Ann. rheum. Dis. (1961), 20, 274.

TREATMENT OF RHEUMATOID ARTHRITIS BY

INTRAMUSCULAR TRIAMCINOLONE ACETONIDE

AND TRIAMCINOLONE DIACETATE

BY

JACK ZUCKNER

Section on Arthritis, Department of Medicine, Saint Louis University School of Medicine and the UniversityHospital (Firmin Desloge Hospital), Saint Louis, Missouri

The results of a study (Zuckner, 1961) evaluatingthe therapeutic response of intra-articularly ad-ministered triamcinolone acetonide* (hereafter refer-red to as TActn) and triamcinolone diacetate*(TDac) suggested that large doses of these hormoneshad a profound systemic effect. The injection ofeither of these hormones in a dose of 100 mg. intoa knee joint affected by rheumatoid arthritis resultedin a generalized anti-inflammatory response, includ-ing improvement in other inflamed joints as well asthat injected. This generalized improvement usuallypersisted for 2 to 3 weeks. These favourablefindings led to further study with these steroids,utilizing the more practical intramuscular route ofadministration.

Procedure

The acetonide and diacetate derivatives oftriamcinolonewere injected intramuscularly into 36 patients withrheumatoid arthritis. There were 112 injections, 68of TActn and 44 of TDac. The dose per injection was100 mg. These steroids were compared with hydro-cortisone acetate (FAc) given by intramuscular injectionin the same patients; there were seven injections of the100 mg. dose of FAc, and eleven of 500 mg.

Patients were examined once a week at first in mostinstances, less often later. Subjective improvement inpain and stiffness and objective evidence of tenderness,heat, swelling, range of motion, capsular thickening,and fluid in involved articulations were determined andan estimated composite percentage recorded. Thesesigns and symptoms were evaluated at each visit. Theinterval between injections was usually determined by thepatient's subjective response, particularly the mani-festation of pain. An effort was made to maintain at

* Supplied by Lederle Laboratories Division, American CyanamidCompany, Pearl River, New York.

least 50 per cent. improvement as determined by theestimated composite figure. The triamcinolone steroidswere administered in rotation for the most part.

Clinical evidence of toxicity was sought at each visit.Observations were made for moon facies, hirsutism,ecchymoses, blood pressure changes, body weight,oedema, and other possible alterations. Laboratoryprocedures included urine analyses, blood counts, anderythrocyte sedimentation rates (Westergren). Thesewere performed at varying intervals, usually the day ofan injection and one week later at the beginning of thestudy, and less frequently afterwards.

Other therapeutic measures were continued withoutmodification with the exception of orally-administeredsteroids. 23 patients were receiving such medicationwhen the study was instituted, and an additional threepatients were taking steroids orally at other times duringthe study. In nineteen individuals the oral dose ofsteroid was lowered, and in ten of these it was completelydiscontinued. 28 patients were receiving gold salttherapy (gold sodium thiomalate or gold thioglucose);in eight of these individuals the gold was begun at thetime of the first steroid injection. Twelve patients hadalready received more than 700 mg. gold salt beforethe first intramuscular injection of a triamcinolonederivative; in two others, the total dose of gold salt wasbetween 500 and 600 mg. at the start of the study.The duration of observation varied; seventeen patients

were studied for 100 or more days, and six of these forapproximately one year. The remaining nineteen patientswere observed for an average of about 70 days each.

Results

The anti-inflammatory response to intramuscularinjections of triamcinolone acetonide (TActn) andtriamcinolone diacetate (TDac) was satisfactory inmost patients. Improvement was considered satis-factory if there was at least 50 per cent. relief ofthe non-permanent clinical manifestations of the

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INTRAMUSCULAR TRIAMCINOLONE

disease for a period of 7 or more days after aninjection. 83 per cent. of the patients showed suchbenefit at some time during treatment with TActnand 80 per cent. had similar results with Thac(Table I). When the results of individual injectionswere analysed, approximately 73 per cent. ofinjections with either TActn or TDac were followedby a satisfactory response. The average durationof improvement after an injection was 20-2 and16 2 days for TActn and TDac respectively; themaximum period of relief after an injection was69 and 75 days respectively. When these resultswere compared with those which followed theintramuscular injection of hydrocortisone acetate(FAc) in doses of 100 and 500 mg., the latter steroidproved inferior (Table I). The 100-mg. dose ofFAc was almost completely ineffective by com-parison, and the 500-mg. dose gave significantlypoorer results. The average duration of improve-ment with the 500-mg. dose of FAc was 5-2 days,and six injections were followed either by noimprovement or by not more than 3 days of benefit.The maximum period of relief was 17 days with this500-mg. dose. The 100-mg. dose of FAc wasfollowed by an average of 1 1 days of improvement.

