Ann Rheum Dis: first published as 10.1136/ard.17.2.145 on 1 June 1958. Downloaded from Ann. rheum. Dis. (1958), 17, 145. PREDNISONE IN RHEUMATOID ARTHRITIS: METABOLIC AND CLINICAL EFFECTS BY L. EMMERSON WARD, HOWARD F. POLLEY, MARSCHELLE H. POWER, HAROLD L. MASON, CHARLES H. SLOCUMB, AND PHILIP S. HENCH Mayo Clinic and Mayo Foundation,* Rochester, Minn. The initial reports (Hench, Kendall, Slocumb, and strated that chemists could alter the steroid molecule Polley, 1949; Sprague, Power, Mason, Albert, so as to prepare synthetic compounds with even Mathieson, Hench, Kendall, Slocumb, and Polley, more selective effects. This paved the way for the 1950; Hench and others, 1950) of the antirheumatic dissociation of one effect from another, so that one potency of cortisone emphasized the fact that or more of these effects could be enhanced rela- excessive doses produced not only desirable but also tively. certain undesirable effects. At that time (1949), we The chemical structure of prednisone (delta expressed our hope and belief that analogues 1-cortisone) and prednisolone (delta I-hydro- superior to cortisone would be discovered. Since cortisone) differs from that of cortisone and hydro- then, at least seven more cortisone-like steroids have cortisone, respectively, only in the possession of a copyright. been found useful clinically; these include hydro- double bond (hence the designation "delta") between cortisone, 9-alpha-fluorohydrocortisone (Fludro- the first and second carbon atoms in ring A of the cortisone), prednisone, prednisolone, a compound molecule (Fig. 1, overleaf). It is this slight change whose structure is 9-alpha-fluoro, delta 1-hydro- that invests these synthetic cortisone-like steroids cortisone, and the two most recent additions, with an increased antirheumatic potency and a de- namely triamcinolone and 6-methyl, delta I-hydro- creased effect on the metabolism ofelectrolytes when cortisone. compared, milligram for milligram, with cortisone http://ard.bmj.com/ Each of these eight compounds has distinctive and hydrocortisone. It was hoped that a similar characteristics. Cortisone is the least costly to alteration of the 9-alpha-fluorohydrocortisone prepare synthetically; it is still useful in many cases molecule might lessen the pronounced effect of that and preferable in some. Hydrocortisone, appar- compound on electrolytes and perhaps might even ently the major product of the normal human enhance its great antirheumatic effect. Such did adrenal cortex, has proved to be superior to cortisone not prove to be the case, however, and the afore- in local, especially intra-articular, administration. mentioned 9-alpha-fluoro, delta 1-hydrocortisone on September 24, 2021 by guest. Protected Fludrocortisone possesses a greatly enhanced anti- proved to be similar in effect to 9-alpha-fluoro- rheumatic effect (about ten times greater than that hydrocortisone (Thorn, Renold, Morse, Goldfien, of cortisone, milligram for milligram); however, and Reddy, 1955; Bunim, 1957). its effect on the retention of sodium and chloride Triamcinolone has the chemical structure 16 alpha- and the excretion of potassium is even more en- hydroxy, 9-alpha-fluoro, delta 1-hydrocortisone. Its hanced. Thus, fludrocortisone is especially useful rheumatic potency appears to be approximately that in the adrenal insufficiency of Addison's disease and of prednisone (Hellman, Zumoff, Schwartz, Galla- when used in ointments for certain dermatological gher, Berntsen, and Freyberg, 1957). Medrol, conditions, but the qualities that make it superior which is the afore-mentioned 6-methyl, delta 1- to cortisone or hydrocortisone in the management hydrocortisone, also is said to have about the same of Addison's disease interfere with its usefulness for anti-rheumatic potency as prednisone (Glenn, rheumatic patients. Nevertheless, its production Stafford, Lyster, and Bowman, 1957). Whether represented a distinct advance, because it demon- these two newest steroids will have additional prac- tical therapeutic * The Mayo Foundation, Rochester, Minnesota, is a part of the advantages remains to be deter- Graduate School of the University of Minnesota. mined by further clinical studies. 145 Ann Rheum Dis: first published as 10.1136/ard.17.2.145 on 1 June 1958. Downloaded from 146 ANNALS OF THE RHEUMATIC DISEASES CH2OHIC. C-0 Cortisone acetate Hydrocortisone CH2OH CHZOH COO c~o 1_- OH copyright. Prednisone Prednisolone Fig. 1.