ongoing clinical trials in humans are eagerly awaited. As a result of these developmental activities, a further improvement of the benefits-risk balance of glucocorticoids or glucocorticoid receptor ligands is expected.

[1]  B. Schmidt,et al.  The selective glucocorticoid receptor agonist mapracorat displays a favourable safety–efficacy ratio for the topical treatment of inflammatory skin diseases in dogs , 2017, Veterinary dermatology.

[2]  R. Rojo,et al.  Predicting the probability of successful efficacy of a dissociated agonist of the glucocorticoid receptor from dose–response analysis , 2016, Journal of Pharmacokinetics and Pharmacodynamics.

[3]  J. Jacobs,et al.  Rediscovering the therapeutic use of glucocorticoids in rheumatoid arthritis , 2016, Current opinion in rheumatology.

[4]  C. Baerwald,et al.  Efficacy and safety of modified-release prednisone in patients with rheumatoid arthritis , 2016, Drug design, development and therapy.

[5]  Y. Barenholz,et al.  A liposomal steroid nano-drug for treating systemic lupus erythematosus , 2016, Lupus.

[6]  W. Dixon,et al.  Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force , 2016, Annals of the rheumatic diseases.

[7]  M. Cutolo Glucocorticoids and chronotherapy in rheumatoid arthritis , 2016, RMD Open.

[8]  J. Heath Nanotechnologies for biomedical science and translational medicine , 2015, Proceedings of the National Academy of Sciences.

[9]  F. Buttgereit,et al.  The novel strategy of glucocorticoid drug development via targeting nongenomic mechanisms , 2015, Steroids.

[10]  K. Barraclough,et al.  2015 Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative , 2015, Annals of the rheumatic diseases.

[11]  R. Holt,et al.  Delayed-release prednisone improves fatigue and health-related quality of life: findings from the CAPRA-2 double-blind randomised study in rheumatoid arthritis , 2015, RMD Open.

[12]  C. Libert,et al.  Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds. , 2015, Pharmacology & therapeutics.

[13]  G. Storm,et al.  [(18)]F FDG PET/CT imaging to monitor the therapeutic effect of liposome-encapsulated prednisolone in experimental rheumatoid arthritis. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[14]  F. Buttgereit,et al.  Novel glucocorticoids: where are we now and where do we want to go? , 2015, Clinical and experimental rheumatology.

[15]  R. Holt,et al.  Morning stiffness response with delayed-release prednisone after ineffective course of immediate-release prednisone , 2015, Scandinavian journal of rheumatology.

[16]  F. Buttgereit,et al.  Clocking in: chronobiology in rheumatoid arthritis , 2015, Nature Reviews Rheumatology.

[17]  M. Baiula,et al.  Mapracorat, a novel non-steroidal selective glucocorticoid receptor agonist for the treatment of allergic conjunctivitis. , 2015, Inflammation & allergy drug targets.

[18]  S. Feldon,et al.  Mapracorat, a selective glucocorticoid receptor agonist, upregulates RelB, an anti-inflammatory nuclear factor-kappaB protein, in human ocular cells. , 2014, Experimental eye research.

[19]  G. Storm,et al.  Liposomal corticosteroids for the treatment of inflammatory disorders and cancer. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[20]  T. Pincus,et al.  Clinical Trials Documenting the Efficacy of Low-Dose Glucocorticoids in Rheumatoid Arthritis , 2014, Neuroimmunomodulation.

[21]  R. Caporali,et al.  Oral Low-Dose Glucocorticoids Should Be Included in Any Recommendation for the Use of Non-Biologic and Biologic Disease-Modifying Antirheumatic Drugs in the Treatment of Rheumatoid Arthritis , 2014, Neuroimmunomodulation.

[22]  R. Rau Glucocorticoid treatment in rheumatoid arthritis , 2014, Expert opinion on pharmacotherapy.

