oral hydrocortisone therapy rheumatoid …for this report the results of prolonged oral...

Ann. rheum. Dis. (1955), 14, 232.

ORAL HYDROCORTISONE THERAPY IN RHEUMATOIDARTHRITIS

AN APPRAISAL OF GENERAL RESULTS OF PROLONGEDADMINISTRATION

BY

EDWARD W. BOLANDLos Angeles, California

(RECEIVED FOR PUBLICATION JUNE 6, 1955)

When hydrocortisone was made available forclinical trials in the spring of 1951, three facts seemedrelevant:

(1J The hormone was the principal, probably thenatural, glycogenic steroid secreted by the adrenal cortex(Hechter, 1950; Hechter and others, 1951; Reich andothers, 1950; Savard and others, 1952; Bush, 1951;Conn and others, 1951; Jacobsen and Pincus, 1951;Pincus, 1949; Mason, 1950).

(2) It was considerably more potent than cortisonein certain metabolic activities, as measured by laboratoryexperiments in animals (Ingle and Kuizenga, 1945;Pabst and others, 1947).

(3) It possessed antirheumatic activity, this havingbeen demonstrated by Hench, Kendall, Slocumb, andPolley (1950) in a rheumatoid arthritic patient given900 mg. of the substance over a 12-day period.

During 1951 and 1952 clinical studies were con-ducted to compare the therapeutic effectiveness ofhydrocortisone and cortisone in patients with rheu-matoid arthritis (Boland, 1952a, b, c, d; 1953a, b;1954; Boland and Headley, 1952).The general results of these studies may be sum-

marized as follows:(I) The pattern of improvement resulting from the

administration of the two steroids was much the same,but smaller initial suppressive doses of hydrocortisonewere required to produce corresponding inhibition of thedisease manifestations.

(2) By comparing the effects of oral doses in the samepatient, the antirheumatic potency of hydrocortisonewas estimated to be about 50 per cent. greater than thatof cortisone acetate or its free ester. In other words,the average milligram dosage of hydrocortisone neededfor roughly the same degree of improvement was approxi-mately two-thirds that of cortisone.

(3) Smaller maintenance doses of hydrocortisone werefound to provide equal or superior rheumatic control,and when these were used, certain endocrine complica-tions appeared to be fewer or less pronounced, especiallypsychic stimulation, salt-and-water retention, and exces-sive appetite.

These preliminary observations suggested thatthere might be a greater dissociation between thedesirable anti-inflammatory action and certain un-desirable physiological effects with hydrocortisonethan with cortisone, and that hydrocortisone mightpossess a higher therapeutic index-i.e. it mightprovide equal or greater benefits with smaller dosesand fewer or less marked untoward reactions.

Subsequently a study of the effects of oral hydro-cortisone given uninterruptedly was undertaken ina large series of patients with rheumatoid arthritis,the relatively short-term results of which have beenpublished (Boland, 1953b; 1954). It now seemsopportune, particularly since new synthetic analoguesof the adrenocortical hormones have been dis-covered, to record the results of longer-termobservations.

Present AnalysisFor this report the results of prolonged oral

hydrocortisone therapy* in 150 consecutive patientswith active peripheral rheumatoid arthritis wereanalysed. As statistical results are necessarily con-tingent on a number of factors (including the com-position of the series in relation to disease severityand duration, therapeutic plan and objective,method of dosage regulation, opinion as to whatconstitutes satisfactory response, and judgment asto the acceptability and safety of hormonal com-plications), some of these aspects, as applied to thepresent study, deserve clarification.Each patient selected for the study first had been

given a fair but unsuccessful trial on conventionalconservative measures. The majority of the patientssuffered from more severe forms of the disease;the arthritis was graded as severe in 39 patients(26 per cent.), moderately severe in seventy (47 per

* The hydrocortisone (free alcohol) used for this investigationwas supplied in part through the courtesy of the Medical Department,Merck and Co., Inc., Rahway, N.J.

