DexamethasoneAntirheumatic properties hormonal effects and adverse reactions A 16 month study.код для вставкиСкачать
Dexamethasone : Antirheumatic Properties, Hormonal Effects and Adverse Reactions (A 16 Month Study) By ROGER L. BLACK, WILLIAME. REEFE,JOHNR. DAVID, KURTJ. BLOCH, GEORGE E. EHRLIMAND JOSEPH J. BUNIM Dexamethasone has been administered for 8 to 16 months (0.5 to 4.0 mg. daily), with satisfactory antirheumatic response in 20 of 27 patients with rheumatoid arthritis. This compound has been found to be the most potent anti-inflammatory corticosteroid thus far produced. It suppresses ACTH and possibly thyroid-stimulating hormone production by the anterior pituitary. Thyroid function, as measured by radioactive iodine uptake, was reduced in 11 of 19 patients during dexamethasone administration. The most common side effect in this group was striking weight gain-more than 4 Kg. in 19 patients. Three patients experienced pathologic fractures and one, a peptic ulcer during dexamethasone therapy. There were two deaths during the period of study. Dexamethasona esseva administrate durante 8 a 16 menses in dosages de 0,5 a 4,O mg per die con satisfacente responsas antirheumatic in 20 de 27 patientes con arthritis rheumatoide. Esseva constatate que iste composito es le plus potente corticosteroide antiinflammatori producite usque a iste tempore. Ill0 supprime le production de ACTH e possibilemente de hormon thy. roido-stimulatori in le pituitario anterior. Le function thyroide, mesurate como function del acceptation de iodo radioactive, esseva reducite in 11 de 19 patientes durante le administration de dexamethasona. Le plus commun effect0 lateral in iste gruppo esseva un frappante ganio de peso. Isto amontava a plus que 4 kg in 19 del casos. Tres patientes experientiava fracturas pathologic durante le c u s o de dexamethasona. Un patiente habeva un ulcere peptic. Duo mortes occurreva durante le period0 del studio. I N PRELIMINARY PUBLICATIONS,1~2 it was reported that dexamethasone was the most potent anti-inflammatory corticosteroid thus far produced, that it was free of certain undesirable side effects and, therefore, that it was worthy of further investigation. This is a follow-up report on clinical, metabolic, hormonal and adverse effects of dexamethasone administration in 27 patients with rheumatoid arthritis treated for periods ranging from eight to 16 months. CLINICAL OBSERVATIONS The series consists of 14 males and 13 females who ranged in age from seven to 68 years and had had rheumatoid arthritis for one to 10 years (table 1). Twenty patients exhibited seven or more of the features listed in the Revised Diagnostic Criteria Classification of the American Rheumatism Association,s From the National Institute of Arthritis and Metabolic Diseases, Ndionul Institutes of Heulth, Bethesda, Md., and the Rheumdology S d e - G e o r g e t o w n Medtcol Division, Georgetown Unloersity School of Aledicine, District of Columbia General Hospital, Washington, D. C . 112 113 DEXAMETHASONE permitting a diagnosis of “classical” rheumatoid arthritis. The remaining seven patients had five or more criteria, permitting the diagnosis of “definite” rheumatoid arthritis. None presented symptoms or findings listed among the criteria for exclusion from the diagnosis of rheumatoid arthritis. By American Rheumatism Association criteria, three patients were in Stage I, five in Stage 11, 17 in Stage 111, and two in Stage IV. Twenty-two patients had a positive bentonite flocculation test, and five a negative reaction. Subcutaneous nodules were present in 12 patients, each of whom had a positive bentonite flocculation test. Twenty-one of this group had received corticosteroids previously for three months to six years, with inadequate control of symptoms. The remaining six patients had received salicylates without sufficient relief. The benefit achieved during dexamethasone therapy, as measured by indexes” shown in figure 1, was maintained over the entire period of observation in most cases. The column at the left in each box (fig. 1 ) represents the total of the scores for this group of patients prior to dexamethasone administration. Improvement achieved at the time maintenance dose was established (within the first six weeks) is reflected by the lower second columns in each box. The status after eight to 16 months is represented by the third columns. Pain on motion, tenderness, swelling and ring size all decreased, indicating progressive improvement in patient status. The range of motiont score was the only parameter to show regression; a larger percentage deficit was found at the latest observation period. Morning stiffness (shown as an average for all patients) showed significant decrease in duration during dexamethasone administration. Attempts were made periodically to lower the maintenance dose of dexamethasone. Salicylate, either enteric-coated acetylsalicylic acid or a buffered preparation, was