TABLE I

RESULTS WITH INTRAMUSCULAR INJECTIONS OF TRI-AMCINOLONE ACETONIDE (TActn), TRIAMCINOLONEDIACETATE (TDac), AND HYDROCORTISONE ACETATE

(FAc) IN PATIENTS WITH RHEUMATOID ARTHRITIS

Drug.TActn TDac FAc

Dose (mg.)..100 100 100 500

No. of Injections .. 68 44 7 11

Average Duration of Improve-ment (days).20-2 16*2 1*1 5 *2

Maximum Improvement (days) 69 75 5 17

Injections with No. .. 50 32 0 4Satisfactory iImprovement Per cent. 73 5 72-7 0 36

A comparison of the relative efficacy of the tri-amcinolone derivatives in individual cases was madein fourteen patients who received at least twoinjections each of TActn and TDac. Fewerinjections in a patient were not satisfactory forevaluation because of the wide variability in im-provement sometimes observed from one injectionto the next. Thus, it was possible for one injectionof either of the triamcinolone steroids to give verysatisfactory results, and for this to be followedby a very poor response to the next injection of thesame drug. Causative factors for this variability in

response (such as an obvious change in the courseof the disease or an increase in physical activity)were not apparent. In patients in whom suitablecomparisons were made, ten derived greater benefitfrom TActn, and four had more improvementfrom TDac.

Patients receiving gold salts simultaneously withintramuscular steroid therapy were divided intotwo groups for analysis:

(1) Those who were either beginning gold salttherapy or who had received a total doseof less than 700 mg. when intramuscularsteroid injections were started;

(2) Those who had a total dose greater than700 mg. during the period of intramuscularhormone administration.

Four patients initially in the first group (less than700 mg.) had received enough gold salt by the endof the study to fall into the second group (more than700 mg. gold salt) making a total of sixteen patientsin each group. This division into two groups wasdone to evaluate any possible effect of gold saltson the results. The separation at the 700-mg.total dose level was selected on the assumption thattotal doses greater than this would be less likely toinfluence the improvement attained from oneinjection of steroid to the next. There were 23injections of TActn and fifteen injections of TDacin the group that received less than 700 mg. gold saltand these resulted in improvement after each intra-muscular steroid injection averaging 23-4 and 15 9days respectively. In the second group, there were31 injections of TActn which resulted in an averageduration of improvement after each injection of19 days, and twenty injections of TDac, followedby improvement averaging 16 6 days. Simul-taneous treatment with gold salts apparently had nosignificant effect on the results.The average daily maintenance dose of orally

administered steroids at the beginning of the studywas equivalent to 7- 5 mg. triamcinolone (freealcohol form, hereafter referred to as triamcinolone).Sixteen patients were receiving triamcinoloneorally, three dexamethasone, two prednisone, andtwo 6-methyl prednisolone. Dosages of the lattersteroids were converted to triamcinolone dosagesfor evaluation purposes, using the following dosageratios:triamcinolone: dexamethasone: prednisone: 6-methyl prednisolone

4 05 5 4

At the end of the period of observation, theaverage daily maintenance dose was equivalentto 4 mg. triamcinolone.

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ANNALS OF THE RHEUMATIC DISEASESThe total daily steroid dose, that is, the daily oral

maintenance dose plus the daily intramuscular dose(the latter obtained by dividing the dose of steroidinjected intramuscularly by the days of satisfactoryimprovement) was determined at the end of thestudy and compared with the daily oral maintenancedose initially. To balance the doses of TActnand TDac, it was assumed that these steroids whengiven intramuscularly were equivalent mg. for mg.to the orally-administered free alcohol form oftriamcinolone. Thus, of nineteen patients in whoman attempt was made to lower the oral steroid dose,there were ten in whom the total oral plus intra-muscular dose daily at the end of the study wasgreater than the original oral dose daily; and intwo the comparative doses for each period wereequal. In seven patients the total oral plus intra-muscular dose daily at the end of the period ofobservation was less than the daily oral dose at thebeginning. These seven patients had a daily oralmaintenance dose of triamcinolone initially of7-3 mg. as compared with the combined oral plusintramuscular dose daily at the termination of thestudy of 4-5 mg.The onset of improvement after the intramuscular

administration of TActn and TDac was usuallyfirst noted on the morning after an injection. Attimes, patients described improvement beginning3 to 5 hours after an injection, and less frequently,48 hours after an injection. In some cases theimprovement was gradual over a few days, but mostoften, maximum improvement developed by theday following the injection and then would persistas such for approximately 2 to 3 weeks.

