Revisiting the Toxicity of Low-Dose Glucocorticoids
Risks and Fears
JOSÉ A. P. DA SILVA
Reumatologia, Hospitais da Universidade de Coimbra, Coimbra, Portugal
Search for more papers by this authorJOHANNES W. G. JACOBS
Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht the Netherlands
Search for more papers by this authorJOHANNES W. J. BIJLSMA
Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht the Netherlands
Search for more papers by this authorJOSÉ A. P. DA SILVA
Reumatologia, Hospitais da Universidade de Coimbra, Coimbra, Portugal
Search for more papers by this authorJOHANNES W. G. JACOBS
Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht the Netherlands
Search for more papers by this authorJOHANNES W. J. BIJLSMA
Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht the Netherlands
Search for more papers by this authorAbstract
Abstract: We have recently participated in a careful literature search and critical evaluation of glucocorticoids, and we have revised the side-effects data of four recent controlled trials of low-dose glucocorticoids (GCs) in rheumatoid arthritis. The toxicity profile stands out as remarkably more benign than expected from most textbook recommendations. Data regarding low-dose therapy are scarce and of low quality, as no controlled trials have been designed to specifically address toxicity. Common fears of GC toxicity seem to originate from an excessive weight on anecdotal data and observations with high doses, as in organ transplantation. There is now evidence that mechanisms of action of GCs vary considerably according to the dose, thus allowing the possibility of a different toxicity profile. Data from recent controlled trials are quite reassuring, overall. Certainly, risks and benefits of GCs need to be carefully weighed in every patient. But we need to make a clear distinction between established risks and unchecked fears while trying to get the best result for our patient. Clearly, there is a need for studies that are appropriately designed to address the toxicity of GCs and to avoid the risk of “throwing out the baby with the bath water.”
REFERENCES
- 1 Townsend, H.B. & K.G. Saag. 2004. Glucocorticoid use in rheumatoid arthritis: benefits, mechanisms, and risks. Clin. Exp. Rheumatol. 22: S77–S82.
- 2 Da Silva, J.A., J.W. Jacobs, J.R. Kirwan, et al . 2006. Low-dose glucocorticoid therapy in rheumatoid arthritis: a review on safety: published evidence and prospective trial data. Ann. Rheum. Dis. 64: 285–293.
- 3 Kirwan, J.R. 1995. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. N. Engl. J. Med. 333: 142–146.
- 4 Rau, R., S. Wassenberg & H. Zeidler. 2000. Low dose prednisolone therapy (LDPT) retards radiographically detectable destruction in early rheumatoid arthritis—preliminary results of a multicenter, randomized, parallel, double blind study. Z. Rheumatol. 59: II/90–II/96.
- 5 Van Everdingen, A.A., J.W. Jacobs, D.R. Siewertsz van Reesema, et al . 2002. 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. Ann. Intern. Med. 136: 1–12.
- 6 Capell, H.A., R. Madhok, J.A. Hunter, et al . 2004. Lack of radiological and clinical benefit over two years of low dose prednisolone for rheumatoid arthritis: results of a randomised controlled trial. Ann. Rheum. Dis. 63: 797–803.
- 7 Pisu, M., N. James, S. Sampsel, et al . 2005. The cost of glucocorticoid-associated adverse events in rheumatoid arthritis. Rheumatology (Oxford) 44: 781–788.
- 8 Buttgereit, F., J.A. Da Silva, M. Boers, et al . 2002. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology. Ann. Rheum. Dis. 61: 718–722.
- 9 Ton, F.N., S.C. Gunawardene, H. Lee, et al . 2005. Effects of low-dose prednisone on bone metabolism. J. Bone Miner. Res. 20: 464–470.
- 10 Van Staa, T.P., P. Geusens, H.A. Pols, et al . 2005. A simple score for estimating the long-term risk of fracture in patients using oral glucocorticoids. QJM 98: 191–198.
- 11 Haugeberg, G., A. Strand, T.K. Kvien, et al . 2005. Reduced loss of hand bone density with prednisolone in early rheumatoid arthritis: results from a randomized placebo-controlled trial. Arch. Intern. Med. 165: 1293–1297.
- 12 Laan, R.F., P.L. Van Riel, L.B. Van De Putte, et al . 1993. Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis: a randomized, controlled study. Ann. Intern. Med. 119: 963–968.
- 13 De Nijs, R.N., J.W. Jacobs, J.W. Bijlsma, et al . 2001. Prevalence of vertebral deformities and symptomatic vertebral fractures in corticosteroid treated patients with rheumatoid arthritis. Rheumatology (Oxford) 40: 1375–1383.
- 14 Van Staa, T.P., H.G. Leufkens & C. Cooper. 2002. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos. Int. 13: 777–787.