added to the regimen of 13 patients (table 2 ) . Ten of this group (77 per cent) tolerated a decrease averaging 1.8 mg. in the daily dexamethasone dose. One of this group, after receiving her “final” maintenance dose for several months, tolerated complete withdrawal of corticosteroid during the fourth month of pregnancy. On the other hand, among the 14 patients not receiving salicylate, only two (14 per cent) tolerated a modest decrease of 0.3 and 0.5 mg., respectively, in the maintenance dose. One other tolerated slow tapering and discontinuation of the corticosteroid after 12 ‘Complete indexes were obtained in 24 of the 27 cases. Pain on motion, tenderness and swelling are rated for each joint on a scale of 1 to 3, and the patient’s individual score represents the total for all his joints at the time measured. The ring size, measured with standard jeweler’s rings, represents the total for the 10 proximal interphalangeal joints of both hands. The range of motion is determined by measuring the passive range for each joint (except the small joints of hands and feet and the spine) and expressing the total number of degrees of motion found as a percentage of the total possible, according to a standard norm. The percentage deficit is then taken as the score for the patient. Morning stiffness is recorded as the number of hours between arising and the disappearance of stiffness. , ! . 1 , jll .it ! ’! tWe are indebted to Dr. David Fried and the Department of Physical Medicine and Rehabilitation at the Clinical Center, National Institutes of Health, for range of motion determinations. ~ 114 BLACK, REEFE, DAVID, BLOCH, EHRLICH AND BUNIM Table 1.-Composition of Series: Dexamethasone Administration for 8 to 16 Months; 27 Rheumtoid Arthritis Patients' Ape distribution Decade Under29 30-39 40-49 50-59 80-69 Chsi6cstion Duration of disease No.pta. Stage No.pta. Years No.pta. 3 I 11 111 3 5 1-2 3-5 17 6-8 IV 2 9-10 8 8 9 2 8 8 7 1 Previous corticosteroid therapy Duration No. ~ta. 7 4 7 3 6 Over 3 yr. 2-3 yr. 1-2 yr. Less than 1 yr. None previously 'Males, 14, females, 13. Table 2.-Administration of Salicylate to Facilitate Lowering Daily Maintenance Dose of Dexamethone Case, Age. Sex c. P., 57, M I. D., 36, M W. B., 50, M E. B., 43, F hi. Bl., 42, F M. Bo., 38, F c. s.,45, M T. B., 68, M I. M . , 49, M W. T., 39, M H. H., 36, F G. Mc., 31, F C. D., 16, F Dexamethasone original maintenance dose (mg./day) 4 4 4 4 4 4 3.6 3.2 3 2.4 2 2 1 Salicylate added ( Gm./day ) 3.6 2.4 3.6 3.6 4.5 4.5 6 3.6 4.5 2.4 3 3 2.4 Dexamethaeone final maintenance dose (mg./day) 4 4 1 0.5 3.5 3 1.5 4 1 1 1.5 1 0.5 months of therapy. Several previous attempts to decrease the dose had failed. The improved functional status achieved by 20 patients was maintained throughout the period of eight of 16 months of therapy (table 3).* Three severely handicapped patients, and nine with moderately impaired ability, improved to the point of complete functional capacity. The five remaining patients in Classes 11, I11 and IV were more comfortable during dexamethasone therapy but failed to improve in ability to perform daily tasks. Three of the five with most severe impairment were receiving high maintenance doses of 3.5 to 4.0 mg. daily, and two of these received supplementary salicylate. Although residual, potentially reversible, idammatory changes seemed iesponsible for the continued impairment of function, a further increase in corticosteroid dosage seemed imprudent. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) determinations showed a general trend toward normal values. Since corticosteroid dosage was adjusted to the minimum consistent with good control of the disease and no attempt made at complete suppression, the laboratory values were frequently in the abnormal range. HORMONAL EFFECTS Previously reported studies have shown that dexamethasone is 30 times 'One patient who died during tile fourth month of therapy, and another whose dexamethasone was discontinued during pregnancy, were not included in this table. 115 DEXAMETHASONE Table 3.-Functional Capacity of 25 Patients with Rheumatoid Arthritis Before and After Dexamethasone Administration for Periods up to 16 Months After 8 to 16 month8 of therapy Before dexamethasone Clans ~~ Class 1 I1 111 IV 0 - - - - 10 9 1 - - 11 2 6 3 - 4 1 1 1 1 Number of patients I Complete functional capacity I1 Capacity adequate, but with discmmfort 111 Can perform few normal activities 1V Incapacitated-wheel chair or bedridden more potent than prednisone in suppressing the pitnitary-adrenal axis in man.2 Aldosterone production was found to be independent of this pituitary effect.2 Since those studies were reported, we have had an opportunity to observe, in addition, the effect of dexamethasone on thyroid function. Eflect on Thyroid Function Earlier experience with ACTH and cortisone4J indicated that corticosteroids decreased radioactive iodine uptake ( HA1 ) or accumulation gradient, lowered serum protein-bound iodine concentration ( PBI ), ultimately decreased basal metabolic rate (BMR) and, rarely, produced marked elevation of serum cholesterol. Decreased thyroid uptake of RAI during corticosteroid administration was accompanied by increase in urinary excrction of an dose.0 Administration of cortisone was also associated with a highly significant reduction in rate of release of thyroid h ~ r m o n eThyroid-stimulating .