718 EXTENDED REPORT Ann Rheum Dis: first published as 10.1136/ard.61.8.718 on 1 August 2002. Downloaded from Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology F Buttgereit,JAPdaSilva, M Boers, G-R Burmester, M Cutolo, J Jacobs, J Kirwan, L Köhler, P van Riel, T Vischer,JWJBijlsma ............................................................................................................................. Ann Rheum Dis 2002;61:718–722 See end of article for authors’ affiliations ....................... In rheumatology and other medical specialties there is a discrepancy between the widespread use and Correspondence to: the imprecise designation of glucocorticoid treatment regimens. Verbal descriptions of glucocorticoid Dr F Buttgereit, Department treatment regimens used in various phases of diseases vary between countries and institutions. Given of Rheumatology and this background, a workshop under the auspices of the EULAR Standing Committee on International Clinical Immunology, Clinical Studies including Therapeutic Trials was held to discuss this issue and to seek a consensus on Charité University Hospital, Schumannstrasse 20/21, nomenclature for glucocorticoid treatment. This report summarises the panel’s discussion and 10117 Berlin, Germany; recognises that answers derived from consensus conferences are not definitive. Nevertheless, [email protected] recommendations on glucocorticoid treatment are presented that (1) reflect current and best knowledge Accepted available and (2) take into account current clinical practice. A question-answer rationale presentation 25 February 2002 style has been chosen to convey the messages, to summarise the meeting in a readable format, and to ....................... avoid dogmatism. lucocorticoids have profound anti-inflammatory and dom, Italy, Portugal, Switzerland and The Netherlands who immunosuppressive actions when used therapeuti- met in Berlin on 7 April 2001 for the First European Workshop Gcally. The therapeutic dose is very wide and depends on on Glucocorticoid Therapy. This report summarises the panel’s the indication for treatment, but can vary more than 200-fold. discussion and recognises that answers derived from consen- Clearly, different dosages and dosing regimens have distinct sus conferences are not definitive. Nevertheless, we present therapeutically relevant effects mediated by genomic and recommendations on glucocorticoid treatment that (1) reflect non-genomic actions. Genomic actions involve the binding to current and best knowledge available and (2) take into cytosolic glucocorticoid receptors, occur at any therapeutically account current clinical practice. We have chosen a question- http://ard.bmj.com/ relevant dosage, and are seen not earlier than 30 minutes after answer rationale presentation style to convey the messages, to receptor binding. In contrast, non-genomic actions are medi- summarise our meeting in a readable format, and to avoid ated via biological membranes, and are seen at higher concen- dogmatism. trations and within seconds or minutes (see below). However, the basis for the use of different dosages in different clinical WHAT TERM SHOULD BE USED TO DESCRIBE THIS conditions is essentially empirical as the evidence to support preferences in specific clinical settings is very scarce. This is CLASS OF DRUGS (STEROIDS, CORTICOSTEROIDS, CORTICOIDS, GLUCOCORTICOSTEROIDS, aggravated by the discrepancy between the widespread use on September 26, 2021 by guest. Protected copyright. and the imprecise designation of glucocorticoid treatment GLUCOCORTICOIDS)? regimens in rheumatology, as in other medical specialties. Answer Nomenclature and terminology of glucocorticoid treatment We suggest the use of the term glucocorticoids. regimens used in various indications and phases of diseases varies between countries and institutions. The current termi- Rationale nological confusion is exemplified by the different interpreta- The term steroids is too broad as it simply describes chemical tions of the various terms used to describe dosage (very low, compounds characterised by a common multiple ring struc- low, mild, mild to moderate, moderate, high, very high, ultra- ture that include molecules such as cholesterol, sex hor- high, and megadoses) and by the great variation in interpret- mones, and corticosteroids. The terms corticosteroids and ation of the terms “low dose therapy”, “high dose therapy”, corticoids are insufficiently exact as the adrenal cortex syn- and “pulse therapy”. A clarification of this situation is needed, thesises two classes of steroids: the corticosteroids in the firstly, for scientific conciseness in clinical terms to compare narrower sense, which have 21 carbon atoms, and