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ORAL HYDROCORTISONE IN RHEUMATOID ARTHRITIS

cent.), and moderate in 41 (27 per cent.). Nopatients with mild disease were included.The guiding therapeutic policy was to maintain

as much relief as possible with doses of hydrocorti-sone which could be well tolerated. Completeinhibition of the disease manifestations and totalfunctional rehabilitation were not sought unlessthese could be accomplished with so-called safelevels of dosage. Submaximal improvement ofabout 75 to 85 per cent. of the pretreatment statuswas considered optimal for long-term administra-tion. This policy was adopted because it wasrecognized that benefits from the hormone wereonly suppressive, not curative, and it had beenlearned from previous experience with cortisone thatthe incidence and severity of hormonal complica-tions were directly related to the size of doseemployed, and that their occurrence was a majorfactor influencing the success of long-term therapy.Adequate or major improvement by our appraisals

meant very marked or marked, and corresponded tooverall improvement of approximately 75 per cent.or more as compared with the pretreatment status.It should be emphasized that improvement desig-nated as inadequate was at least worthwhile ortreatment would have been discontinued.The following plan of dosage, consisting of three

stages, was used:(a) Initial Suppressive Doses.-As a rule, total daily

dosages in the neighbourhood of the following wereemployed at the beginning: for severe cases, 50 to 70 mg.;for moderately severe cases, 40 to 60 mg.; for moderatecases, 40 to 50 mg. These amounts were continueduntil the clinical manifestations were satisfactorilysuppressed, ordinarily for one to three weeks.

(b) Reduction of Dosage.-Dosage was then graduallylowered in stepdown fashion, reductions of 5 mg. beingmade every 7 to 14 days, or sometimes even more slowly.The smallest total daily amount which would controlthe manifestations adequately, not necessarily completely,and which could be safely tolerated, was considered as themaintenance dose.

(c) Maintenance Dosage.-Maintenance doses ordin-arily ranged from 45 to 65 mg. in severe cases, 40 to50 mg. in moderately severe cases, and 25 to 40 mg. inmoderate cases. Once established, maintenance therapywas continued without interruption, the dosage beingmanipulated from time to time to accommodate shifts indisease activity or to control adverse reactions. Routine-ly the total daily requirement was taken in four divideddoses, with a portion ingested at mealtimes and at bed-time. Dosage adjustments were usually made by smallincreases or decreases of 5 or 10 mg. at a time; large"booster" doses were rarely needed.

Minor endocrine side-effects, such as slight tomoderate facial mooning or hypertrichosis, slight

peripheral oedema, or irregular glycosuria, wereusually looked upon as acceptable annoyances andnot as reasons for stopping treatment.

Adjunctive measures such as regulated rest,avoidance of emotional stress, physiotherapy, anda well-balanced diet, relatively low in salt and withcaloric restriction when indicated, were prescribedsimultaneously. Salicylates were used regularly orirregularly by some patients and intra-articularinjections of hydrocortisone acetate were occasion-ally employed in others to suppress exacerbationsin one or two joints.

General ResultsStatistical data were analysed in the hope of

finding answers to a few general but pertinentquestions:

(1) What percentage of patients who were startedon hydrocortisone therapy discontinued the hormoneandfor what reasons? The 150 patients in this studywere under observation for periods of 9 to 36 monthsfrom the beginning of therapy; more than one-thirdof them (37 per cent.) were followed for 2 years orlonger. Treatment was stopped in 24 patients(16 per cent.), and the remaining 126 (84 per cent.)were still taking the steroid at the time of analysis.Reasons for discontinuances were as follows:

Insufficient clinical response to warrant furtheradministration in four (2-7 per cent.),

Major complications attributable to the hormone intwo (1 -3 per cent.),

Complication unrelated to hydrocortisone in one(0 7 per cent.),

Death from extraneous causes in five (3 3 per cent.),Complete or nearly complete remission in twelve

(8 per cent.) patients (Table).