~ hormone (TSH) reversed these effects even when administered in the presence of high levels of circulating adrenal cortico~teroids.~ Nevertheless, it has not yet been definitely demonstrated that suppression of thyroid function in steroid-treated patients results directly from reduction of TSH secretion. Thyroid function studies were performed on 16 patients of the present series and on three additional patients with rheumatoid arthritis receiving dexamethasone, three to nine months after the start of therapy. Figure 2 summarizes the effect of various doses of dexamethasone on four parameters of thyroid function. RAI uptake was reduced below 15 per cent in 24 hours in two of six patients receiving 0.5 to 1.0 mg. of dexamethasone per day, three of five patients receiving 1.5 to 2.0 mg. per day, four of six patients receiving 2.5 to 3.25 mg. per day, and both patients receiving 4.0 mg. dexamethasone per day. The serum level of protein-bound iodine was found to be between 5.9 and 6.3 Pg. per cent in patients receiving 0.5 to 1.0 mg. dexamethasone, and tended to be near or below the lower limit of normal (3.4 ug. per cent) in patients receiving larger doses of dexamethasone. The PBI vdues in three patients were markedly different from the rest; two patients receiving 3.5 and 3.0 mg. dexamethasone daily had a PBI of 7.8 pg. per cent and 9.0 ,ug.per cent,* and one *It was later found that the PBI concentration was spuriously elevated by the ingestion of “cough medicine” containing potassium iodide. 116 BLACK, REEFE. DAVID, BLOCH, EHRLICH AND BUNIM 25 15- Prw To mOw.amlhosmm After I Mo of ~osxomattlarcna mAfter0to16Mos of Dsiomelhasona 20 10 15 10 5 05 " W O NW O l N TENERNSS SWELLING RING SIZE %DEFICIT MORNING STIFFNESS R A M E OF MOTION (KXIRS-AVERAGE) IN PATIENTS THE EFFECT OF DEXAMETHASONE O N THYROID FUNCTION WITH RHEUMATOID ARTHRITIS P iI BMR CHOLESTEROL - 300- r +I0 - +5- 0-5 % UPTAKE IN 24 HRS. % 205 - 270 - 255 - - i o -. mg. -15 - __ . 240 -20 -25 - -30 -35 - 1 1 i 23- Wn,. DEXAMETHASONE OEXAMETHASONE DEXAMETHASONE DEXAMETHASONE Fig. 1.-Dexamethasone therapy. Antirheumatic indexes in 24 rheumatoid arthritis patients treated for 8 to 16 months. Fig. 2.-The effect of dexamethasone on thyroid function in patients with rheumatoid arthritis. patient receiving 1.0 mg. dexamethasone had a PBI value of 1.2 pg. per cent ( E. B.) . There was no correlation between the dose of dexamethasone and the basal metabolic rate, a wide range of BMR values being encountered at each dose. However, 10 of 17 patients tested had a BMH of less than -10 per cent. DEXAMETHASONE 117 Serum total cholesterol exceeded the upper limit of normal (250 mg. per cent) in five patients. Again, there was no direct relation between the dose of dexamethasone and the level of serum cholesterol. [n three of the five patients with elevated serum cholesterol, the RAI uptake was below 15 per cent, PBI at or below the lower limit of normal, and BMR at or below -15 per cent. Intramuscular administration of thyroid-stimulating hormone, 10 U. per day for three days, produced an increase in RAI uptake, PBI and BMR in patients J. R. and I. M., and a fall in serum cholesterol in patient I. M. There was no change in thyroid function, however, following TSH administration in patient E. B. (fig. 3). The response of J. R. and I. M. is similar to that observed in patients with hypothyroidism secondary to hypopituitarism. The response of E. B. suggests primary hypothyroidism with completely inactive thyroid tissue. Thyroid function studies in this patient prior to dexamethasone administration and while she was receiving 15 mg. prednisone daily revealed an RAI uptake of 13.6 per cent, PBI of 7.4 ,ug. per cent, BMR of 21.8 per cent, and cholesterol of 290 mg. per cent. After 10 months of therapy with dexamethasone, RAI uptake was 0 per cent, PBI 1.2 pg. per cent, BMR -151 per cent, and cholesterol 272 mg. per cent. However, the presence of elevated titers of thyroglobulin antibodies ( determined with the use of thyroglobulin-coated, tannic acid treated sheep erythrocytes ) prior to and during dexamethasone administration ( 1:1250 and 1:6000, respectively) suggests that some process destroying thyroid gland may be responsible for myxedema in this patient. Five other patients with abnormal thyroid functions had no demonstrable antibodies to thyroglobulin.” Five patients in this series had had thyroid function studies performed while they were receiving 16-a methylprednisone (MK-log), and two of these were