androgens, trials and, secondly, because glucocorticoid actions are which have 19 carbon atoms. The adrenal corticosteroids in strongly dose dependent in both a quantitative and qualitative the narrower sense differ in their relative glucocorticoid (car- manner.12Moreover, it should be noted that there is currently bohydrate metabolism regulating) and mineralocorticoid a renewed interest in glucocorticoids based on studies (electrolyte balance regulating) activity and were, therefore, describing their disease modifying effects in rheumatoid historically described as glucocorticoids and arthritis.3–5 mineralocorticoids.6 Corticosteroids are grouped according to Given this background, a workshop was held to discuss this their relative potencies in Na+ retention, effects on carbohy- issue and to seek a consensus on nomenclature for glucocorti- drate metabolism (hepatic deposition of glycogen and coid treatment. A panel of experts was convened under the glucogenesis), and anti-inflammatory effects.6 Potencies based auspices of the EULAR Standing Committee on International on effects on glucose metabolism (but not effects on Na+ Clinical Studies including Therapeutic Trials. The panel retention!) closely parallel those for anti-inflammatory effects. comprised rheumatologists from Germany, the United King- This was the reason for using the term glucocorticoids where www.annrheumdis.com Standardised nomenclature for glucocorticoid doses and glucocorticoid treatment regimens 719 Figure 1 Ann Rheum Dis: first published as 10.1136/ard.61.8.718 on 1 August 2002. Downloaded from A B Relative potencies of various glucocorticoids to produce 25 25 25 genomic and non-specific 25 22.7 non-genomic effects. The figure shows a comparison between genomic and 20 20 non-genomic potencies of various 20 Prednylidene glucocorticoids. (A) Data for classic Prednisolone (genomic) effects were taken from Goodman and Gilman6 and are rela- Methylprednisolone 15 15 Dexamethasone 13.3 tive to cortisol. (B) Data for non- specific non-genomic effects were Betamethasone taken from Schmid et al8 and are rela- 10 tive to prednisolone. The value for Relative potencies 10 prednisolone was set to 4 and values for the other glucocorticoids were 5 scaled accordingly to allow direct 5 4 5 4 3.5 <2.7 comparison with the classic poten- cies. It should be noted that non- specific non-genomic effects are 0 0 especially relevant in higher doses. anti-inflammation is the therapeutically desired effect. In usable for daily clinical work in terms of general therapeu- humans, hydrocortisone (cortisol) is the main glucocorticoid, tic guidelines, but their dogmatic use should be avoided. We and aldosterone is the main mineralocorticoid.6 Glucocorti- suggest therefore that (1) these values continue to be used coids in therapeutic use for anti-inflammatory and immuno- until more exact data are available and (2) doses of different suppressive effects are nowadays exclusively synthetic mol- glucocorticoids are expressed by converting them into doses of ecules that have pronounced anti-inflammatory potencies “prednisone equivalent”; in other words to express doses of compared to relative weak or even zero Na+ retaining different glucocorticoids in mg prednisone (=mg pred- potencies. nisolone, as prednisone is equally as potent as prednisolone) For these reasons the terms glucocorticoid(s) or gluco- by using the relative potencies given above. The suggestion for corticosteroid(s) are scientifically correct and appropriate to further using the term prednisone equivalent is recommended describe the use of these drugs for the treatment of rheumatic for historical reasons because prednisone was the first diseases and other conditions where anti-inflammatory and synthetic, pharmacologically relevant glucocorticoid drug to immunomodulatory effects are desired. However, the term be introduced into clinical medicine. “glucocorticosteroids” is not very often used (only 368 However, (1) It should be noted that the use of equivalent citations in Medline 1994–2000) compared to the term dosages is according to recent data only a valid procedure if “glucocorticoids” (11 178 citations). In summary, we suggest doses of less than 100 mg prednisone are considered. At generally the use of the term glucocorticoid(s). higher doses non-genomic effects come into play. This is important because the relative potencies of different glucocor- ticoids producing these non-genomic effects are completely different from their classic genomic effects.289 Figure 1B HOW CAN GLUCOCORTICOID THERAPY http://ard.bmj.com/ SCHEDULES BE DESCRIBED AS PRECISELY AS shows the data that rationalise the empirical use of glucocor- POSSIBLE? ticoids for high dose therapy. For instance, for