Introduction Neuroimmunomodulation 2015;22:3–5 DOI: 10.1159/000362737
Published online: September 12, 2014
The co-editors, Maurizio Cutolo, George P. Chrousos and Theodore Pincus, are pleased to present this special issue of Neuroimmunology, concerning contemporary use of low-dose glucocorticoids in the treatment of patients with rheumatic diseases. Prednisolone was introduced for the treatment of rheumatoid arthritis (RA) in 1949 [1]. Spectacular results were documented not only in the medical literature, but also in a short film and descriptions in US national magazines. The 1950 Nobel Prize in Medicine and Physiology was awarded to Hench and collaborators for their achievement [2]. In 1949, the time of the discovery of the clinical benefits of prednisolone, new medications could be introduced for marketing without evidence of superiority to placebo in randomized controlled clinical trials, which was introduced only in the 1940s [3, 4]. Furthermore, no requirement existed to analyze the risk/benefit ratio or dose-response relations at different doses. Therefore, guidelines were not available concerning optimal dosages for different indications, or for how long therapy should be continued. In 1955, the Mayo Clinic group that discovered the use of clinical prednisone actually suggested that doses of 10 years had always received these agents [11]. Almost all patients with vasculitis, polymyositis, polymyalgia rheumatica and most other inflammatory rheumatic diseases are treated with glucocorticoids. Historically, it is of interest that one clinical trial was reported by de Andrade et al. [6] in 1964, which compared treatment with 5 mg of prednisone per day in the morning versus 5 mg per day in the evening. The authors reported that the evening dose was preferred by the majority of patients. They also noted that many patients in their clinical setting had never taken a dose greater than 7.5 mg per day (on the basis of recommendations from the Mayo Clinic group [5]), and most never more than 5 mg per day [6]. However, this practice did not become widespread, possibly in part because even these investigators and the rheumatology community did not believe 5 mg could be disease modifying in RA [6] (see article by Pincus et al., this issue p. 46). A reassessment of oral glucocorticoids for treatment of RA began in the mid-1980s, concomitant with recognition that the long-term consequences of RA were more severe than had been recognized previously, including frequent work disability [12, 13], early radiographic damage within the first 2 years of disease [14], and premature mortality rates [13, 15, 16]. Mortality rates in patients with severe RA were similar to those seen in severe hypertension and diabetes [17]. These observations modified concepts concerning the risk/benefit ratio of glucocorticoids for RA. (Even at present, patients with neoplastic disease may be treated with doses of prednisone of 60 mg per day for months, without any recommendations that these doses may have a long-term negative risk/benefit ratio.)
References
Introduction
13 Pincus T, Callahan LF, Sale WG, Brooks AL, Payne LE, Vaughn WK: Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum 1984;27:864–872. 14 Scott DL, Grindulis KA, Struthers GR, Coulton BL, Popert AJ, Bacon PA: Progression of radiological changes in rheumatoid arthritis. Ann Rheum Dis 1984;43:8–17. 15 Isomäki HA, Mutru O, Koota K: Death rate and causes of death in patients with rheumatoid arthritis. Scand J Rheumatol 1975;4:205– 208. 16 Rasker JJ, Cosh JA: The natural history of rheumatoid arthritis: a fifteen year follow-up study: the prognostic significance of features noted in the first year. Clin Rheumatol 1984; 3:11–20. 17 Pincus T, Callahan LF, Vaughn WK: Questionnaire, walking time and button test measures of functional capacity as predictive markers for mortality in rheumatoid arthritis. J Rheumatol 1987;14:240–251. 18 Harris ED Jr, Emkey RD, Nichols JE, Newberg A: Low dose prednisone therapy in rheumatoid arthritis: a double blind study. J Rheumatol 1983;10:713–721. 19 Kirwan JR: The effects of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med 1995;333:142–146. 20 Boers M, Verhoeven AC, Markusse HM, van de Laar MAFJ, Westhovens R, van Denderen JC, et al: Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997; 350:309–318. 21 van Everdingen AA, Jacobs JWG, van Reesema DRS, Bijlsma JWJ: Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects. Ann Intern Med 2002;136:1–12. 22 Svensson B, Boonen A, Albertsson K, van der Heijde D, Keller C, Hafstrom I: Low-dose prednisolone in addition to the initial diseasemodifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a two-year randomized trial. Arthritis Rheum 2005;52:3360–3370. 23 Wassenberg S, Rau R, Steinfeld P, Zeidler H: Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, doubleblind, placebo-controlled trial. Arthritis Rheum 2005;52:3371–3380. 24 Pincus T, Swearingen CJ, Luta G, Sokka T: Efficacy of prednisone 1–4 mg/day in patients with rheumatoid arthritis: a randomised, double-blind, placebo controlled withdrawal clinical trial. Ann Rheum Dis 2009; 68: 1715– 1720.