also studied while receiving prednisone (fig. 4).8Patient J. R. had an increase in RAI uptake while receiving 16-(Ymethylprednisone; however, on dexamethasone it again declined below normal limits. Following the change from 16-(Ymethylprednisone to dexamethasone in approximately equivalent antirheumatic doses, four other patients also had a decline in RAI uptake. In both J. R. and I. M., serum PBI concentration decreased following 16-01 methylprednisone administration, as compared to the values obtained during prednisone administration. However, there was no significant change in PBI in four other patients who received dexamethasone following a course of 16-or methylprednisone. One patient, F. M., showed an unexplained rise in PBI to 5.9 p g . per cent while on dexamethasone. The BMR tended to decrease in all five patients while they were receiving dexamethasone, but only F. M. and I. M. showed a significant change. Comment.-The interpretation of the observed changes in thyroid function during dexamethasone administration is made difficult by the paucity of studies prior to the start of therapy, the simultaneous administration of salicylate in some cases, the knowledge that abnormal thyroid function occurs in “untreated” rheumatoid patients, and the almost complete absence of clinical signs and symptoms of hypothyroidism in these patients. *We are indebted to Dr. Howard Goodman of the National Heart Institute for the thyroid antibody determinations. 118 BLACK, IIEEFE, DAVID, BLOCH, EHRLICH AND BUNIM CHANGES IN THYROID FUNCTION FOLLOWING T.S.H. ADMINISTRATION IN PATIENTS TREATED WITH DEXAMETHASONE PBI RAI Before Before After 50 After 40 % 30 PQ% UPTAKE 20 24 HRS. 10 2 0 0 CHOLESTEROL BMR Before Before After After 0 mq% 300 -30 -40 r ----- I 200 J.R.; Denornethasone I.Omg dolly M I. M.; Denomethosone 3.01110 dally fb-A E.B.8 Doxometharone O.5mg dolly M COMPARISON OF THE EFFECT OF EQUIVALENT ANTIRHEUMATIC DOSES OF PREONISONE, 16-a-METHYL-PREDNISONE AND DEXAMETHASONE ON THYROID FUNCTION Prtdnirone 16-a-MelhylPrtdnlsone Dexanuthaone % x 24 HRS. Prtdniront 10 l6-a-Udhyl- Dtaomtlhasone Predniront *27% 16-a-MethylPrednlranc Dtxametharw PBI Alcq 7 . 4.0 -- ----- 3.0 - -- - - - - - - - -40 - J.R. I.M. CCI H.H. L_1 F.M. M.B. M.S. Fig. 3.-Changes in thyroid function following TSH administration in patients treated with dexamethasone. Fig. 4.-Comparison of the effect of equivalent antirheumatic doses of 16-amethyl-prednisone and dexamethasone on thyroid function. DEXAMETHASONE 119 As was mentioned, administration of ACTH and cortisone, as well as prednisone,' may be associated with laboratory changes indicative of hypothyroidism. Since many patients in our series had received other corticosteroids prior to dexamethasone, we may assume that some already had suppression of thyroid function. The administration of large doses of salicylate (6.0 to 9.0 Gm. daily) to euthyroid patients was found to increase BMR, reduce serum concentration of PBI and reduce thyroid uptake and rate of release of RAI.9 Exogenous TSH increased RAI uptake, elevated serum PBI concentration, and accelerated release of 113' despite the maintenance of serum salicylate levels of 35 to 51 mg./ 100 rn1.l" Nine patients in our series received 2.5 to 6.0 Gm. of salicylate daily in addition to dexamethasone. There was no significant difference, however, in thyroid function of patients receiving dexamethasone plus salicylate and those receiving dexamethasone alone. Wolfson et alS5found that nine of 18 patients with rheumatoid arthritis had serum concentrations of PBI below the normal limit, and six of 13 patients had an RAI uptake below normal, prior to corticosteroid therapy. However, in the absence of information concerning salicylate intake of these patients, it is uncertain whether these data reflect the thyroid status of completely untreated rheumatoid patients. Short et al." reported that about 25 per cent of patients with rheumatoid arthritis had a BMR below -10 per cent, but other thyroid function studies were not performed. Wolfson et a1.j remarked that the diagnosis of hypothyroidism was unusually difficult in corticosteroid-treated patients. They felt that the usual symptoms were either absent or well hidden beneath the manifestations of the primary disease being treated, or obscured by the often striking effects of ACTH and cortisone. In our series we encountered few symptoms and signs indicative of hypothyroidism, even in those patients with markedly abnormal laboratory determinations. Only two such patients were treated for hypothyroidism-I. M. and E. B. In I. M., reduction in dose of dexamethasone from 3.0 to 0.5 mg. daily led to a rise in RAI uptake to 23 per cent, an increase in BMR to the normal range, and a fall in serum cholesterol to 355 mg. per cent after three weeks on the lower dose. Serum concentration of PRI remained abnormal. Patient E. B. received 75 pg. of triiodothyronine; serum cholesterol promptly