[23]  P. Govoni,et al.  Mapracorat, a selective glucocorticoid receptor agonist, causes apoptosis of eosinophils infiltrating the conjunctiva in late-phase experimental ocular allergy , 2014, Drug design, development and therapy.

[24]  R. Kondratov Circadian clock and cancer therapy: an unexpected journey , 2014, Annals of medicine.

[25]  L. Gossec,et al.  When and for how long should glucocorticoids be used in rheumatoid arthritis? International guidelines and recommendations , 2014, Annals of the New York Academy of Sciences.

[26]  A. Kavanaugh,et al.  Benefits and risks of low-dose glucocorticoid treatment in the patient with rheumatoid arthritis , 2014, Rheumatology.

[27]  M. Cooper,et al.  TNFα regulates cortisol metabolism in vivo in patients with inflammatory arthritis , 2014, Annals of the rheumatic diseases.

[28]  J. Kirwan,et al.  The intelligent use of systemic glucocorticoids in rheumatoid arthritis , 2014, Expert review of clinical immunology.

[29]  J. Tavernier,et al.  How glucocorticoid receptors modulate the activity of other transcription factors: A scope beyond tethering , 2013, Molecular and Cellular Endocrinology.

[30]  Désirée van der Heijde,et al.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update , 2013, Annals of the rheumatic diseases.

[31]  N. Bateman Use of glucocorticoids and risk of venous thromboembolism: a nationwide population‐based case–control study , 2013 .

[32]  D. Ray,et al.  EULAR evidence-based and consensus-based recommendations on the management of medium to high-dose glucocorticoid therapy in rheumatic diseases , 2013, Annals of the rheumatic diseases.

[33]  J. Reginster,et al.  What do we know about the safety of corticosteroids in rheumatoid arthritis? , 2013, Current medical research and opinion.

[34]  B. Pfeiffer,et al.  Impact of modified-release prednisone on functional ability in patients with rheumatoid arthritis , 2013, Rheumatology International.

[35]  David W Ray,et al.  The circadian clock and asthma , 2013, Thorax.

[36]  M. Cutolo,et al.  Efficacy of the switch to modified-release prednisone in rheumatoid arthritis patients treated with standard glucocorticoids. , 2013, Clinical and experimental rheumatology.

[37]  C. Libert,et al.  New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation. , 2013, Endocrinology.

[38]  P. Sfikakis,et al.  Low-Dose Prednisone Inclusion in a Methotrexate-Based, Tight Control Strategy for Early Rheumatoid Arthritis , 2012, Annals of Internal Medicine.

[39]  A. Sigal,et al.  Glucocorticoids in nano-liposomes administered intravenously and subcutaneously to adjuvant arthritis rats are superior to the free drugs in suppressing arthritis and inflammatory cytokines. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[40]  M. Boers,et al.  Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2) , 2012, Annals of the rheumatic diseases.

[41]  M. Cutolo Chronobiology and the treatment of rheumatoid arthritis , 2012, Current opinion in rheumatology.

[42]  M. Miccoli,et al.  Adverse Events During Longterm Low-dose Glucocorticoid Treatment of Polymyalgia Rheumatica: A Retrospective Study , 2012, The Journal of Rheumatology.

[43]  X. Hu,et al.  The antagonists but not partial agonists of glucocorticoid receptor ligands show substantial side effect dissociation. , 2011, Endocrinology.

[44]  M. Cavet,et al.  Anti-allergic effects of mapracorat, a novel selective glucocorticoid receptor agonist, in human conjunctival fibroblasts and epithelial cells , 2011, Molecular vision.

[45]  P. Tak,et al.  Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. , 2011, Arthritis and rheumatism.

[46]  M. Boers,et al.  Monitoring adverse events of low-dose glucocorticoid therapy: EULAR recommendations for clinical trials and daily practice , 2010, Annals of the rheumatic diseases.

[47]  Tsutomu Takeuchi,et al.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update , 2010, Annals of the rheumatic diseases.