25 Bakker MF, Jacobs JW, Welsing PM, Verstappen SM, Tekstra J, Ton E, et al: Low-dose prednisone inclusion in a methotrexatebased, tight control strategy for early rheumatoid arthritis: a randomized trial. Ann Intern Med 2012;156:329–339. 26 Montecucco C, Todoerti M, Sakellariou G, Scire CA, Caporali R: Low-dose oral prednisone improves clinical and ultrasonographic remission rates in early rheumatoid arthritis: results of a 12-month open-label randomised study. Arthritis Res Ther 2012;14:R112. 27 Pincus T, Sokka T, Castrejón I, Cutolo M: Decline of mean initial prednisone dosage from 10.3 to 3.6 mg/day to treat rheumatoid arthritis between 1980 and 2004 in one clinical setting, with long-term effectiveness of dosages less than 5 mg/day. Arthritis Care Res 2013; 65:729–736. 28 Buttgereit F, Doering G, Schaeffler A, Witte S, Sierakowski S, Gromnica-Ihle E, 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. Lancet 2008;371:205–214. 29 Buttgereit F, Mehta D, Kirwan J, Szechinski J, Boers M, Alten RE, et al: Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann Rheum Dis 2013;72:204–210. 30 Danowski TS, Bonessi JV, Sabeh G, Sutton RD, Webster MW Jr, Sarver ME: Probabilities of pituitary-adrenal responsiveness after steroid therapy. Ann Intern Med 1964;61:11–26. 31 Wood JB, Frankland AW, James VH, Landon J: A rapid test of adrenocortical function. Lancet 1965;1:243–245. 32 Daly JR, Myles AB, Bacon PA, Beardwell CG, Savage O: Pituitary adrenal function during corticosteroid withdrawal in rheumatoid arthritis. Ann Rheum Dis 1967;26:18–25. 33 LaRochelle GE Jr, LaRochelle AG, Ratner RE, Borenstein DG: Recovery of the hypothalamic-pituitary-adrenal (HPA) axis in patients with rheumatic diseases receiving low-dose prednisone. Am J Med 1993;95:258–264. 34 Wei L, MacDonald TM, Walker BR: Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 2004;141:764–770. 35 Pincus T, Sokka T, Stein CM: Are long-term very low doses of prednisone for patients with rheumatoid arthritis as helpful as high doses are harmful? Ann Intern Med 2002; 136: 76– 78.
Neuroimmunomodulation 2015;22:3–5 DOI: 10.1159/000362737
5
Downloaded by: NYU Medical Center Library 128.122.253.212 - 4/27/2015 2:49:44 PM
1 Hench PS, Kendall EC, Slocumb CH, Polley HF: The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of the pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin 1949; 24: 181–197. 2 Hench PS: The reversibility of certain rheumatic and non-rheumatic conditions by the use of cortisone or of the pituitary adrenocorticotropic hormone. Ann Intern Med 1952; 36:1–38. 3 Medical Resarch Council: Streptomycin treatment of pulmonary tuberculosis. Br Med J 1948;2:769–782. 4 Hill AB: Suspended judgment: memories of the British streptomycin trial in tuberculosis – the first randomized clinical trial. Controlled Clin Trials 1990;11:77–79. 5 Polley HF, Slocumb CH, Ward LE, Hench PS: Recognition and treatment of patients with chronic hypercortisonism. Ann Rheum Dis 1955;14(4):416–417. 6 de Andrade JR, McCormick JN, Hill AGS: Small doses of prednisolone in the management of rheumatoid arthritis. Ann Rheum Dis 1964;23:158–162. 7 Empire Rheumatism Council: Multi-centre controlled trial comparing cortisone acetate and acetyl salicylic acid in the long-term treatment of rheumatoid arthritis: results of three years treatment. Ann Rheum Dis 1957; 16: 277–289. 8 West HF: Rheumatoid arthritis: the relevance of clinical knowledge to research activities. Abstr World Med 1967;41:401–417. 9 Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, et al: EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73: 492–509. 10 Sokka T, Kautiainen H, Pincus T, Toloza S, da Rocha Castelar Pinheiro G, Lazovskis J, et al: Disparities in rheumatoid arthritis disease activity according to gross domestic product in 25 countries in the QUEST-RA database. Ann Rheum Dis 2009;68:1666–1672. 11 Zonana-Nacach A, Barr SG, Magder LS, Petri M: Damage in systemic lupus erythematosus and its association with corticosteroids. Arthritis Rheum 2000;43:1801–1808. 12 Yelin E, Meenan R, Nevitt M, Epstein W: Work disability in rheumatoid arthritis: effects of disease, social, and work factors. Ann Intern Med 1980;93:551–556.