- 15 Haugeberg, G., B. Griffiths, K.B. Sokoll, et al . 2004. Bone loss in patients treated with pulses of methylprednisolone is not negligible: a short term prospective observational study. Ann. Rheum. Dis. 63: 940–944.
- 16 Lodder, M.C., W.F. Lems, P.J. Kostense, et al . 2003. Bone loss due to glucocorticoids: update of a systematic review of prospective studies in rheumatoid arthritis and other diseases. Ann. Rheum. Dis. 62: 94.
- 17 Gluck, O.S., W.A. Murphy, T.J. Hahn, et al . 1981. Bone loss in adults receiving alternate day glucocorticoid therapy: a comparison with daily therapy. Arthritis Rheum. 24: 892–898.
- 18 Ruegsegger, P., T.C. Medici & M. Anliker. 1983. Corticosteroid-induced bone loss: a longitudinal study of alternate day therapy in patients with bronchial asthma using quantitative computed tomography. Eur. J. Clin Pharmacol. 25: 615–620.
- 19 Reid, I.R. & S.W. Heap. 1990. Determinants of vertebral mineral density in patients receiving long-term glucocorticoid therapy. Arch. Intern. Med. 150: 2545–2548.
- 20 Lems, W.F., Z.N. Jahangier, J.W. Jacobs, et al . 1995. Vertebral fractures in patients with rheumatoid arthritis treated with corticosteroids. Clin. Exp. Rheumatol. 13: 293–297.
- 21 Van Staa, T.P., H.G. Leufkens, L. Abenhaim, et al . 2000. Use of oral corticosteroids and risk of fractures. J. Bone Miner. Res. 15: 993–1000.
- 22 Sambrook, P. & N.E. Lane. 2001. Corticosteroid osteoporosis. Best. Pract. Res. Clin. Rheumatol. 15: 401–413.
- 23 Kumagai, S., S. Kawano, T. Atsumi, et al . 2005. Vertebral fracture and bone mineral density in women receiving high dose glucocorticoids for treatment of autoimmune diseases. J. Rheumatol. 32: 863–869.
- 24 Yeap, S.S. & D.J. Hosking. 2002. Management of corticosteroid-induced osteoporosis. Rheumatology (Oxford) 41: 1088–1094.
- 25 Sambrook, P.N. 2005. How to prevent steroid induced osteoporosis. Ann. Rheum. Dis. 64: 176–178.
- 26 American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis . 2001. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. Arthritis Rheum. 44: 1496–1503.
- 27 The Royal College of Physicians, The Bone and Tooth Society of Great Britain & The National Osteoporosis Society . 2002. Glucocorticoid-induced osteoporosis. Guidelines for prevention and treatment. http://www.rcplondon.ac.uk/pubs/books/glucocorticoid/index.asp.
- 28 Geusens, P.P., R.N. De Nijs, W.F. Lems, et al . 2004. Prevention of glucocorticoid osteoporosis: a consensus document of the Dutch Society for Rheumatology. Ann. Rheum. Dis. 63: 324–325.
- 29 Gurwitz, J.H., R.L. Bohn, R.J. Glynn, et al . 1994. Glucocorticoids and the risk for initiation of hypoglycemic therapy. Arch. Intern. Med. 154: 97–101.
- 30 Black, D.M. & A.T. Filak. 1989. Hyperglycemia with non-insulin-dependent diabetes following intraarticular steroid injection. J. Fam. Pract. 28: 462–463.
- 31 Hirsch, I.B. & D.S. Paauw. 1997. Diabetes management in special situations. Endocrinol. Metab. Clin. North Am. 26: 631–645.
- 32 Hricik, D.E., M.R. Bartucci, E.J. Moir, et al . 1991. Effects of steroid withdrawal on posttransplant diabetes mellitus in cyclosporine-treated renal transplant recipients. Transplantation 51: 374–377.
- 33 Hoogwerf, B. & R.D. Danese. 1999. Drug selection and the management of corticosteroid-related diabetes mellitus. Rheum. Dis. Clin. North Am. 25: 489–505.
- 34 Greenstone, M.A. & A.B. Shaw. 1987. Alternate day corticosteroid causes alternate day hyperglycaemia. Postgrad. Med. J. 63: 761–764.
- 35 Saag, K.G., R. Koehnke, J.R. Caldwell, et al . 1994. Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am. J Med. 96: 115–123.
- 36 Rooklin, A.R., S.I. Lampert, E.A. Jaeger, et al . 1979. Posterior subcapsular cataracts in steroid-requiring asthmatic children. J. Allergy Clin. Immunol. 63: 383–386.