Eleven patients showed marked subjective andobjective improvement as compared with resultsfrom previous methods of therapy, including rela-tively much larger doses of steroids administeredorally in some. One patient (A.R.A. Classi-fication II, III: Steinbrocker, Traeger, and Batter-man, 1949) has been free of objective evidence ofsynovitis and almost completely asymptomatic fora period of 70 days after only one injection ofTActn, whereas, she previously had marked (3+)activity and synovitis continuously for 3 yearsbefore the injection.The side-effects of TActn and TDac injected intra-

muscularly are recorded in Table II (opposite).Many of these are similar to those noted with orallyadministered steroids. Since 23 patients were takingsteroids orally at some time during the study, it wasdifficult to evaluate hormonal reactions in theseindividuals as those due specifically to the intra-muscular preparations. To overcome this difficulty,different categories are tabulated regarding the

dose of steroid both before and during the study.It is noted that not all injections resulted in similarreactions in the same individual. Thus, only sixout of twenty injections of TActn or TDac in fourpatients resulted in euphoria. In one of theseindividuals, the euphoria developed within 2 minutesafter an injection and was associated with a "hot"feeling in the abdomen, suggesting possible entranceof the steroid into the systemic circulation at thetime of injection. This reaction lasted 3 hours.Nine out of fifteen injections in four other patientsresulted in a diuresis, usually beginning severalhours after an injection and, at times, persistingfor 3 to 4 days. When the period of anti-inflam-matory improvement had run its course in theselatter patients, those who had noted previous ankleoedema found that some swelling returned at thetime of worsening, only to be relieved again by asubsequent intramuscular injection of TActn orTDac.Marked weakness, nausea, and vomiting occurred

in one individual about 10 days after each of twoinjections. These manifestations lasted 2 to 3 daysand coincided with worsening of the joint findingsafter an initial 10-day period of improvement.Another patient described marked weakness, tired-ness, and dyspnoea after each of three injectionsoccurring simultaneously with the reappearance ofincreased synovitis following 10 days of satisfactoryimprovement. Two injections in this last patientwere not followed by these symptoms. In eachinstance relief was obtained by another steroidinjection. It was not possible to obtain biochemicalproof of possible adrenal insufficiency in these cases.Electrolyte determinations of Na, K, and C1 per-formed at the time of one of the episodes of vomitingin the first individual gave normal results.The features of moon facies, ecchymoses, and

hirsutism are also tabulated. There were fewerecchymoses in two patients and less moon faciesin three as compared with the previous period of oralsteroid therapy. In only one of three patients withless moon facies was the total daily dose of oral plusintramuscular steroid less than the daily dose oforal steroid originally.

Epigastric burning developed in one case; this didnot occur previously while the patient was takingsteroids by mouth. In another patient, there wasless epigastric burning during the period of intra-muscular steroid therapy; in this patient it waspossible to lower the oral dose of dexamethasone,but the total daily dose of steroid was still greaterthan the previous oral dose alone. The loweringof the dexamethasone dose may have been respon-sible for the decreased gastrointestinal symptoms.

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277INTRAMUSCULAR TRIAMCINOLONETABLE It

SIDE-EFFECTS OF INTRAMUSCULAR THERAPY WITH TActn AND TDac

Total Daily Dose of Oral

ReactionsNo. of Patients Total Number of plus Intramuscular SteroidsReactions | Patients on Oral No. of Injections Compared with PreviousAffected Steroids Injections followed by Oral Doses

ReactionsGreater Equal Less

Euphoria .. 4 3 20 6 3 -

Diuresis.4 3 15 9 1 1 1

Muscle Cramps.2 2 9 2 1 - I

Questionable Adrenal Insufficiency 2 0 7 5 -

Irritability and "Nervousness"..2 2 6 3 2

Severe Pain locally after an Injection 1 1 5 1 - - 1

Flushes.1 0 3 1 i _ _

Dizziness and Nausea shortly after an Injection 12 1 1 - -

Abdomen "Hot", and Euphoria shortly after anInjections 0 5 1

-. .