[48]  R. Landewé,et al.  Current evidence for the management of rheumatoid arthritis with glucocorticoids: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis , 2010, Annals of the rheumatic diseases.

[49]  John Wong,et al.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs , 2010, Annals of the rheumatic diseases.

[50]  K. Asadullah,et al.  Characterization of ZK 245186, a novel, selective glucocorticoid receptor agonist for the topical treatment of inflammatory skin diseases , 2009, British journal of pharmacology.

[51]  M. Boers,et al.  Patient and rheumatologist perspectives on glucocorticoids: an exercise to improve the implementation of the European League Against Rheumatism (EULAR) recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases , 2009, Annals of the rheumatic diseases.

[52]  R. Hermida,et al.  Chronotherapy With the Angiotensin-Converting Enzyme Inhibitor Ramipril in Essential Hypertension: Improved Blood Pressure Control With Bedtime Dosing , 2009, Hypertension.

[53]  G. Tofler,et al.  Circadian rhythm and cardiovascular disease , 2009, Current atherosclerosis reports.

[54]  J. Listing,et al.  Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. , 2009, JAMA.

[55]  J. Wallace,et al.  Suppressive effects of nitric oxide‐releasing prednisolone NCX‐1015 on the allergic pleural eosinophil recruitment in rats , 2008, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[56]  F. Buttgereit,et al.  Genomic and nongenomic effects of glucocorticoids , 2008, Nature Clinical Practice Rheumatology.

[57]  F. Buttgereit,et al.  Circadian rhythms of nocturnal hormones in rheumatoid arthritis: translation from bench to bedside , 2008, Annals of the rheumatic diseases.

[58]  J. Kirwan,et al.  Overnight variations in cortisol, interleukin 6, tumour necrosis factor α and other cytokines in people with rheumatoid arthritis , 2008, Annals of the rheumatic diseases.

[59]  K. Saag,et al.  The epidemiology of glucocorticoid-associated adverse events , 2008, Current opinion in rheumatology.

[60]  F. Buttgereit,et al.  Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial , 2008, The Lancet.

[61]  E. Vajda,et al.  Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein–protein interaction profile , 2007, Proceedings of the National Academy of Sciences.

[62]  P. Emery,et al.  Local and systemic glucocorticoid metabolism in inflammatory arthritis , 2007, Annals of the rheumatic diseases.

[63]  K. Asadullah,et al.  Selective glucocorticoid receptor agonists (SEGRAs): Novel ligands with an improved therapeutic index , 2007, Molecular and Cellular Endocrinology.

[64]  J. Tuckermann,et al.  Glucocorticoid receptor action in beneficial and side effects of steroid therapy: Lessons from conditional knockout mice , 2007, Molecular and Cellular Endocrinology.

[65]  A. Clark Anti-inflammatory functions of glucocorticoid-induced genes , 2007, Molecular and Cellular Endocrinology.

[66]  D. Hommes,et al.  Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists , 2007, Molecular and Cellular Endocrinology.

[67]  M. Boers,et al.  EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases , 2007, Annals of the rheumatic diseases.

[68]  F. Tronche,et al.  Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy. , 2007, The Journal of clinical investigation.

[69]  R. Straub,et al.  Circadian rhythms in rheumatoid arthritis: implications for pathophysiology and therapeutic management. , 2007, Arthritis and rheumatism.

[70]  H. Cohen,et al.  Optimal Low-Density Lipoprotein Cholesterol Lowering—Morning Versus Evening Statin Administration , 2007, The Annals of pharmacotherapy.

[71]  E. Ongini,et al.  The nitrosteroid NCX 1015, a prednisolone derivative, improves recovery of function in rats after spinal cord injury , 2005, Brain Research.

[72]  R. Rau,et al.  Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo-controlled trial. , 2005, Arthritis and rheumatism.

[73]  M. Cutolo,et al.  Altered circadian rhythms in rheumatoid arthritis patients play a role in the disease's symptoms. , 2005, Autoimmunity reviews.