Published online: September 12, 2014
The co-editors, Maurizio Cutolo, George P. Chrousos and Theodore Pincus, are pleased to present this special issue of Neuroimmunology, concerning contemporary use of low-dose glucocorticoids in the treatment of patients with rheumatic diseases. Prednisolone was introduced for the treatment of rheumatoid arthritis (RA) in 1949 [1]. Spectacular results were documented not only in the medical literature, but also in a short film and descriptions in US national magazines. The 1950 Nobel Prize in Medicine and Physiology was awarded to Hench and collaborators for their achievement [2]. In 1949, the time of the discovery of the clinical benefits of prednisolone, new medications could be introduced for marketing without evidence of superiority to placebo in randomized controlled clinical trials, which was introduced only in the 1940s [3, 4]. Furthermore, no requirement existed to analyze the risk/benefit ratio or dose-response relations at different doses. Therefore, guidelines were not available concerning optimal dosages for different indications, or for how long therapy should be continued. In 1955, the Mayo Clinic group that discovered the use of clinical prednisone actually suggested that doses of 10 years had always received these agents [11]. Almost all patients with vasculitis, polymyositis, polymyalgia rheumatica and most other inflammatory rheumatic diseases are treated with glucocorticoids. Historically, it is of interest that one clinical trial was reported by de Andrade et al. [6] in 1964, which compared treatment with 5 mg of prednisone per day in the morning versus 5 mg per day in the evening. The authors reported that the evening dose was preferred by the majority of patients. They also noted that many patients in their clinical setting had never taken a dose greater than 7.5 mg per day (on the basis of recommendations from the Mayo Clinic group [5]), and most never more than 5 mg per day [6]. However, this practice did not become widespread, possibly in part because even these investigators and the rheumatology community did not believe 5 mg could be disease modifying in RA [6] (see article by Pincus et al., this issue p. 46). A reassessment of oral glucocorticoids for treatment of RA began in the mid-1980s, concomitant with recognition that the long-term consequences of RA were more severe than had been recognized previously, including frequent work disability [12, 13], early radiographic damage within the first 2 years of disease [14], and premature mortality rates [13, 15, 16]. Mortality rates in patients with severe RA were similar to those seen in severe hypertension and diabetes [17]. These observations modified concepts concerning the risk/benefit ratio of glucocorticoids for RA. (Even at present, patients with neoplastic disease may be treated with doses of prednisone of 60 mg per day for months, without any recommendations that these doses may have a long-term negative risk/benefit ratio.)
References
Introduction
13 Pincus T, Callahan LF, Sale WG, Brooks AL, Payne LE, Vaughn WK: Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum 1984;27:864–872. 14 Scott DL, Grindulis KA, Struthers GR, Coulton BL, Popert AJ, Bacon PA: Progression of radiological changes in rheumatoid arthritis. Ann Rheum Dis 1984;43:8–17. 15 Isomäki HA, Mutru O, Koota K: Death rate and causes of death in patients with rheumatoid arthritis. Scand J Rheumatol 1975;4:205– 208. 16 Rasker JJ, Cosh JA: The natural history of rheumatoid arthritis: a fifteen year follow-up study: the prognostic significance of features noted in the first year. Clin Rheumatol 1984; 3:11–20. 17 Pincus T, Callahan LF, Vaughn WK: Questionnaire, walking time and button test measures of functional capacity as predictive markers for mortality in rheumatoid arthritis. J Rheumatol 1987;14:240–251. 18 Harris ED Jr, Emkey RD, Nichols JE, Newberg A: Low dose prednisone therapy in rheumatoid arthritis: a double blind study. J Rheumatol 1983;10:713–721. 19 Kirwan JR: The effects of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med 1995;333:142–146. 20 Boers M, Verhoeven AC, Markusse HM, van de Laar MAFJ, Westhovens R, van Denderen JC, et al: Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997; 350:309–318. 21 van Everdingen AA, Jacobs JWG, van Reesema DRS, Bijlsma JWJ: Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects. Ann Intern Med 2002;136:1–12. 22 Svensson B, Boonen A, Albertsson K, van der Heijde D, Keller C, Hafstrom I: Low-dose prednisolone in addition to the initial diseasemodifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a two-year randomized trial. Arthritis Rheum 2005;52:3360–3370. 23 Wassenberg S, Rau R, Steinfeld P, Zeidler H: Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, doubleblind, placebo-controlled trial. Arthritis Rheum 2005;52:3371–3380. 24 Pincus T, Swearingen CJ, Luta G, Sokka T: Efficacy of prednisone 1–4 mg/day in patients with rheumatoid arthritis: a randomised, double-blind, placebo controlled withdrawal clinical trial. Ann Rheum Dis 2009; 68: 1715– 1720.