Reaction to Oral plus Intramuscular Steroid Therapy combined as compared with Oral Steroid Therapy Alone

More .. 1 1 2 1 -

Ecchymoses. Same .. 9 9 27 6 2 1Fewer 2 2 7 - - 2

Greater. 5 5 20 5 - -

Moon Facies Same .. 6 6 18 4 1 ILess 33 3 9 1 1 I

Hirsutism.More .. 1 1 7 1 - -

Same 22 2 8 1 - I

Epigastric Burning.Greater 1 1 5_Less 1 1 2 1 - -

Appetite .Same .. I1 1 3 1 - -Improved 1 1 5

Another patient had anorexia and lost 27 lb. whilereceiving oral triamcinolone in a maintenance doseof 8 mg. daily. During the period of intramuscularsteroid therapy in this patient, no steroids were givenorally; her desire for food returned, and she gained7 lb. over a 3-month period.

Coincident with improvement was a decrease inthe erythrocyte sedimentation rate in most patientstested. When the beneficial effects of the hormonewere no longer present, the sedimentation rateusually rose again in conjunction with clinicalworsening. Leucocytosis also appeared after manyinjections. No glycosuria was detected. Bloodpressure elevation was not encountered with onepossible exception; this patient had a history ofhypertension before the study, but had had onlyone recorded blood pressure as a control (132/88).Subsequent values during the next 6 months ofintramuscular steroid therapy averaged about200/116. During this interval she had seven intra-muscular injections of TActn and TDac. In the

past month reserpine and chlorothiazide have beenadministered, and the blood pressure has fallento 160/110.

This intramuscular method of steroid adminis-tration was discontinued in nine patients for thefollowing reasons: inadequate or no improvement-five; no further need for steroids-two; patientcontact lost-two. Two of the five patients withunsatisfactory improvement had sufficient "irrit-ability and nervousness" to also warrant the dis-continuation of therapy.

DiscussionThe aim of much research in the field of rheumatic

diseases in the past several years has been to obtainsteroids with greater anti-inflammatory action butwith fewer side-effects. The most recent oralpreparations, triamcinolone free alcohol (or tri-amcinolone), 6-methyl-prednisolone, and dexa-methasone, offer certain advantages, but are asso-ciated with undesirable physiological reactions

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similar in many respects to those of the originallyintroduced anti-rheumatic hormones. No oralpreparation combining a good anti-inflammatoryresponse with relatively minor toxicity is yet avail-able. The possibility of administering steroidsintramuscularly in an attempt to obtain a satis-factory response with fewer or less severe side-effects has been examined in this study. Oneinvestigator (West, 1958) has previously reported hisexperiences with intramuscular injections of pred-nisolone acetate in the treatment of rheumatoidarthritis. He administered the steroid at regularweekly intervals for periods of 16 to 45 weeks. Hispatients derived satisfactory improvement from thistreatment, and, in some instances, had a decrease ingastric disturbances.

In this study 100-mg. doses of triamcinoloneacetonide (TActn) and triamcinolone diacetate(TDac) gave marked systemic responses wheninjected intramuscularly. Relief of both subjectiveand objective rheumatic manifestations as regardspain, stiffness, range of motion, and degree ofsynovitis was very striking in the majority of in-stances with either of these preparations. Theimprovement usually persisted at a satisfactorylevel for 2 to 3 weeks after a single injection. Theduration of improvement was usually greater follow-ing an injection of TActn than of TDac, the reverse

being true significantly less often. Improvementfrom intramuscular injections of the triamcinolonederivatives was far greater than the benefit derivedfrom intramuscular injections of hydrocortisoneacetate (FAc) in 100- or 500-mg. doses.

