BRIEF REPORT Serum Urate in Degenerative Joint Disease and Rheumatoid Arthritis By WALTF. WEAVER AND CHARLEY J. SMYTH I N THE DIFFERENTIAL DIAGNOSIS of patients with arthritic symptoms, the serum urate is frequently determined, and often when gouty arthritis is considered only as a remote possibility, Occasionally an “elevated value is obtained. When the usual causes of an elevation in the serum mate have been searched for and eliminated, this laboratory finding may cause considerable concern and confusion. In these circumstances it is not unusual that patients with rheumatoid arthritis with cystic changes in the bones are falsely interpreted as having gouty arthritis. Lockiel has suggested that the serum urate may be increased in patients with rheumatoid arthritis. In a more recent paper, Grayzel et a1.2 have also suggested this phenomenon. Further difficulty in the interpretation of an elevated serum urate value may be due to the number of different methods that are currently used, each with a different range for normal values. The clinician is frequently not aware of the method used nor the range of normal valces for the particular serum urate method. In the Arthritis Clinic of the University of Colorado, the Archibald modifications of the Kern-Stransky methodl has been used since 19S5. This study was undertaken to determine the incidence of hyperuricemia in patients with rheumatoid arthritis, and to compare this group with the uric acid values obtained in this same clinic in a series of patients with degenerative arthritis who served as the control group. METHOD It has heen the policy in this clinic to obtain a serum urate determination on each new patient at the time of the original examination. At times, more than one determination was made on a single patient because the initial value was elevated. To include all of these values or even their mean would introduce a sampling error into the study. When thc data obtained at the time of the initial determination (the first of several measurements in an individual patient) was compared with the data obtained as a single measurement (only one determination per patient), there was no significant difference in any of the groups tested. This data is not presented here but serves to validate the method of this study. Accordingly, the first uric acid determination on each patient was the one selected for this report. All of the new patients with rheumatoid arthritis and degenerative joint disease seen during a 5-year period were selected for a review. The effects of salicylates and other drug ingestion, renal status and hematologic factors were not included in this retrospective study. The serum urate determinations, age, and sex were analyzed and the results are summarized. RESULTS The serum urate values found in the different decades of both male and female patients are present in table 1. The over-all means for males and feFront the Department of Medicine, Section of Rheumtic Diseases: UrtiVerSity of Colorado School of Medicine, Denver, Colo. 372 ARTHRITIS AND RHEUMATISM,VOL. 6, No. 4 (AUGUST), 1963 373 SERUM URATE VALUES males indicate that the serum urate values were higher in the male patients both with degenerative joint disease (5.6 mg. per cent) and with rheumatoid arthritis (5.3 per cent) than the female patients with degenerative joint disease (5.1 mg. per cent) and with rheumatoid arthritis (4.3 mg. per cent). When analyzed in this manner it is apparent that thce serum urate values for the patients with degenerative joint disease and rheumatoid arthritis were similar. These difkerent age groups were combined into those above and below the age of 50 years (table 2 ) and the mean serum urate levels with their standard deviations were determined. In patients older than 50 years the serum urate in rheumatoid arthritis was slightly but definitely lower than in degenerative arthritis ( p = 0.002 for females and 0.05 for males). This relationship did not hold in patients below 50 years of age. It was also apparent that while males over 50 (in either the R.A. or control groups) had slightly higher serum urate values than females over 50, the differences were not statistically significant. In the groups under 50 years of age, the serum urate of males with rheumatoid arthritis was considerably