-Structural formulae showing relationship between cortisone and prednisone, and between hydrocortisone and prednisolone. http://ard.bmj.com/ Present Study electrocardiograms, and electroencephalograms. We have studied the antirheumatic and other clinical effects of prednisone and prednisolone on Report of Cases many patients who had rheumatoid arthritis. In Case 1, a 51-year-old woman, who had had severe three such cases, we also made special studies con- rheumatoid arthritis for 1 year, received first a constant cerning the metabolic effects of prednisone and in dose of prednisone, starting on February 27, 1955, and on September 24, 2021 by guest. Protected two of these three cases we compared these effects then hydrocortisone; after this, prednisone was given in with those of cortisone or hydrocortisone. decreasing doses. Initially, 20 mg. prednisone per day The metabolic balances of sodium, chloride, was given orally (5 mg. every 6 hrs) for 36 days, after total and which its use was discontinued for 12 days. Thereafter, potassium, nitrogen, calcium, inorganic hydrocortisone (free alcohol) was administered orally in phosphorus were studied by procedures and doses of 80 mg. per day (20 mg. every 6 hrs) for 24 days. methods described previously (Sprague and others, Then prednisone was again given orally as follows: 1950; Hench and others, 1950; Ward, Polley, 20 mg. daily (5 mg. every 6 hrs) for 6 days; 17-5 mg. Slocumb, Hench, Mason, Mattox, and Power, 1954; daily (5 mg. at 2 a.m., 8 a.m., and 2 p.m., 2 5 mg. at Salassa, Power, Ulrich, and Hayles, 1954). Obser- 8 p.m.) for 6 days; 15 mg. daily (5 mg. at 8 a.m. and vations were made on electrolytes, urea, uric acid, 8 p.m., 2 5mg. at 2a.m. and 2p.m.) for 6 days. proteins, sugar, and various lipids in the blood, and Antirheumatic Effects.-Symptomatic relief was noted on the urinary excretion of corticosteroids, 17-keto- 3 hours after the first dose of prednisone, and objective steroids, uric acid, and creatinine; studies also were improvement was noted within the first 24 hours. Both made of the erythrocyte sedimentation rate, glucose progressed rapidly so that by the 36th day of treatment tolerance, basal metabolic rate, blood pressure, the over-all improvement (loss of the patient's disability) Ann Rheum Dis: first published as 10.1136/ard.17.2.145 on 1 June 1958. Downloaded from PREDNISONE IN RHEUMATOID ARTHRITIS 147 Prednisone Hydrocortisone Prednisone U0mgoa4hr( ) ( 80mi./4hr ) ( mo/24hr) 14 10 E -K 3 Haematocrit Body Wt. 5 (kg.) copyright. 4 . a ~~~~~~Days Fig. 2.-Case, 1, effect of prednisone and hydrocortisone on concentration of electrolytes in plasma and on haematocrit and body weight. was rated as 90 per cent. When administration of Laboratory Data.-The laboratory data are sum- prednisone was stopped, rheumatoid symptoms and signs marized in Table I (overleaf) and Figs 2 to 5. recurred rapidly. Hydrocortisone was found, as had http://ard.bmj.com/ been expected from other studies, to be only one- Additional Sodium Chloride.-To test this patient's fourth as effective, milligram for milligram, as pred- tolerance for additional salt, 3 g. sodium chloride was nisone, 80 mg. of the former being the antirheumatic added to the diet from the 25th to the 30th day inclusive equivalent of 20 mg. of the latter. The subsequent use of the first course of prednisone. This did not alter of prednisone in doses of 20 mg. per day maintained the the balances or the serum levels of sodium or chloride. same degree of symptomatic relief as 80 mg. hydrocorti- sone. The smaller doses of prednisone, namely 17-5 Case 2, a 54-year-old woman, who had had rheumatoid and 15 mg. daily, were proportionately less effective, arthritis of moderate severity for 1 year, was given on September 24, 2021 by guest. Protected as one might anticipate. 30 mg. prednisone orally per 24 hrs (7 5 mg. every 6 hrs) for 12 days, starting on July 27, 1955; then, after Other Clinical Effects. The pitting oedema of the steroids had not been given for 12 days, she received lower legs that was present in this patient before treat- four times as much cortisone, or 120 mg. per day orally ment, probably from rheumatoid inflammation, de- (30 mg. every 6 hrs) for 12 days. creased notably during both courses of prednisone; the body weight decreased concomitantly (Fig. 2). On the Antirheumatic Effects.-The daily dose of 30 mg. other hand, administration of hydrocortisone led to prednisone afforded 90 per cent. relief of the signs and retention of fluid, with increased oedema, presumably symptoms of rheumatism, whereas the daily dose of non-inflammatory, and body weight. Neither steroid 120 mg. cortisone afforded only 80 per cent. relief. With altered the blood pressure. Both steroids produced both steroids, the onset of relief was rapid, and dis- transient mild mental stimulation (euphoria, restless- ability gradually recurred after treatment was stopped. ness, insomnia). Obstipation developed during the Other Clinical Effects.-Both steroids produced first course of prednisone. (Its occurrence in this moderate insomnia and increased hot flushes. patient and in a few others observed subsequently suggests that this rarely may be a complication of Laboratory Data.-These are summarized in Table I treatment with prednisone.) and in Figs 6 to 9. Ann Rheum Dis: first published as 10.1136/ard.17.2.145 on 1 June 1958. Downloaded from 148 ANNALS OF THE RHEUMATIC DISEASES TABLE I SUMMARY OF EFFECTS OF STEROIDS IN THREE CASES OF RHEUMATOID ARTHRITIS Drug .. Prednisone Hydrocortisone Cortisone Case No.