In an attempt to explain the difference in responseto these hormones, one might question the relativeequality of the doses as used in this study. Was100 mg. TActn equal to 100 mg. TDac? Werethese latter doses equivalent to 500 mg. FAc?Triamcinolone and FAc when administered orallyhave an anti-inflammatory ratio of 5: 1 whenequal weights are compared; but there has been noevaluation of the relative effectiveness of these drugswhen administered intramuscularly. The authorhas not found any description in the literature of thecomparative efficacy of intramuscular doses of tri-amcinolone, TActn, and TDac. Preliminary studies(Zuckner, 1961) with the intra-articular administra-tion ofTActn and TDac revealed no significant differ-ence in local anti-inflammatory response between the20-mg. dose of TActn and the 25-mg. dose of TDac.However, the minimal effective dose of each prepara-tion was not determined and, therefore, basic doselevels were not compared. Animal studies byRingler, Bortle, Heyder, Monteforte, Perrine, andRoss (1959) indicated that TActn was 21 times as

potent as hydrocortisone for liver glycogen deposi-tion in rats when injected subcutaneously, and 167times as potent as hydrocortisone when adminis-tered orally. Liver glycogen deposition was sixtimes greater with subcutaneously administeredtriamcinolone than with hydrocortisone, and 42times greater with oral administration than withhydrocortisone. These values for triamcinolonewere lower than those previously reported byPerrine, Bortle, Heyder, Partridge, Ross, andRingler (1959). When thymus involution in ratswas studied by Ringler and others (1959), TActninjected subcutaneously was 29 times more potentthan hydrocortisone, and 75 times more potentthan hydrocortisone when both drugs were givenorally. It is, therefore, possible that the differentanti-rheumatic responses to the intramuscularinjection of TActn, TDac, and FAc could beexplained at least in part by inequalities of dosagesince relative dosages have not been clearly evalu-ated. Other factors, however, have to be con-sidered.

It is interesting to speculate on the significantlygreater duration of improvement which followedintramuscular injections of the triamcinolonederivatives as compared with FAc. Is this greaterimprovement due to a depot effect of TActn andTDac, whereby the hormone is slowly releasedinto the circulation over the period of sustainedimprovement? This suggested depot mechanismrequires evaluation, but its substantiation may haveto await the availability of isotopically labelledtriamcinolone or, perhaps, an adequate method ofmeasuring blood levels of triamcinolone in order tofollow the absorption of the injected material. Apartial answer may be derived by studying the bloodlevels of 17-hydroxycorticoids after an injection ofTActn or TDac. One such experiment (Zuckner,1961, unpublished) was performed in a rheumatoidpatient after a 100-mg. intramuscular injection ofTDac. This subject did not show an anti-inflam-matory response to the injection. An initial sup-pression of the 1 7-hydroxycorticoid level in theblood was noted within 4 hours, with a subsequentreturn to normal values 7 days later. The adrenalcortex was evidently suppressed for approximately7 days, but interpreting this in terms of absorptionrates is hazardous.Another possible explanation of the greater

improvement with TActn and TDac might berelated to the initial massive steroid dose employed.This would imply that a sudden high level ofhormone in the blood would have a greaterphysiological effect than a prolonged lower level.This has proved to be a vital factor in certain

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experimental conditions as, for example, in theproduction of Alloxan diabetes in rats (Lazarow,1946; Gomori and Goldner, 1945). A suddenhigh blood level of the agent might cause a greatereffect in cells that have a greater avidity for thematerial than in other cells in the body. Theinflammatory cells in synovial tissue probablywould have an increased permeability and so mightabsorb large molecules much more rapidly. Inorder to get enough steroid into inflamed cells, ahigh concentration for a short time might be moreapt to overcome the cell wall barrier than a moreprolonged lower level. Another considerationwould be that, if the agent is inactivated rapidly,it must be able to act before inactivation occurs;higher blood levels would then be more likelyto provide the opportunity for the action to takeplace than prolonged lower blood levels.