TABLEGENERAL DATA ON 150 CONSECUTIVE RHEUMATOIDARTHRITIC PATIENTS STARTED ON HYDROCORTISONE

THERAPY (ANALYSIS 9 TO 36 MONTHS AFTERINSTITUTION OF THERAPY)

No. %

Patients still on Therapy 126 84Therapy discontinued 24 16Reasons for discontinuing Therapy:

1. Insufficient Clinical Result .. 4 2-72. Major Complication from Hydro-

cortisone.2 1 33. Death from Causes Unrelated to

Hydrocortisone.5 3-34. Complication Unrelated to Hydro-

cortisone.1 0-75. Disease Remission.12 8

Complete.9 6Partial.3 2

(2) What overall results may be achieved fromprolonged hydrocortisone therapy? At the time ofanalysis, improvement was considered to be ade-quate or satisfactory in 59per cent. of patients and

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ANNALS OF THE RHEUMATIC DISEASESless than satisfactory in 41 per cent. Inadequatedegrees of improvement were noted in 62 patientsfor one or more reasons:

37 (62 per cent.) failed to respond satisfactorily toreasonable sized doses from the beginning oftreatment,

Thirteen (22 per cent.) were controlled well at first,but later improvement deteriorated and respon-siveness to the hormone diminished,

37 (62 per cent.) developed hormonal side-reactionswhich prohibited the use of optimally effectivedoses,

Five (8 per cent.) presented miscellaneous otherreasons for limited improvement.

Female patients fared almost as well as malepatients: inadequate improvement was recorded in42 per cent. of the former and in 39 per cent. of thelatter.

(3) What are the chieffactors which influence thesuccess of therapy? Apart from recognized cor-rectible mistakes in management (i.e. poor selectionof patients, inadequate supervision, improper dosageregulation, neglect of appropriate rest, and simplecomplemental measures such as avoidance of trauma,

jj ADEQUATE E INADEQUATE F8%

(39 CASES) (70 CASES) (41 CASES) (ISEVERE MODERATELY MODERATE

SEVEREFig. I.-Improvement on adequate and inadequate dosage in relation

etc.), which may lead to failure, it was apparentfrom this study that therapeutic results bore impor-tant relationship to two factors-the severity oractivity of the disease and the duration of arthritisbefore treatment.At the time of analysis improvement was graded

as adequate in 36 per cent. of patients with severe,57 per cent. of patients with moderately severe, and88 per cent. of patients with moderate disease(Fig. 1). In general, the same problem pertained aswith cortisone: for satisfactory control the moresevere cases all too often required excessive doseswhich could not be tolerated or which were con-sidered unsafe for long-term administration. Surely,statistical results would have been more favourablehad the series contained a larger percentage ofmoderate and some mild cases. As might beexpected, the remission rate was greater in patientswith moderate disease (l4 5 per cent.) than in thosewhose arthritis was moderately severe (7- 1 per cent.)or severe (0O-025 per cent.).

Percentagewise, results were most favourablewhen the arthritis was of relatively recent origin.Interestingly, the crucial point was about 2 years,and thereafter as the duration of disease lengthened,

the proportion of adequate responses,% lessened progressively (Fig. 2). Not sur-

prising was the finding that the remission41 rate was decidedly lower in patients whose

disease had been established more than 2IB1 years (4 per cent.) than when the duration

was 2 years or less (22 per cent.).8 S (4) What deterioration of improvement'150 CAtES) may be expected as treatment isprolonged?TOTAL Analyses made at intervals during theto severity of disease.

78%

H

14.

22%

79%._--

II.

