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Four new derivatives of hydrocortisone, each containing in common a methyl grouping at the 16a-carbon position of the steroid molecule, have been synthesized and are being studied in human subjects. The compounds are 16a-methyl 9a-fluoroprednisolone (MK-125: hexadecadrol), 16a-methyl 9a-fluorohydrocortisone (MK-126), 16a-methylprednisolone (MK-110), and 16a-methylhydrocortisone (MK-117). Biologic tests in animals have indicated that these analogues exhibit, in varying degrees, striking alterations of several physiologic properties, including enhanced anti-inflammatory activity unassociated with corresponding disturbance of electrolyte metabolism. In the present study preliminary observations of the effects of the four new compounds were made in patients with rheumatoid arthritis. Clinical estimates of the antirheumatic potencies of the compounds, as compared with prednisolone, were accomplished by determining the milligram dosages required to maintain similar degrees of improvement of active rheumatoid manifestations. The approximate antirheumatic potencies of the compounds, on an average, were gauged as follows: for 16a-methyl 9a-fluoroprednisolone, about seven times greater than prednisolone; for 16a-methyl 9a-fluorohydrocortisone, about three times greater; for 16a-methylprednisolone, approximately one-third greater; and for 16a-methylhydrocortisone, about 70 per cent that of prednisolone. In the dosage used, none of the compounds promoted discernible salt and water retention. These observations would indicate that 16a-methyl 9a-fluoroprednisolone (hexadecadrol) possesses greater anti-inflammatory potency per milligram than any steroid yet produced. The therapeutic efficiency of the compound on longterm administration is being studied.

Recent experimental evidence suggests that hydrocortisone (Kendall's Compound F) is probably the principal glycogenic steroid secreted by the adrenal cortex and that under conditions of stress it may participate more than cortisone in physiologic reactions. Laboratory studies indicate that hydrocortisone has greater physiologic activity, milligram for milligram, than cortisone and with certain assays its potency is twice as great.Two forms of hydrocortisone, the free alcohol preparation and the acetate, were given systemically to patients with rheumatoid arthritis and were observed to possess significant differences in ability to suppress the disease manifestations. When administered orally in large initial doses, hydrocortisone (free alcohol) appeared to produce greater suppressive effects, milligram for milligram, than either hydrocortisone acetate or cortisone acetate. Comparisons of potency made by determining maintenance dosage requirements for equivalent degrees of clinical control in the same patients indicated that the effectiveness of hydrocortisone (free alcohol) is more than 50 per cent greater than that of either the free or acetated forms of cortisone and approximately twice as great as that of hydrocortisone acetate. Certain observations suggested that the greater antirheumatic activity of hydrocortisone (free alcohol) is not accompanied by a correspondingly greater tendency toward endocrine complications. If more extensive future investigations support this observation, hydrocortisone (free alcohol), by producing equally efficient results with smaller doses, may prove superior to cortisone as a therapeutic agent.Intra-articular injections of hydrocortisone acetate appear to have only a limited place in the management of rheumatoid arthritis but may be used for temporary relief under certain conditions. In preliminary studies by the author it was noted that whereas improvement resulted in 80 per cent of the treated joints, the improvement was graded as pronounced or very pronounced in only one-half of the joints so injected. In almost all instances the benefits derived were quite temporary. Results observed in treatment of osteoarthritic joints by this method were decidedly poorer than in rheumatoid arthritis.

To appraise the efficiency of complemental antacid administration in preventing and reducing digestive disturbances during prolonged treatment with prednisone and prednisolone, 100 patients with active rheumatoid arthritis who were maintained on combined antacid and prednisone or prednisolone therapy for periods of one year or longer, were studied clinically and roentgenographically. Antacid therapy consisted of 300 mg. of dried aluminum hydroxide gel and 50 mg. of magnesium trisilicate taken with each 2.5 mg. dose of the steroids. Digestive symptoms, such as indigestion, heartburn, sour eructations, gnawing epigastric distress and the like, were experienced by 18 per cent of patients during treatment with prednisone or prednisolone combined with antacids. Among patients who had been maintained on the steroids without antacids beforehand, the incidence of digestive complaints was reduced from 38 per cent to 17 per cent by the addition of alkali therapy, and the severity of the distress decreased in others. Active peptic ulcers were detected roentgenographically in three of the 100 patients. In two instances the ulcers were asymptomatic and in two instances they were considered as reactivations of previously healed lesions. The incidence of active ulcers in this series was substantially lower than that reported by several investigators among patients treated with prednisone and prednisolone without the concomitant administration of alkalis. The size of dosage and individual susceptibility appeared to be important factors in the development of digestive disturbances from steroids. Results of the study indicated that the complemental use of antacids with each divided dose of steroid is highly effective in reducing the frequency and severity of digestive symptoms during prednisone and prednisolone administration. The low incidence (3 per cent) for roentgenographically demonstrable active lesions in the series suggests that the addition of acid-neutralizing agents during prolonged treatment with these steroids may afford at least partial protection against the development and reactivation of peptic ulcers.