This intramuscular method of administeringsteroids, in particular TActn and TDac, offeredcertain advantages and partially satisfied thecriteria for a more effective anti-inflammatory drug.In approximately 25 per cent. of the patients thedisease was controlled on a smaller daily main-tenance intramuscular dose of steroid than that givenorally before this study. Six individuals who hadtaken steroids orally for prolonged periods had betterand more sustained relief from the intramuscularinjections of TActn and TDac, and were maintainedon this latter therapy alone. In eight others, thecombination of oral and intramuscular steroidtherapy proved more beneficial than the oral medica-tion by itself; the oral dose in these patients wasgradually decreased, but was supplemented byoccasional intramuscular injections of TActn orTDac. Nine patients who had never taken steroidspreviously were adequately controlled by intra-muscular injections of TActn and TDac. Toxicitywas generally the same as that seen with previoushormone therapy. In two patients there werefewer ecchymoses and, in three, less moon faciesduring the period of parenteral therapy. Thosewho developed a greater degree of moon facies andmore ecchymoses while on the study were receivingrelatively larger daily doses of steroid and would,therefore, have been expected to show more ofthese changes. Euphoria was the only complicationin slight excess as compared with the previouscontrol period of oral steroid medication, but thiswas not severe enough to require discontinuationof treatment. The period of observation was notsufficiently long to study other reactions associatedwith steroid therapy, such as osteoporosis and pepticulceration. Further evaluation will be necessary todetermine the true incidence of toxicity. These

preliminary findings suggest that fewer side-effectsoccur in some cases with this intramuscular methodof administration than with oral administration.

Summary

Triamcinolone acetonide (TActn) and triamcino-lone diacetate (TDac) were injected intramuscularlyin 100-mg. doses into 36 patients with rheumatoidarthritis. There were 68 injections of the acetonidederivative and 44 of the diacetate. Satisfactoryimprovement lasted an average of 20-2 days afteran injection of triamcinolone acetonide and 16 2days after an injection of triamcinolone diacetate.The results from this form of treatment comparedvery favourably with those from previous oralsteroid administration, and in approximately 25 percent of cases was more satisfactory. Undesirableside-effects were possibly slightly diminished, but afurther long-term study would be required for finalevaluation.

REFERENCES

Gomori, G., and Goldner, M. G. (1945). Proc. Soc.exp. Biol. (N. Y.), 58, 232.

Lazarow, A. (1946). Ibid., 61, 441.Perrine, J. W., Bortle, L., Heyder, E., Partridge, R.,

Ross, E. K., and Ringler, I. (1959). Endocrinology,64, 437.

Ringler, I., Bortle, L., Heyder, E., Monteforte, A.,Perrine, J. W., and Ross, E. K. (1959). Proc.Soc. exp. Biol. (N. Y.), 102, 628.

Steinbrocker, O., Traeger, C. H., and Batterman, R. C.(1949). J. Amer. med. Ass., 140, 659.

West, H. F. (1958). Ann. rheum. Dis., 17, 273.Zuckner, J. (1961). Unpublished observations.

Traitement de l'arthrite rhumatismale par des injectionsintramusculaires d'acetonide de triamcinolone et de

diacetate de triamcinolone

REsuME

On administra par voie intramusculaire l'acetonidede triamcinolone (TActn) et diacetate de triamcinolone(TDac) en doses de 100 mg. a 36 malades atteintsd'arthrite rhumatismale. En tout, on donna 68 injec-tions du d&eiv acetonide et 44 injections du derivediacetate. Une amelioration satisfaisante persista enmoyenne pendant 20,2 jours apres l'injection d'acetonidede triamcinolone et pendant 16,2 jours apres l'injectionde diacetate de triamcinolone. Les resultats de cetteforme de traitement ne le cedent en rien A ceux obtenusauparavant par administration orale des stWroldes, etdans 25 pour cent des cas ils furent plus satisfaisants.Les effets secondaires furent peut-etre moins accuses,mais des recherches ulterieures seraient necessaires pourune evaluation finale.

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280 ANNALS OF THE RHEUMATIC DISEASESTratamiento de la artritis reumatoide por administraci6n mejoria perdur6 un termino medio de 20,2 dias despuesintramuscular de acetonido de triamcinolona y de diacetato de la inyecci6n de acet6nido de triamcinolona y 16,2

de triamcinolona dias despues de la de diacetato de triamcinolona. Los

SUMARIO resultados de esta forma de tratamiento no fueroninferiores a los obtenidos anteriormente por adminis-

Se administraron intramuscularmente acetonido de tration oral de esteroides, y en un 250o de los casostriamcinolona (TActn) y diacetato de triamcinolona fueron mas satisfactorios. Efectos colaterales indese-(TDac) a dosis de 100 mg. a 36 enfermos con artritis ables fueron quizas algo menores, pero para una valora-reumatoide. Fueron practicadas 68 inyecciones de ci6n final son necesarios estudios ulteriores a largoderivado acetonido y 44 del diacetato. La satisfactoria plazo.

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