21%

65%r_-

20

35%

(18 CASES) (14 CASES) (31 CASES)Less than I 1-2 3-5Duration of Disease before starting Treatment (years)

63%

22

LI ADEQUATE

37%

INADEQUATE

46%

,-p

24

54%

28

59%

'88

41 %

(35 CASES) (52CASES) ( 150 CASES)6-10 Over 10 Total

Fig. 2.-Improvement on adequate and inadequate dosage in relation to duration of disease before starting treatment (years).

l * o r rI I. I I 1.1110111.11 A-kIII

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ORAL HYDROCORTISONE IN RHEUMATOID ARTHRITIS

D ADEQUATE INADEQUATE

1081 9541f p471 175 1 L4 531 7 36 6 23 1 °/3 8 ,,

(150CASES) (142 CASES) (II7CASES) (90 CASES) (52 CASES) (33 CASES) (I5O CASES)6 9 12 is 24 25-36 Final

Duration of Therapy (months)Fig. 3.-Improvement on adequate and inadequate dosage in relation to duration of therapy (months).

period of observation revealed, as anticipated, that astreatment was continued over the months, the numberof patients showing adequate improvement becamesmaller. The figures (Fig. 3) may be confusing unlessit is understood that patients were added to the seriesas the study progressed and that others were droppedfrom time to time because of remission, insufficientbenefit, or other reasons. The disease was satis-factorily restrained in 72 per cent. of patients at theend of 6 months, but this percentage declined to59 per cent. at 18 months. At 24 monthsand later the number demonstrating satis- 44%factory control rose to around 70 per cent.;ythis is explained by the fact that the majorityof patients who became unresponsive ordeveloped unacceptable complications dis-continued the hormone within a 2-yearperiod. (39 CASEi

SEVER

the frequency of disease progression and the durationof the arthritis before therapy (Fig. 5).

It is impossible to judge with full assurance whatinfluence hydrocortisone therapy may have exertedon the natural course of the disease. There areno statistical data available with which to comparethe incidence or rate of disease progression in

E WITH

WITHOUT

34%

INTERFERENCE IN FUNCTIONAL CAPACITY

ES) (70CASES) (41 CASES) (ISOIE MODERATELY MODERATE T

Cchine T) CASES)7OTAL

(5) What influence does long-term hydro- SEVER

cortisone therapy have on the progress of the Fig. 4.-Disease progression in relation to severity of disease.disease ? Among the 150 patients, fifty (33per cent.) showed evidence of disease progression 40%during the observation period. Functional capacity 38% 38%was altered significantly by advancement of the 33%arthritis in 31 patients but not in the nineteen others. 29%The ability of steroid therapy to restraindisease progress varied indirectly with the Il%I MXseverity or activity of the rheumatoid 2 5 19arthritis. Clinical evidences of progression l I

were noted in 44 per cent. of severe cases, (ISCASES) (13CASES) (31 CASES) (35CASES) (53CASES) (150 CASES)34 per cent. of moderately severe cases, and Less than 1-2 3-5 6-10 Over 10 Total22 per cent. of moderate cases (Fig. 4). Duration of Disease before starting Treatment (years)An unexpected finding in patients of this Fig. 5.-Disease progression in relation to duration of disease before startingseries was a lack of correlation between treatment (years).

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ANNALS OF THE RHEUMATIC DISEASESuntreated or conservatively treated patients in aseries of similar composition. Furthermore, theperiods of observation in the present study wererelatively short (9 to 36 months) in respect to theaverage span of the disease. However, when con-sideration is given to the facts that the majority ofpatients (73 per cent.) suffered from severe ormoderately severe forms of rheumatoid arthritisand that they had already failed to respond satis-factorily to conservative management, the incidenceof disease progression seems smaller than mighthave been expected for a similar untreated series.The impression was gained that in cases amenableto hydrocortisone, advancement of the rheumatoidprocess may frequently be retarded during the periodof steroid administration, and perhaps more fre-quently than heretofore considered.

(6) How satisfactory is hydrocortisone as a long-term treatment agent for rheumatoid arthritis ?Orally administered, hydrocortisone must be re-garded as a very valuable agent in the managementof selected cases of rheumatoid arthritis. It pro-motes a high rate of immediate therapeutic responseand, with relatively low maintenance doses, it iscapable of providing continuous, adequate controlof the rheumatic manifestations in a significantpercentage of cases. Nearly 60 per cent. of patientsin the present series, whose arthritis was unsuccess-fully regulated by measures other than steroidtherapy, were held in major improvement by thedrug during observation periods ranging from 9 to36 months. Though benefits were less than desired,varying amounts of helpful relief and enhancedfunctional capacity were furnished to many patientsin the remaining 40 per cent.