25 Bakker MF, Jacobs JW, Welsing PM, Verstappen SM, Tekstra J, Ton E, et al: Low-dose prednisone inclusion in a methotrexatebased, tight control strategy for early rheumatoid arthritis: a randomized trial. Ann Intern Med 2012;156:329–339. 26 Montecucco C, Todoerti M, Sakellariou G, Scire CA, Caporali R: Low-dose oral prednisone improves clinical and ultrasonographic remission rates in early rheumatoid arthritis: results of a 12-month open-label randomised study. Arthritis Res Ther 2012;14:R112. 27 Pincus T, Sokka T, Castrejón I, Cutolo M: Decline of mean initial prednisone dosage from 10.3 to 3.6 mg/day to treat rheumatoid arthritis between 1980 and 2004 in one clinical setting, with long-term effectiveness of dosages less than 5 mg/day. Arthritis Care Res 2013; 65:729–736. 28 Buttgereit F, Doering G, Schaeffler A, Witte S, Sierakowski S, Gromnica-Ihle E, 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. Lancet 2008;371:205–214. 29 Buttgereit F, Mehta D, Kirwan J, Szechinski J, Boers M, Alten RE, et al: Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann Rheum Dis 2013;72:204–210. 30 Danowski TS, Bonessi JV, Sabeh G, Sutton RD, Webster MW Jr, Sarver ME: Probabilities of pituitary-adrenal responsiveness after steroid therapy. Ann Intern Med 1964;61:11–26. 31 Wood JB, Frankland AW, James VH, Landon J: A rapid test of adrenocortical function. Lancet 1965;1:243–245. 32 Daly JR, Myles AB, Bacon PA, Beardwell CG, Savage O: Pituitary adrenal function during corticosteroid withdrawal in rheumatoid arthritis. Ann Rheum Dis 1967;26:18–25. 33 LaRochelle GE Jr, LaRochelle AG, Ratner RE, Borenstein DG: Recovery of the hypothalamic-pituitary-adrenal (HPA) axis in patients with rheumatic diseases receiving low-dose prednisone. Am J Med 1993;95:258–264. 34 Wei L, MacDonald TM, Walker BR: Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 2004;141:764–770. 35 Pincus T, Sokka T, Stein CM: Are long-term very low doses of prednisone for patients with rheumatoid arthritis as helpful as high doses are harmful? Ann Intern Med 2002; 136: 76– 78.
Neuroimmunomodulation 2015;22:3–5 DOI: 10.1159/000362737
5
Downloaded by: NYU Medical Center Library 128.122.253.212 - 4/27/2015 2:49:44 PM
1 Hench PS, Kendall EC, Slocumb CH, Polley HF: The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of the pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin 1949; 24: 181–197. 2 Hench PS: The reversibility of certain rheumatic and non-rheumatic conditions by the use of cortisone or of the pituitary adrenocorticotropic hormone. Ann Intern Med 1952; 36:1–38. 3 Medical Resarch Council: Streptomycin treatment of pulmonary tuberculosis. Br Med J 1948;2:769–782. 4 Hill AB: Suspended judgment: memories of the British streptomycin trial in tuberculosis – the first randomized clinical trial. Controlled Clin Trials 1990;11:77–79. 5 Polley HF, Slocumb CH, Ward LE, Hench PS: Recognition and treatment of patients with chronic hypercortisonism. Ann Rheum Dis 1955;14(4):416–417. 6 de Andrade JR, McCormick JN, Hill AGS: Small doses of prednisolone in the management of rheumatoid arthritis. Ann Rheum Dis 1964;23:158–162. 7 Empire Rheumatism Council: Multi-centre controlled trial comparing cortisone acetate and acetyl salicylic acid in the long-term treatment of rheumatoid arthritis: results of three years treatment. Ann Rheum Dis 1957; 16: 277–289. 8 West HF: Rheumatoid arthritis: the relevance of clinical knowledge to research activities. Abstr World Med 1967;41:401–417. 9 Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, et al: EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73: 492–509. 10 Sokka T, Kautiainen H, Pincus T, Toloza S, da Rocha Castelar Pinheiro G, Lazovskis J, et al: Disparities in rheumatoid arthritis disease activity according to gross domestic product in 25 countries in the QUEST-RA database. Ann Rheum Dis 2009;68:1666–1672. 11 Zonana-Nacach A, Barr SG, Magder LS, Petri M: Damage in systemic lupus erythematosus and its association with corticosteroids. Arthritis Rheum 2000;43:1801–1808. 12 Yelin E, Meenan R, Nevitt M, Epstein W: Work disability in rheumatoid arthritis: effects of disease, social, and work factors. Ann Intern Med 1980;93:551–556.