higher ( p = 0,001) than females with rheumatoid arthritis. The small size of the control (degenerative arthritis) groups under 50 years of age did not permit a similar statistical statement. DISCUSSION It is apparent from a statistical viewpoint that the serum urate by the method employed is not elevated in patients with rheumatoid arthritis. The data also substantiate the well-known fact that serum urate values for males and females are similar in the age groups after the menopause. Prior to the menopause, males have higher serum urate values than females (with exception of the years prior to the menarche).5,6 In the article by Grayzel et aL2 it is stated that, “in a series of 57 male patients with rheumatoid arthritis admitted to the Clinical Center of the National Institutes of Health, 10 (18 per cent) were found to have serum urate levels greater than 6 mg. per 100 ml. after patients with renal disease, as shown by nitrogen retention, had been eliminated.” In an earlier paper, it would appear that at least ten per Lockiel makes a similar statement: cent of patients with well-developed rheumatoid arthritis will have a uric acid concentration greater than 6 mg./100 ml.” These statements might suggest to the reader that the serum urate is elevated in rheumatoid arthritis. However, other authors, using a variety of methods, have reported serum mate levels greater than 6 mg. per cent in 13.1 per cent (spectrophotometric),’ 17.6 per cent ( enzymatic spectrophotometric),8 32 per cent (enzymatic spectrophotometric),8 and 40 per cent (enzymatic spectrophotometric)O of apparently normal individuals. Had we reported our data in this manner, it would show that 48 of 222 (21.6 per cent) of our patients with rheumatoid arthritis had serum urate values of 6 mg. per cent or greater. In our control group (degenerative arthritis), 47 of 172 (27.4 per cent) had serum mate levels of 6 mg. per cent or greater. These statements might imply that 6 “. . . 50-59 80-89 70- 14-29 30-39 4WD Age Groups 5 9 21 31 37 103 5.4 5.1 4.5 4.3 5.4 4.9 1.4 30 26 141 28 19 25 13 ~ _ 4.1 3.9 4.0 4.4 4.4 4.8 4.3 ~ _ _ _ 3 16 19 29 69 2 . 5.6 5.6 7.0 4.6 4.1 6.4 _ _ ~ - 1.5 _ 1.5 Mean serum No.of uratein Standard patients mg./100 cc. deviation Mean serum No. of urate in Standard patients mg./100 ec deviation Mean serum No.of uratein Standard Datients m g . / l O O cc. deviation Ostmwthritis Rheumatoid Arthritis - . . Urate in Degenerative and Rheumatoid Adwitis (Distribution b y Decades) Ostemrthritis Females Table 1.-Serum lala 4.9 4.2 5.7 5.7 3.1 6.0 . 1.8 4.9 -. - mg./100 cc. deviation Meart B e r u m urate in Standard 81._ _ 5.3 10 8 19 21 11 12 No.of patients Rheumatoid Arthritis 375 SERUM URATE VALUES - Table 2.--Serum Urate in Degenerative and Rheumatoid Arthritis and _ _ _ (Distribution ~ _ _ _ _ _under ___ _ over Age_50_Years) ~ - -__.Females osteo. -~ Males RA Osteo. RA Under 50 yrs. 4.4 f 0.9 4.0 & 1.4 Sample too small 5.6 2 1.8 Over 50 yrs. 5.2 f 1.5 4.5 r+ 1.6 5.6 * 1.5 5.0 & 1.6 69pts. 5.6 f 1.5 81 pts. 5.3 1.8 ___141 pts. 4.3 & 1.5 -__mg. per cent is the upper limit of normal, Presentation of data in this fashion is misleading and should be avoided if possible. Why the figure of 6 mg. per cent is chosen as the reference point in so many studies is unclear. Certainly males, females and patients of various ages should not be compared in terms of one single serum urate value. It is important to recall a common clinical practice: namely, that laboratory values are usually reported as the mean plus or minus one standard deviation. Thus, in most hospitals the laboratory reports give the range for only 68 per cent of the patients. As a result of this general practice, 32 per cent of normal patients will fall outside this “normal” range. Since it is difficult to assign limits for normal ranges, some authorslOJ1 in writing about serum urate levels suggest that t w o times the standard deviation of a single observation (95.4 per cent of all observations) would make desirable limits. On cursory inspection, this might appear to be the practical solution to the reporting of normal and elevated serum urate levels. However, one must also enlarge the frequency distribution curve of the patients with abnormal purine metabolism by this one standard deviation in each direction. A greater