Nevertheless, hydrocortisone is far from an idealtherapeutic agent for rheumatoid arthritis. Apartfrom its main deficiency, that of having suppressiverather than curative action, it has, like cortisone,many serious shortcomings. Among these may belisted:

(1) The intervention of hormonal side-effects whichserve to limit dosage and often satisfactorymanagement, especially in patients with moresevere or long-established disease whose dailyrequirements for the drug are large;

(2) The tendency to aggravate certain co-existingpathological conditions, which contra-indicateits use;

(3) The decrease in responsiveness and improvementin some patients after prolonged administration;

(4) The frequent failure of the hormone to preventprogression of the disease during treatment.

Thus, until a cure for rheumatoid arthritis is found,there is need for an agent which, on systemic

administration, will suppress the disease moresuccessfully over long periods and in a higher pro-portion of patients. A steroid with wide disparitybetween its anti-inflammatory power and its ten-dency to produce unwanted effects would partiallyfulfil this need. That it may be possible to preparesuch compounds is suggested by a number ofencouraging new developments, which have shownthat modifications in the chemical structures ofhydrocortisone and cortisone may attenuate thosephysiological actions which lead to troublesomecomplications.

SummaryThe results of prolonged oral hydrocortisone

therapy (9 to 36 months) in 150 consecutive patientswith active peripheral rheumatoid arthritis wereanalysed. The following pertinent statistical in-formation was derived:

(1) At the time of analysis, treatment with the hormonehad been discontinued in 24 patients (16 per cent.) forthe following reasons: insufficient clinical response infour (2-7 per cent.); major complications in two (1-3per cent.); complications unrelated to hydrocortisonein one (0 7 per cent.); death from extraneous causes infive (3 3 per cent.); remission in twelve (8-0 per cent.).

(2) Improvement was considered as adequate in 59 percent. of patients and less than satisfactory in 41 per cent.at the time of analysis.

(3) The chief factors which influenced the success oftherapy were the severity or activity of the disease andthe duration of arthritis before treatment. At analysis,improvement was graded as adequate in 36 per cent.with severe disease, 57 per cent. with moderately severedisease, and 88 per cent. with moderate disease. Resultswere more favourable when the arthritis was of relativelyrecent origin; the crucial duration was about 2 years,and thereafter as duration lengthened the proportionof adequate response lessened.

(4) As time went on, fewer patients showed adequateimprovement. The disease was restrained satisfactorilyin 72 per cent. at 6 months and in 59 per cent. at I8months.

(5) Fifty of the 150 patients (33 per cent.) showedevidence of disease progression during the observationperiod. Functional capacity was not reduced signi-ficantly by advancement of the arthritis in 19 of them,but was altered in the remaining 31 patients.The following conclusions were drawn:Although hydrocortisone is a very valuable agent in

the management of selected cases of rheumatoid arthritis,it is far from an ideal suppressive agent. Like cor-tisone, it has many shortcomings, chief among whichare the intervention of hormonal side-effects, especiallywhen dosage requirements are large; the tendency toaggravate certain co-existing pathological conditions;the development of unresponsiveness in some patientsafter prolonged administration; the failure to preventdisease progression in an appreciable percentage of cases.

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ORAL HYDROCORTISONE IN RHEUMATOID ARTHRITISThus, until a cure for rheumatoid arthritis is found,

there is still need for an agent which will suppress thedisease more successfully. That such a compound maybe forthcoming is suggested by recent discoveries ofsteroids related to hydrocortisone and cortisone whichpossess wider dissociation the anti-inflammatory pro-perties and the other unwanted physiological activities.