The administration of cortisone acetate to patients with rheumatoid arthritis usually produces prompt and often dramatic suppression of the disease manifestations. The effects of the hormone are not lasting, however, and after withdrawal relapse ensues. For sustained improvement in a chronic disease such as rheumatoid arthritis, it appears that cortisone must be given more or less continuously. This raises the question whether administration may be continued effectively and safely for long periods.Seventy-six patients with rheumatoid arthritis were given cortisone in the hope that treatment could be continued uninterruptedly for extended periods. For various clinical reasons it was necessary to discontinue treatment in 16 of these before six months, but the remaining 60 patients received the hormone uninterruptedly for six to 15 months. By using initial large suppressive amounts, then gradually reducing the dosage, and finally employing smaller maintenance doses, adequate degrees of rheumatic control were maintained in approximately two-thirds of the original 76 patients. The ability to sustain satisfactory improvement varied indirectly, in general, with the severity of the rheumatoid arthritis. The chief detriment to better results in the more severe cases was the intervention of adverse hormonal side effects which developed frequently when large or relatively large maintenance doses were required to support satisfactory improvement. Unwanted signs of hormonal excess developed in 40 per cent of cases at some time during the course of treatment. Most of them were mild or transient and disappeared or lessened when the dose of cortisone was reduced, but when the dose was reduced the degree of improvement often declined also. During prolonged cortisone therapy evidence of functional suppression of the adrenal cortices, as indicated by a decreased response of circulating eosinophils to exogenous ACTH, was present. The depression of cortical function was temporary, however. Whether irreversible damage may result when the drug is employed for longer periods cannot yet be answered.

A number of acute and chronic inflammatory disorders are amenable to varying degrees of therapeutic control with the administration of nonspecific anti-inflammatory drugs. An evaluation of these suppressive agents in the field of rheumatic diseases and practical suggestions regarding their administration are presented. Eight synthetically modified corticosteroid compounds are available commercially. Each of them exhibits qualitative differences in one or several physiologic actions, each has certain advantages and disadvantages in therapy, and each shares the major deterrent features of corticosteroids. Prednisone, prednisolone, methylprednisolone, fluprednisolone and paramethasone have similar therapeutic indices, and there is little choice between them for the usual rheumatoid patient requiring steroid therapy. Conversely, the therapeutic indices of dexamethasone, betamethasone and triamcinolone are lower than that of prednisolone; they are less desirable for routine use and should be reserved for specially selected cases. Salicylates are preferred to adrenocortical steroids in the treatment of the ordinary patient with acute rheumatic fever. Steroid therapy should be reserved for resistant cases and for those with significant carditis. Salicylates are mainstays for pain relief in rheumatoid arthritis, but with the analgesic doses usually employed their anti-inflammatory action is slight.Phenylbutazone is a highly useful anti-inflammatory agent, especially in management of acute gouty arthritis and ankylosing (rheumatoid) spondylitis; its metabolite, oxyphenylbutazone, does not exhibit clear-cut advantages. Colchicine specifically suppresses acute gouty arthritis. Its analogues, desacetylcolchicine and desacetylthiocolchicine, produce fewer unpleasant gastrointestinal symptoms, but may promote agranulocytosis and alopecia.A number of indole preparations with anti-inflammatory activity have been tested clinically. One of them, indomethacin, has received extensive therapeutic trial; with dosages that can be tolerated the drug is fairly effective in the symptomatic control of ankylosing (rheumatoid) spondylitis but it is of questionable value in peripheral rheumatoid arthritis.

The adrenal cortical hormone, cortisone, and the pituitary adrenocorticotropic hormone (ACTH) possess potent antirheumatic properties. Their administration produces strikingly beneficial effects on a number of rheumatic diseases including rheumatoid arthritis, rheumatoid (ankylosing) spondylitis, acute rheumatic fever, disseminated lupus erythematosus, periarteritis nodosa, psoriatic arthritis, dermatomyositis, and gout. In general the effects of these substances are temporary and they cause suppression rather than cure of the disease processes. Improvement is maintained usually only by continuing administration, and on hormonal withdrawal prompt or fairly prompt relapse of the disease manifestations ensues. In addition to their antirheumatic effects cortisone and ACTH influence a wide variety of physiologic functions. Administration of them therefore may produce a number of metabolic and clinical changes, some of which are not advantageous from a therapeutic standpoint. Adverse side-reactions are more liable to occur when large doses of the hormones are given for prolonged periods; such reactions appear to be reversible and disappear when administration of the hormones is stopped. With cortisone, comparatively few untoward signs develop when smaller amounts are administered continuously even for periods of months. Greater clinical experience is needed before optimal doses and schedules of administration are finally determined. It appears that some severe cases, many moderately severe cases, and most moderate and mild cases of rheumatoid arthritis may be adequately controlled with smaller "maintenance" doses of cortisone ranging from 32 to 65 mg. a day, providing larger doses to suppress the disease manifestations are employed initially. Neither cortisone nor ACTH should be considered as a therapeutic agent for general use until more information regarding their physiologic activities and the consequences of prolonged or repeated administration of them are available. Until the potential dangers of these hormones can be determined precisely, the use of them should be considered as an investigative procedure.