decreased to within normal limits and BMR increased. Her somnolence and fatigue diminished appreciably, and no increase in corticosteroid dosage was required to control joint symptoms. E8ect on Carbohydrate Metabolism The relatively modest effect of dexamethasone on glycogen deposition in rats1'J3 suggested at first that this corticosteroid might exercise decreased diabetogenic properties in patients receiving therapeutic doses. Indeed, preliminary clinical studies supported this possibility.2 Serial glucose utilization rate ( GUR ) determinations according to the method of Amatuzio et al." were performed at three month intervals during dexamethasone administration on 22 subjects in this series. Similar 120 BLACK, REEFE, DAVID, BLOCH, EHRLICH AND BUNIM determinations were made on 13 of these while they were receiving older steroids prior to institution of dexamethasone therapy. Five patients listed in table 4 showed progressive impairment of glucose utilization during the administration of dexamethasone in doses of 0.5 to 4.0 mg. daily. One of these patients had normal, and another only moderately impaired, function while receiving a related steroid, 16-a methylprednisone. One had had borderline function while taking triamcinolone. The other two had been receiving aspirin only, prior to dexamethasone, and both had normal function when first studied. Six other patients, not included in table 4, had diabetic or borderline GUR's throughout the period of the study. Another group of six continued to have normal rates. The remaining five patients are of interest. All exhibited diabetic rates prior to dexamethasone administration, four receiving prednisone in doses of 18 to 24 mg. daily, and one, aspirin only. Three of the five were given dexamethasone, 3.0 to 4.0 mg. daily, and the others 1.0 and 2.0 mg., respectively. All five showed improvement in glucose utilization with normal rates after three to 12 months of dexamethasone administration. None of the 27 patients in this study had elevated fasting blood glucose levels or glucosuria. Comment.-As pointed out in a recent review by Frawley and associates,'j corticosteroid effect upon carbohydrate metabolism can be measured by at least two parameters in man-glucosuria and anti-insulin. Bastenie and coworkers'6 have demonstrated that although impairment of carbohydrate metabolism occurs almost universally early in the course of corticosteroid administration, in most cases function returns to normal in the face of continued corticosteroid therapy. It has been suggested by Fajans and ConnI7 that the islets of Langerhans may respond with increased function to the hyperglycemic effect of the adrenal corticosteroids. Hyperplasia and hypertrophy Table I.-Patients Showing Zncreasing lmpairment of the Glucose Utilization Rate during Dexamethasone Administration Glucose utilization rate9 Case J. R. I. Y. M. Bl. N. A. C. D. Dexamethasone daily Previous therapy maintenance daily dose dose (mg.) 16-Methylprednisone 8 mg. 16-Methslprednisone 8 mg. Aspirin 3.6 Gm. Triamcinobne 8 mg. Aspirin 3.6 Gm. 0.5 3.0-1.0 4.0-3.6 3.5 1.0-0.5 During dexamethaaone administration Prior to dexamethasone Normal (0GTT)t Borderline (2.6) %Borderline (2.6 J - 1-3 mo. Diabetic (2.4) 4-8 mo. 7-9 mo. 10-12 mo. Borderline (2.7) - Diabdic (1.7) Normal Normal Diabetic (3.0) (2.9) (1.9) Diabetic (1.9) Normal (3.4) Diabetic (2.8) - Diabetic (2.2) *Glucose utilization rates were determined by the method of Amatuzio e t al." The K values in parentheses represent the rate of disappearance of administered glucose (excees above fasting level) in per cent disappearing per minute. Normal 2.87 to 4.86 Borderline 2.46 to 2.91 Diabetic less than 2.46 tOGTT = Oral Glucose Tolerance Test. $Dashes indicate procedure not performed. DEXAMETHASONE 121 of the islet cells have been observed by H o u s ~ a y ’in~ animals experiencing corticosteroid suppression of carbohydrate metabolism. Hence, the development of a diabetic state secondary to glucocorticoid excess is probably related directly to the individual‘s capacity to increase insulin production.’; Dexamethasone has been compared to triamcinolone and to hydrocortisone in terms of anti-insulin effect in a diabetic patient.‘!’ Dexamethasone, 3 mg. daily, produced a greater increase in insulin requirement (40to 180 U.) than either prednisone, 30 mg. daily (40 to 100 U.) or triamcinolone, 20 mg. daily (40 to 120 U.). The glucosuric effect of dexamethasone has also been compared to that of other corticosteroids. Frawley*5found dexamethasone in dosage of 3 mg. daily equivalent to cortisone 100 mg. daily and hydrocortisone 80 mg. daily in the production of glucosuria in a diabetic patient. Slater et a1.,2O also studying a diabetic patient, found a similar ratio in that dexamethasone, 2.4 mg. daily, produced glucosuria comparable to that produced by cortisone, 90 mg. daily. These studies clearly indicate that dexamethasone, early in its course of administration, causes impairment of carbohydrate metabolism in man. Our observations have been concerned with the effects of long-term dexamethasone administration, as manifested by changes in the glucose utilization rate (GUR) and fasting blood glucose levels. It is difficult to explain with certainty conflicting results in the two groups of five patients who “converted” their CUR’S (normal to diabetic and diabetic to normal, respectively). The dosage range of dexamethasone in the two groups was nearly equal, being, in fact, somewhat less in the group showing impairment. The factor of diet might be considered, but nine of the 10 were consistently studied as inpatients while on a standard hospital diet, consisting of more than 300 Gin. of carbohydrate daily. The degree of activity also influences the GUR, inactive patients tending to show more impaired rates.21 Paradoxically, the most inactive of these 10 patients were in the group which converted to normal GUR’s. Two patients in this group showed no change in functional ability, and the other three improved only by one class. None was in remission. On the other hand, in the group showing ;I diabetic tendency, four of the five improved to a Full functional capacity, two showing an increase of two functional classes. It appears then that the conversions in GUR’s were not related to change in physical activity. The hypoglycemic eflect of acetylsalicylate has been demonstrated by Hecht and GoldneP in diabetic and nondiabetic patients. Glucose tolerance curves obtained after the administration of acetylsalicylate were parallel to but lower than the pre-treatment curves. This would suggest that in these cases the glucose utilization rate was not changed. In our patients, no consistent relationship existed between alteration in the salicylate regimen and the glucose utilization rate. Since neither fasting hyperglycemia nor glucosriria was demonstrated in this group of 27 patients, it appears that none suffered exhaustion of the “insulin-producing reserve” even after receiving therapeutic doses of dexamethasone for eight to 10 months. The variability in extent of the “reserve” in different patients and at different times in the same patient was reflected by different degrees of impairment of the GUR. 122 BLACK, REEFE, DAVID, BLOCH, EHRLICH AND BUNIM SIDE EFFECTS The incidence of side effects in this group is listed in table 5. Twenty-five of the 27 patients developed facial rounding, a “buffalo hump,” and in some instances, striae. These symptoms developed early-usually between one nncl three weeks after the start of dexamethasone. In one patient who previously exhibited facial rounding while taking 80 to 30 mg. of prednisone daily, this manifestation disappeared during the first month of dexamethasone administration, 1.0mg. daily. It is of interest that two patients, each on a 2 mg. daily dose of dexamethasone, developed side effects including facial rounding, increased appetite, restlessness and profuse sweating between m e and two weeks after beginning the corticosteroid, even though the dose was insufficient to suppress the arthritic symptoms. Weight gain not related to edema formation was one of the most disturbing side effects. The marked increase in appetite resulted in strikingly increased caloric intake in most patients when an unrestricted diet was available after discharge from the hospital. Within three to six months after the start of therapy, 19 patients (nine men and 10 women) gained over 4 Kg. in weight. Although in a few cases this gain was desirable, in most the end result was a grossly oversized face and abdomen. Of the nine patients gaining over 9 Kg., only two were later successful in curbing their appetite enough to lose 3 and 5 Kg., respectively. Other side effects included restlessness and/or jnsoinnia in 11, hirsutism in 10, increased sweating in nine and a mood change with increasing irritability in four. No patient became psychotic. Eleven patients developed petechiae and/or spontaneous ecchymoses. One patient showed this side effect within the Table 5.--Side Efiects Appearing during the Adminktratwn of Dexamethasone to 27 Patients with Rheumatoid Arthritis for Periods of 8 to 16 Months _______ Facial rounding and/or “buffalo hump”. . Appetite increase. . . . . . . . . . . . . . . . . . . . . . Weight gain over 4 Kg.. ............................... Petechiae and/or ecchymoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Restlessness and insomnia. Hirsutism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Increased sweating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Edema ................................................ Mood change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epigastric p a i n ’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fractures after mild trauma., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vertebrae ................. 2 fibula . . . . . . . . . . . . 