- 37 Garbe, E., J. LeLorier, J.F. Boivin, et al . 1997. Risk of ocular hypertension or open-angle glaucoma in elderly patients on oral glucocorticoids. Lancet 350: 979–982.
- 38 Tripathi, R.C., S.K. Parapuram, B.J. Tripathi, et al . 1999. Corticosteroids and glaucoma risk. Drugs Aging 15: 439–450.
- 39 Stone, E.M., J.H. Fingert, W.L. Alward, et al . 1997. Identification of a gene that causes primary open angle glaucoma. Science 275: 668–670.
- 40 Akingbehin, A.O. 1982. Corticosteroid-induced ocular hypertension. I. Prevalence in closed-angle glaucoma. Br. J. Ophthalmol. 66: 536–540.
- 41 Brodie, S. 2002. Corticosteroids and the eye. In Principles of Corticosteroid Therapy. A.N. Lin & S.A. Paget, Eds.: 131–134. Arnold. London .
- 42 Allen, D.B. 1996. Growth suppression by glucocorticoid therapy. Endocrinol. Metab. Clin. North Am. 25: 699–717.
- 43 Byron, M.A., J. Jackson & B.M. Ansell. 1983. Effect of different corticosteroid regimens on hypothalamic-pituitary-adrenal axis and growth in juvenile chronic arthritis. J. R. Soc. Med. 76: 452–457.
- 44 Wang, S.J., Y.H. Yang, Y.T. Lin, et al . 2002. Attained adult height in juvenile rheumatoid arthritis with or without corticosteroid treatment. Clin. Rheumatol. 21: 363–368.
- 45 Simon, D., N. Lucidarme, A.M. Prieur, et al . 2001. Linear growth in children suffering from juvenile idiopathic arthritis requiring steroid therapy: natural history and effects of growth hormone treatment on linear growth. J. Pediatr. Endocrinol. Metab. 14: 1483–1486.
- 46 Touati, G., A.M. Prieur, J.C. Ruiz, et al . 1998. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J. Clin. Endocrinol. Metab. 83: 403–409.
- 47 Wolverton, S.E. 2002. Corticosteroids and the integument. In Principles of Corticosteroid Therapy. A.N. Lin & S.A. Paget, Eds.: 166–172. Arnold. London .
- 48 Covar, R.A., D.Y. Leung, D. McCormick, et al . 2000. Risk factors associated with glucocorticoid-induced adverse effects in children with severe asthma. J. Allergy Clin. Immunol. 106: 651–659.
- 49 Marcocci, C., L. Bartalena, M.L. Tanda, et al . 2001. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves' ophthalmopathy: results of a prospective, single-blind, randomized study. J. Clin. Endocrinol. Metab. 86: 3562–3567.
- 50 Hatz, H.J. & K. Helmke. 1992. [Polymyalgia rheumatica and giant cell arteritis; diagnosis and side effects of low-dose long-term glucocorticoid therapy]. Z. Rheumatol. 51: 213–221.
- 51 Piper, J.M., W.A. Ray, J.R. Daugherty, et al . 1991. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann. Intern. Med. 114: 735–740.
- 52 Garcia Rodriguez, L.A. & S. Hernandez-Diaz. 2001. The risk of upper gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents. Arthritis Res. 3: 98–101.
- 53 Whitworth, J.A. 1987. Mechanisms of glucocorticoid-induced hypertension. Kidney Int. 31: 1213–1224.
- 54 Jackson, S.H., D.G. Beevers & K. Myers. 1981. Does long-term low-dose corticosteroid therapy cause hypertension? Clin. Sci. (Lond.) 61: 381s–383s.
- 55 El-Shaboury, A.H. & T.M. Hayes. 1973. Hyperlipidaemia in asthmatic patients receiving long-term steroid therapy. Br. Med. J. 2: 85–86.
- 56 Becker, D.M., B. Chamberlain, R. Swank, et al . 1988. Relationship between corticosteroid exposure and plasma lipid levels in heart transplant recipients. Am. J. Med. 85: 632–638.
- 57 Manzi, S., F. Selzer, K. Sutton-Tyrrell, et al . 1999. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum. 42: 51–60.
- 58 Wallberg-Jonsson, S., H. Johansson, M.L. Ohman, et al . 1999. Extent of inflammation predicts cardiovascular disease and overall mortality in seropositive rheumatoid arthritis: a retrospective cohort study from disease onset. J. Rheumatol. 26: 2562–2571.
- 59 Munford, R.S. 2001. Statins and the acute-phase response. N. Engl. J Med. 344: 2016–2018.
- 60 Boers, M., M.T. Nurmohamed, C.J. Doelman, et al . 2003. Influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis. Ann. Rheum. Dis. 62: 842–845.