[74]  M. Wauben,et al.  Liposomal targeting of glucocorticoids to synovial lining cells strongly increases therapeutic benefit in collagen type II arthritis , 2004, Annals of the rheumatic diseases.

[75]  K. Asadullah,et al.  Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[76]  I. Adcock,et al.  Glucocorticoid Receptor Nitration Leads to Enhanced Anti-Inflammatory Effects of Novel Steroid Ligands 1 , 2003, The Journal of Immunology.

[77]  M. Wauben,et al.  Complete remission of experimental arthritis by joint targeting of glucocorticoids with long-circulating liposomes. , 2003, Arthritis and rheumatism.

[78]  Khusru Asadullah,et al.  Mechanisms involved in the side effects of glucocorticoids. , 2002, Pharmacology & therapeutics.

[79]  M. Nakane,et al.  trans-Activation and repression properties of the novel nonsteroid glucocorticoid receptor ligand 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(1-methylcyclohexen-3-y1)-1H-[1]benzopyrano[3,4-f]quinoline (A276575) and its four stereoisomers. , 2002, Molecular pharmacology.

[80]  M. Boers,et al.  Keeping up appearances , 2002, Annals of the rheumatic diseases.

[81]  M. Paul-Clark,et al.  Potent antiarthritic properties of a glucocorticoid derivative, NCX-1015, in an experimental model of arthritis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[82]  P. Herrlich,et al.  Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor , 2001, The EMBO journal.

[83]  C. Battram,et al.  Therapeutic Benefit of a Dissociated Glucocorticoid and the Relevance of In Vitro Separation of Transrepression from Transactivation Activity , 2001, The Journal of Immunology.

[84]  K. H. Richter,et al.  The DNA Binding-Independent Function of the Glucocorticoid Receptor Mediates Repression of Ap-1–Dependent Genes in Skin , 1999, The Journal of cell biology.

[85]  K. Kaestner,et al.  DNA Binding of the Glucocorticoid Receptor Is Not Essential for Survival , 1998, Cell.

[86]  H. Gronemeyer,et al.  Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit antiinflammatory activity in vivo. , 1997, Molecular endocrinology.

[87]  R. Hällgren,et al.  The timing of glucocorticoid administration in rheumatoid arthritis , 1997, Annals of the rheumatic diseases.

[88]  L. Elfman,et al.  Circadian rhythm of serum interleukin-6 in rheumatoid arthritis. , 1994, Annals of the rheumatic diseases.

[89]  T M Allen,et al.  Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half-lives in vivo. , 1991, Biochimica et biophysica acta.

[90]  R L Juliano,et al.  The effect of particle size and charge on the clearance rates of liposomes and liposome encapsulated drugs. , 1975, Biochemical and biophysical research communications.

[91]  J. Jacobs,et al.  Glucocorticoids in the treatment of rheumatoid arthritis. , 2015, Clinical and experimental rheumatology.

[92]  A. Kramer,et al.  Circadian rhythms of cellular immunity in rheumatoid arthritis: a hypothesis-generating study. , 2015, Clinical and experimental rheumatology.

[93]  P. Cullis,et al.  Liposomal drug delivery systems: from concept to clinical applications. , 2013, Advanced drug delivery reviews.

[94]  K. Saag Short-term and long-term safety of glucocorticoids in rheumatoid arthritis. , 2012, Bulletin of the NYU hospital for joint diseases.

[95]  G. Burmester,et al.  Prednisone chronotherapy. , 2011, Clinical and experimental rheumatology.

[96]  P. Steerenberg,et al.  Targeting pathophysiological rhythms: prednisone chronotherapy shows sustained efficacy in rheumatoid arthritis. , 2010, Annals of the rheumatic diseases.

[97]  J. Jacobs,et al.  Low-Dose Prednisone Therapy for Patients with Early Active Rheumatoid Arthritis: Clinical Efficacy, Disease-Modifying Properties, and Side Effects: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial , 2002, Annals of Internal Medicine.