19 11 11 10 9 8 4 . .4. . . 3 . 1 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peptic ulcer! . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 ‘One patient had a peptic ulcer prior t o dexamethasone administration. tTwenty-two patients had repeated radiologic examination of the gastrointestinal tract during dexamethasone therapy. DEXAMETHASONE 123 first two weeks of dexamethasone therapy, but in the others this first appeared between the fourth and fifteenth week of treatment. Since metabolic studies‘ revealed no sodium retention, edema was a surprising finding in eight of these 27 patients. The edema was pitting and involved the feet, ankles and lower legs. Although the edema seemed related to cardiac and/or venous disease in one case, and to inflammatory process in the ankles or tarsal joints in three others, there were four in whom these factors could not be evoked. All eight of these patients showed ecchymoses. No patient without ecchymoses became edematous. Although these two phenomena, edema and ecchymoses, may occur coincidentally, it is possible that interference with normal capillary integrity during dexamethasone administration may account for edema formation. One patient (D. S . ) developed hypertension. His blood pressure prior to dexamethasone administration ranged around 15O/OO. Four months later, on a maintenance dose of 3 mg., his blood pressure was 174/112, and the hypertension persisted throughout his subsequent coiirsc. A mild acneform eruption was observed in five patients. Incidental findings included lichen planus-like lesions of the oral mucosa in three and spontaneous rupture of the extensor tendons in the hands of two other patientsz3 Pathologic fractures occurred in three men, aged 36, 46 and 49, with rheumatoid arthritis of over four years’ duration. Two sustained compression fractures of the vertebrae, while the third had a fracture of the fibula. None had previous fractures, although all had received other corticosteroids for one to five years prior to this study. These three men wcre among the five patients receiving the highest maintenance doses of dexamethasone, 3.5 to 4.0 mg. daily. Figure 5 shows the radiologic appearance of the spine of patient W. B. before and after vertebral fractures. All fractures occurred during the first three month period of study. Serum calcium remained normal, but the alkaline phosphatase rose in two patients following vertebral compression. Since all the patients with severe osteoporosis had normal serum alkaline phosphatase, the rise in the patients with fractures was thought to be related to the repair process. Change in linear height was observed in two patients of this group and in six prednisone-treated patients of another series who sustained spontaneous vertebral compression. Six of the eight from the two groups who experienced vertebral fractures lost 1 to 2% inches in height. This is in contrast to the total variation of *% inch noted in the dexamethasone-treated patients who did not develop a vertebral fracture during the eight to 16 months of observation. This small variation was probably due to changes in posture occurring with alteration in activity of the patients’ arthritis. Epigastric pain was noted by four of the 27 patients while they were receiving dexamethasone. One of these had had a demonstrable gasfric ulcer while taking 20 mg. of prednisone daily. This patient failed to show healing despite an anti-ulcer regimen while receiving dexamethasone, 4 mg., and buffered aspirin, 3.6 Gm., daily. A subtotal gastric resection was performed three months after dexamethasone therapy was begun. 124 BLACK, REEFE, DAVID, BLOCH, EHRLTCH AND BUNIM Fig. 5.-(A) Radiograph of lumbar spine (patient W. B.) while receiving prednisone, 20 to 25 mg. daily prior to dexamethasone administration. ( B ) Radiograph of lumbar spine (patient W. B.) during third month of dexarnethasone administration, 4 mg. daily. Stool examinations for occult blood ( benzidine test) were performed in series of three or more daily collections at three month intervals, as shown in table 6. During these periods the patients were recei\-ing a standnrd hospital diet which included meat. Eight of 11 patients receiving dexamethasone and salicylate therapy showed positive tests on one or more occasions. However, only one of the seven patients receiving desamethasone alone showed occult blood in his stools. This patient had a history of a gastric ulcer one month before dexamethasone was started. Healing was demonstrated radiologically prior to the first dose of dexamethasone. Salicylate therapy has been shown to cause bleeding from the gastrointestinal tract of a degree sufficient to produce positive tests for occult In our cases the presence of occult blood in the stools is better correlated with salicylate therapy than with dexamethasone administration. Radiographic esamination of the gastrointestinal tract was performed at three to six months intervals in 22 of these 27 patients regardless of the presence or absence of symptoms or of occult blood in the stools. One patient was found to have an asymptomatic gastric ulcer in the fourth month of dexamethasone administration. There were two deaths in this group. One was that of a 57 year old male with rheumatoid arthritis and heart disease, who died following extensive thrombophlebitis of both femoral veins which had required inferior vena caval ligation. Postmortem examination showed bilateral femoral thrombophlebitis, and pericarditis and valvulitis consistent with rheumatoid heart disease. 