- 61 Wei, L., T.M. MacDonald & B.R. Walker. 2004. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann. Intern. Med. 141: 764–770.
- 62 Bia, J.M., K. Tyler & R.A. DeFronzo. 1982. The effect of dexamethasone on renal electrolyte excretion in the adrenalectomized rat. Endocrinology 111: 882–888.
- 63 Kohlmann, O., Jr., A.B. Ribeiro, O. Marson, et al . 1981. Methylprednisolone-induced hypertension: role for the autonomic and renin angiotensin systems. Hypertension 3: II-11.
- 64 Whitworth, J.A., D. Gordon, J. Andrews, et al . 1989. The hypertensive effect of synthetic glucocorticoids in man: role of sodium and volume. J. Hypertens. 7: 537–549.
- 65 Latham, R.D., J.P. Mulrow, R. Virmani, et al . 1989. Recently diagnosed idiopathic dilated cardiomyopathy: incidence of myocarditis and efficacy of prednisone therapy. Am. Heart J. 117: 876–882.
- 66 Mason, J.W., J.B. O'Connell, A. Herskowitz, et al . 1995. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N. Engl. J. Med. 333: 269–275.
- 67 Vreden, S.G., A.R. Hermus, P.A. Van Liessum, et al . 1991. Aseptic bone necrosis in patients on glucocorticoid replacement therapy. Neth. J. Med. 39: 153–157.
- 68 Zizic, T.M., C. Marcoux, D.S. Hungerford, et al . 1985. Corticosteroid therapy associated with ischemic necrosis of bone in systemic lupus erythematosus. Am. J. Med. 79: 596–604.
- 69 Gebhard, K.L. & H.I. Maibach. 2001. Relationship between systemic corticosteroids and osteonecrosis. Am. J. Clin. Dermatol. 2: 377–388.
- 70 Kagen, L.J. 2002. Steroid myopathy. In Principles of Corticosteroid Therapy. N.A. Lin & S.A. Paget, Eds.: 87–90. Arnold. London .
- 71 Nordin, B.E., R.G. Crilly, D.H. Marshall, et al . 1981. Oestrogens, the menopause and the adrenopause. J. Endocrinol. 89: 131P–143P.
- 72 Hampson, G., N. Bhargava, J. Cheung, et al . 2002. Low circulating estradiol and adrenal androgens concentrations in men on glucocorticoids: a potential contributory factor in steroid-induced osteoporosis. Metabolism 51: 1458–1462.
- 73 Janssen, N.M. & M.S. Genta. 2000. The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and lactation. Arch. Intern. Med. 160: 610–619.
- 74 Dale, D.C. & R.G. Petersdorf. 1973. Corticosteroids and infectious diseases. Med. Clin. North Am. 57: 1277–1287.
- 75 Stracher, A.R. & R. Soave. 2002. Infectious complications of Corticosteroid Therapy. In Principles of Corticosteroid Therapy. A.N. Linn & S.A. Paget, Eds.: 419–430. Arnold. London .
- 76 Stuck, A.E., C.E. Minder & F.J. Frey. 1989. Risk of infectious complications in patients taking glucocorticosteroids. Rev. Infect. Dis. 11: 954–963.
- 77 Hellmann, D.B., M. Petri & Q. Whiting-O'Keefe. 1987. Fatal infections in systemic lupus erythematosus: the role of opportunistic organisms. Medicine (Baltimore) 66: 341–348.
- 78 Mpofu, S., C.M. Mpofu, D. Hutchinson, et al . 2004. Steroids, non-steroidal anti-inflammatory drugs, and sigmoid diverticular abscess perforation in rheumatic conditions. Ann. Rheum. Dis. 63: 588–590.
- 79 Demopoulos, A. & B.R. Apatoff. 2002. Corticosteroids and the nervous system. In Principles of Corticosteroid Therapy. N.A. Lin & S.A. Paget, Eds.: 150–165. Arnold. London .
- 80 Reckart, M.D. & S.J. Eisendrath. 1990. Exogenous corticosteroid effects on mood and cognition: case presentations. Int. J. Psychosom. 37: 57–61.
- 81 Byyny, R.L. 1976. Withdrawal from glucocorticoid therapy. N. Engl. J. Med. 295: 30–32.
- 82 Kirwan, J.R., R. Hallgren, H. Mielants, et al . 2004. A randomised placebo controlled 12 week trial of budesonide and prednisolone in rheumatoid arthritis. Ann. Rheum. Dis. 63: 688–695.
- 83 Jacobs, J.W. & J.W. Bijlsma. 2003. Interpretation of trial methodology not always easy: comment on the editorial by Landewé (author reply). Arthritis Rheum. 48: 2693–2695.