percentage of the area of the two frequency distribution curves is thus allowed to overlap. It is to be emphasized that a single determination is not sufficient to establish a distribution curve for a given patient. Thus, using our data, if a female patient has a single serum urate determination of 7.2 mg./100 cc., she may be normal or abnormal as regards purine metabolism. A single high value such as this should prompt the clinician to obtain additional determinations before a diagnosis of hyperuricemia is made on this patient. Jf further determinations were much lower, a “t” test or other significance test would not show a difference between the curve for normal patients and this patient and the high value could be disregarded. However, if further determinations were also elevated (and yet within 1 or 2 standard deviations of normal), a test of significance could show a definite difference between the normal distribution curve and the one for the patient in question. In this latter instance, the clinician must make the final decision regarding normality versus abnormality. These concepts must be taken into consideration when evaluating or reporting data based upon single measurements. Thus, when reporting a serum urate on a group of patients with a given condition, a frequency distribution curve should be calculated for that group and this compared to a similar curve for normal patients. It would be far less valid to take the single value for each patient and individually compare it to the normal value or range of values. Total 103 pts. 5.1 k 1.4 376 WEAVER AND SMYTH SUMMARY A brief report of the serum urate values in patients with degenerative and rheumatoid arthritis using the Archibald modification of the Kern-Stransky method has been presented. The serum urate by this method is not elevated in rheumatoid arthritis. Recognition of the fact that in the usual frequency distribution curve, 32 per cent of normal patients will be outside the “normal” range (mean 1 S.D.) is stressed. To establish that an individual patient has a significant hyperuricemia, several determinations may be required. * ACKNOWLEDGMENT Statistical analyses of the data were made by Charles J. Hlad, Jr. of the Denver Veterans Administration Hospital. REFERENCES 1. Lockie, L. M.: Symposium on gout: Diagnosis. Metabolism 6:269-276, 1957. 2. Grayzel, A. I., Liddle, L., and Seegmiller, J. E.: Diagnostic significance of hyperuricemia in arthritis. New England J. Med. 265:761-768, 1961. 3. Archibald, R. M.: Colorimetric measurenient of uric acid. Clin. Chem. 3:102-105, 1957. 4. Kern, A., and Stransky, E.: Beitrag zur Kolorimetrischen Bestimmung der Harnsaiire. Biochemi. Ztschr. 230: 419-427, 1937. 5. Smyth, C. J., Cotterman, C. W., and Freyberg, R, H,: The genetics gout and hypermicemia--an analysis of nineteen families. J. Clin. Invest. 27:749-759, 1948. 6 . Wolfson, W. Q., Levine, R., Cohn, C., Huddleston, B., Hunt, H. O., Guterman, H. S., Rosenberg, E. F., and Kadota, K.: The transport and excretion of uric acid in man; V. A sex difference in mate metabolism: J. Clin. Endocrinol. 9:749-767, 1949. 7. Gertler, M. M., and Oppenheimer: Serum uric levels in men and women past the age of 65 years. J. Gerontol 8:465-471, 1953. 8. Praetorius, E.: Plasma uric acid in aged and young persons. J. Gerontol 6~135-137, 1951. 9. Cob,,, s., Dunn, p,, Brooks, G,, and Rodnan, G. P.: Serum urate levels in males by social class (abstract). 1961 Annual Meeting of American Rheumatism Assoc., June 1961, New York City. Arth. R Rheumat. 4:412, 1961. 10. Alper, c., and Seitchik, J.: Comparison of the Archibald-Kern and Stransky colorimetric procedure and the Praetorius enzymatic procedure for the determination of uric acid. Clin. Chem. 3:95-101, 1957. 11. GjoruP, s., Poulsen, H.,and Praetorius, E. The uric acid concentration in serum determined by enzymatic spectrophotometry. Scandinav. J. Clin. & Lab. Invest. 7:201-203, 1955. Walt F . Weauer, M.D., formerly Clinical Assistant in Medicine, Department of Medicine, Section of R h & k Diseases, University o j Colorado School of Medicine, Denuer, COO.;present address. Lincoln, Neb. Charley 1. Smyth, M.D., Associate Professor of Medicine, Department of Medicine, Section of Rheumatic Diseases, University of C o h a d o School of Medicine, Denver, C o b .