REFERENCESBoland, E. W. (1952a). Brit. med. J., 1, 559.

(1952b). Calif. Med., 77, 1.(1952c). J. Amer. pharm. Ass. (Pract. Pharm. ed.), 13, 540.

-(1952d). J. Amer. med. Ass., 150, 1281.(1953a). Merck Rep., 62, No. 2, 12.(1953b). Annals of the Rheumatic Diseases, 12, 125.

-(1954). Med. Clin. N. Amer., 38, 337.-, and Headley, N. E. (1952). J. Amer. med. Ass., 148, 981.Bush, I. E. (1951). J. Physiol., 112, lOP.Conn, J. W., Louis, L. H., and Fajans, S. S. (1951). Science,

113, 713.Hechter, 0. (1950). Fed. Proc., 9, 58.

Zaffaroni, A., Jacobsen, R. P., Levy, H., Jeanloz, R. W.,Schenker, V., and Pincus, G. (1951). Prog. Hormone Res.,6, 215.

Hench, P. S., Kendall, E. C., Slocumb, C. H., and Polley, H. F. (1950).Arch. intern. Med., 85, 545.

Ingle, D. J., and Kuizenga, M. H. (1945). Endocrinology, 36, 218.Jacobsen, R. P., and Pincus, G. (1951). Amer. J. Med., 10, 531.Mason, H. L. (1950). "Urinary Excretion of Steroids during

Administration of ACTH." In "Clinical ACTH Conference,Proceedings of the First Meeting", ed. J. R. Mote, p. 168.Blakiston, Philadelphia.

Pabst, M. L., Sheppard, R., and Kuizenga, M. H. (1947).Endocrinology, 41, 55.

Pincus, G. (1950). "Adrenal Cortex: Trans. First Conference,New York, Josiah Macy, Jr., Foundation, 1949", p. 47.

Reich, H., Nelson, D. H., and Zaffaroni, A. (1950). J. biol. Chem.,187, 411.

Savard, K., Kolff, W. J., and Corcoran, A. C. (1952). Endocrinology,50, 366.

Hydrocortisone par voie buccale dans l'arthriterhumatismale

REsuMEOn analysa les resultats du traitement prolongs

(9 a 36 mois) A I'hydrocortisone par voie buccale de 150malades consecutifs atteints d'arthrite rhumatismaleperipherique. On obtint des donnees statistiquespertinentes que voici:

(1) Au temps de l'enquete, le traitement a l'hormone setrouvait interrompu chez 24 malades (16 %) pour des raisonssuivantes: r6ponse clinique insuffisante 4 (2 7%); complica-tions majeures 2 (1-3%); complications independantes del'hydrocortisone 1 (0- 7 %); morts de causes differentes5 (3-3%); remission 12 (80o).

(2) A l'heure de l'enquee, I'amelioration fut consideredsatisfaisante chez 59 0 des malades et moins que satisfaisantechez 41 %.

(3) L'issue du traitement dependait de deux facteursprincipaux: la severite ou bien l'activite de la maladie etla duree de l'arthrite avant le traitement. A l'enquete ona classes 36% des malades graves, 57°0 des assez graves et88 % des moderement atteints parmi les ameliores d'unemaniere satisfaisante. Les resultats ont e plus favorablesdans l'arthrite relativement recente, avec une duree critiquede deux ans a peu prms, apres quoi la proportion des ameliora-tions satisfaisantes diminuait au fur et A mesure quel'anciennete de l'arthrite augmentait.

(4) Avec le temps, le nombre d'ameliorations satis-faisantes diminuait. La maladie se trouvait jugulee dans72 % des cas au bout de 6 mois et dans 59 % des cas seule-ment au bout de 18 mois.