125 DEXAMETHASONE Table 6.-Occurrence of Occult Blood in the Stools of Rheumatoid Arthritis Patients Receiving Dexamethasone and Salicylate Therapy Compared to Dexamethasone Therapy Alone Occult Blood in Stools* Case c. P. I. D. M. B1. h.1. Bo. H. H. c. s. W. B. I. M. W. T. E. B. C. D. Dexamethasone maintenance dose (mg./day) 4 4 3.5 3 1.5 1.5 1 1 1 0.5 0.5 Salicylate maintenance doee (Gm./day) Dexamethasone and Salicylate Prior to dexarnethasonet 0 3.6 2.4 4.5 4.5 3.0 6.0 3.6 4.5 2.4 3.6 2.4 2t 2 0 0 0 0 0 0 1 1 1-3 mo. 4-6 mo. '7-9 mo. 0 2 0 - - 1 1 0 0 0 2 05 0 0 2 2 1 O§ 0 0 2 1 0 0 1 0 1 0 0 1 1 0 PATIENTS RECEIVING DEXAMETHASONE ONLY D. S. N. A. P. Be. P. Ba. V. R. F.M. 3 3 2 1 1 0 0 0 0 0 0 2 0 1 0 0.5 0 0 R.T. 0.5 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 "Benzidine test for occult blood. Stools examined in series of 3 or more specimens driring each period. 0 = all negative. 1 = occasionally positive. 2 z frequently positive. tPatient had an active gastric ulcer. Gastric resection done 3 months after dexamethasone therapy started. ISorne patients received salicylate occasionally. §Patient not on salicylate at this time. There was no evidence of infection or septicemia. The other patient, while at home on a dose of 3.5 mg. of dexamethasone, became acutely ill with shortness of breath and weakness. He was admitted to another hospital under the care of another physician. The daily dosage was abruptly reduced from 3.5 to 1.5 mg. and ACTH and DOCA were supplemented. The patient died on the tenth hospital day. Unfortunately the cause of death could not be clearly established . SUMMARY Dexamethasone was administered for eight to 16 months in daily divided doses of 0.5 to 4.0 mg. with satisfactory antirheumatic response in 20 of 27 patients with rheumatoid arthritis. Five of the 27, although rendered more comfortable, failed to improve in functional status. This compound has been found to be the most potent anti-inflammatory 126 BLACK, REEFE, DAVID, BLOCH, EHRLICH AND BUNIM corticosteroid thus far produced. It suppresses ACTH production by the anterior pituitary. Thyroid function, iis measured by H,4I uptake, was reduced in 11 of 19 patients. This suppression could be reversed by exogenous TSH administration during continued steroid therapy. No direct evidence has been presented, however, to demonstrate that pituitary secretion of TSH is suppressed by dexamethasone. Dexamethasone caused impairment of carbohydrate metabolism in 11 of 22 cases, as reflected in abnormal glucose utilization rates on repeated determinations. In no patient, however, was elevation of fasting blood glucose level or glucosuria observed. The most annoying side effect in this group was striking weight gain-over 4 Kg. in 19 patients. The greatest gain was 18 Kg. Pathologic fractures occurred in three patients. Only one patient developed a peptic ulcer during dexamethasone therapy. Psychosis did not occur. When dexamethasone was combined with salicylnte therapy, it was possible to effect substantial reduction of steroid dosage in 77 per cent of the patients so treated. On the other hand, occult blood in the stools was found in eight of 11 patients receiving combined therapy, but in only one of seven patients taking dexamethasone alone. One gastric ulcer was found thus far among 22 patients who have received periodic radiologic examinations. There were two deaths during the period of the study. Gradual withdrawal of dexamethasone was possible in two of our cases, after seven and 12 months, respectively, at a 2 mg. dosage level, without the appearance of adrenal insufficiency or recurrence of arthritis. 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Dazjid, M.D., Clinical Associate, National Institute of Arthritis and Metabolic Diseases, Betheselei, Mtl. 128 BLACK, REEFE, DAVID, BLOCH, FHRLICH AND BUNIM Kurt J . Bloch, M.D., Senior Investigator, National Institute o f Arthritis and Metabolic Diseases, Bethesda, Md. George E . Ehrlich, M.D., Trainee, National lnstitute of Arthritis and Metabolic D i s m m , Bethesda, Md. Joseph 1. Bunim, M.D., Clinical Director, National Zmtitute of Arthritis and Metabolic Diseases, Bethesda, Md .; Associate Professor o f Medicine, Johns Hopkins Uniuersity, Baltimore, Md.; Clinical Professor of Medicine, Georgetown University School of Medicine, Washington, D. C.