(5) Chez 50 (33 %) malades sur 150 au cours de la periodesous observation on a note des signes devolution de lamaladie. Chez 19 d'entre eux 1'aggravation de l'arthriten'a pas entrained de reduction appreciable de la capacityfonctionnelle, mais elle l'a altered chez les 31 restants.On tire des conclusions suivantes:Bien que l'hydrocortisone soit un moyen tres utile

dans le traitement des cas determines d'arthrite rhuma-tismale, elle est loin d'etre un agent ideal de suppression.Comme la cortisone, elle a ses defauts dont le principalest le pouvoir de provoquer des reactions endocrinessecondaires, surtout lorsqu'on doit administrer desdoses elevees; elle tend A aggraver certains etats morbidescoexistants; certains malades cessant A repondre A sonadministration prolongee et dans un nombre appreci-able des cas elle n'arrive pas A arreter l'evolution de lamaladie.

I1 s'en suit, qu'a moins qu'on trouve une cure, on auratoujours besoin d'un moyen plus satisfaisant pourjuguler l'arthrite rhumatismale. La decouverte recentedes steroides apparentes A l'hydrocortisone et A lacortisone, dans lesquels le pouvoir anti-inflammatoireet certaines proprietes physiologiques indesirables setrouvent plus dissocies, semble indiquer qu'un tel moyenne se fera pas attendre.

Hidrocortisona por via oral en la artritis reumatoideSUMARIO

Se analizaron los resultados de tratamiento prolongado(9 a 36 meses) con hidrocortisona por via oral de 150enfermos consecutivos con artritis reumatoide peri-ferica. Los siguientes datos estadisticos pertinentesfueron obtenidos:

(1) Al tiempo del analisis, en 24 enfermos (16%) se dej6el tratamiento hormonal por razones siguientes: respuestaclinica inadecuada, 4 (2 7%); complicaciones mayores,2 (1 3 %); complicaciones independientes de la hidrocor-tisona, uno (0 7%); muertos de causas arenas, 5 (33°/);remisi6n, 12 (8%).

(2) Al tiempo del analisis, la mejoria se juzg6 satis-factoria en el 59°0 de los e4nfWvsyy --poosatisfactoria enlos demas 41 %.

(3) El exito del tratamiento dependi6 de dos factoresprincipales: la severidad o la actividad de la enfermedady la duraci6n de la artritis antes del tratamiento. En elanalisis el 36 % de los enfermos graves, el 57 % de los bastantegraves y el 88 % de los moderados fueron clasificados comosatisfactoriamente mejorados. Los resultados fueronmejores en la artritis relativamente reciente, con duraci6ncritica de dos afios aproximadamente; luego, la proporci6nde las mejorias satisfactorias bajaba a medida que la anti-quedad de la artritis aumentaba.

(4) El numero de las mejorias satisfactorias disminuiacon el tiempo. La enfermedad estaba contenida en un 720de los casos a cabo de seis meses y en un 59°0 solamentedespues de dieciocho meses.

(5) Durante el periodo de observaci6n se notaron signosde evolution en 50 de los 150 enfermos. En 19 de ellos laagravaci6n de la artritis no fue seguida de reducci6napreciable de la capacidad funcional, alterada en los demas 31.

Se lleg6 a las conclusiones siguientes:Aunque la hidrocortisona sea un medio muy uitil en

el tratamiento de casos determinados de artritis reuma-toide, le falta mucho para ser un agente represivo ideal.Como la cortisone, tiene sus defectos entre los cualesse destaca su propiedead de causar reacciones hormonalessecundarias, en particular cuando se necesitan dosiselevadas; su tendencia a agravar ciertas afeccionescoexistentes; algunas enfermedades dejan de respondera su administraci6n prolongada y, en un nuimero apreci-able de casos, no llega a contener la evoluci6n m6rbida.

Asi pues, a menos de hallar una cura, un medio massatisfactorio para contener la arthritis reumatoide auinnos hace falta. La reciente descubierta de esteroidesrelacionados con la hidrocortisona y la cortisone, enlos cuales el poder anti-inflamatorio y ciertas propie-dades fisiol6gicas indeseables estan disociadas pareceindicar que la descubierta de un tal medio no esta lejos.

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