MONOSODIUM URATE CRYSTALS IN THE KNEE JOINTS OF PATIENTS WITH ASYMPTOMATIC NONTOPHACEOUS GOUT

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1 148 MONOSODIUM URATE CRYSTALS IN THE KNEE JOINTS OF PATIENTS WITH ASYMPTOMATIC NONTOPHACEOUS GOUT JOHN S. BOMALASKI, GERONIMO LLUBERAS, and H. RALPH SCHUMACHER, JR. We aspirated synovial fluid from the knees of 5 patients with asymptomatic, nontophaceous gout, in whom synovial fluid monosodium urate (MSU) crystals had previously been documented in the knees or other joints. Fifty-eight percent of these asymptomatic patients had MSU crystals in their knee joints. Serum uric acid levels, serum creatinine levels, volume of synovial fluid aspirated, and cell counts of the aspirated fluid did not differentiate the MSU crystal-positive group from the group without MSU crystals. Clinical factors such as alcohol abuse, coronary heart disease, hypertension, duration of gout, duration of the intercritical period, and drug therapy did not differentiate the 2 groups. Nineteen patients consented to aspiration of their other knee. Seven of these patients (7%) had MSU crystals bilaterally, and 6 patients (2 %) had them unilaterally. The implications of the persistence of MSU crystals (including those in intracellular locations) in many patients, despite normalization of serum uric acid levels, From the Arthritis-Immunology Center, Veteraps Administration Medical Center, the Department of Medicine, University of Pennsylvania, and the Department of Medicine, Medical College of Pennsylvania, Philadelphia. John S. Bomalaski, MD: Assistant Professor of Medicine, Medical College of Pennsylvania, Adjunct Assistant Professor of Medicine, Rheumatology Section, Department of Medicine, University of Pennsylvania, and Staff Physician, VA Medical Center; Geronimo Lluberas, MD: Rheumatology Fellow, VA Medical Center and Medical College of Pennsylvania; H. Ralph Schumacher, Jr., MD: Professor of Medicine, University of Pennsylvania School of Medicine and Medical College of Pennsylvania, and Director, Arthritis-Immunology Center, VA Medical Center. Address reprint requests to John S. Bomalaski, MD, Arthritis-Immunology Center (151K), Veterans Administration Medical Center, University & Woodland Avenues, Philadelphia, PA Submitted for publication October 2, 1985; accepted in revised form June 18, should be determined. Knee joint aspiration is a sensitive method for the demonstration of MSU crystals in asymptomatic patients. The procedure might also be useful in documenting these crystals in patients who have had attacks of arthritis with features consistent with a diagnosis of gout, but in whom MSU crystals have not been documented. Patients with suspected diagnoses of nontophaceous gout, in whom synovial fluid has not been examined for the presence of monosodium urate (MSU) crystals, are often seen by rheumatologists. Most of the rheumatologists consider that a firm diagnosis of gout can be made only by identifying MSU crystals in the synovial fluid of such patients. Previously, MSU crystals have been documented by examination of synovial fluid from both the symptomatic and the asymptomatic first metatarsophalangeal (MTP) joints of patients with nontophaceous gout (1-). Knee joints are easier to aspirate than are MTP joints, and one would expect that more synovial fluid could be obtained for examination while maintaining the sensitivity of MTP joint aspiration. In one study (4), the synovial fluid from the knees of patients with asymptomatic, clinically tophaceous gout was aspirated, and MSU crystals were documented in 11 of the 1 patients (85%). We attempted to aspirate synovial fluid from the knees of 51 asymptomatic patients with nontophaceous gout, in whom synovial fluid urate crystals had previously been documented in at least 1 joint (not necessarily the knee). We found that 58% of these asymptomatic patients had MSU crystals in their knee joints, and such factors as alcohol abuse, coronary heart disease, and serum uric acid levels did not Arthritis and Rheumatism, Vol. 29, No. 12 (December 1986)

2 ~ ~ ~~ MSU CRYSTALS IN GOUT 1481 indicate which patients would be positive for MSU Table 1. Clinical characteristics of 5 patients with asymptoctystals. matic nontophaceous gout whose knee synovial fluid was examined for the presence of monosodium urate (MSU) crystals* PATIENTS AND METHODS Patients. We studied 51 patients, all but 1 of whom wm: male. All patients underwent a thorough medical history interview and physical examination. None had clinically detectable tophi ( nontophaceous ). All had previously documented MSU crystals in the synovial fluid of 1 jaint, but not necessarily in the knee. All patients, by dqfinition, had met the American Rheumatism Association cdteria for the diagnosis of gout by the documentation of the MSIJ crystals (5). Laboratory evaluatiop. For the knee joint aspiration puocedure, the skin was first cleaned with Betadine soap, and the area for arthrocentesis was sprayed with ethyl aqetate. Aspiration was performed using a medial retropatell@ approach with an 18-gauge needle and a 1-cc syringe. In 19 patients who gave their consent, we aspirated both knees. The synovial fluid was promptly evaluated for fluid volume, wbiie blood cell count, and the presence, location (iptracellular or extracellular), and shape of the crystals. All flqids were examined with a Zeiss polarizing light microscope. Serum uric acid levels were determined by the automated uricase method. Clinical data. The frequency and site of prior attacks, dmg therapy, and the joint in which MSU crystals were first documented were determined by interview with the patients and a review of their clinical records. Initial diagnostic arthirocentesis was not performed at our institution in 14 of the patients. However, subsequent arthrocentesis that documented the MSU crystals was performed at our institution before these patients were included in this study. Statistical analysis. Student s 2-tailed t-test for groups was used to assess the data. RESULTS Synovial fluid was obtained from 69 of the 71 knees aspirated (97%) and from all but 1 of the 51 patilents who entered the study (98%). MSU crystals mrle identified in 7 (54%) of the 69 knees from which fluid was obtained and in 29 (58%) of the 5 patients fmni whom synovial fluid was obtained. Interestingly, 6 patients, although asymptomatic, had a synovial fluid bulge sign, and MSU crystals were found in 5 of tl-iese patients (8%). Nineteen patients consented to bilateral knee aspiration. Six of these patients (2%) had MSU crystals unilaterally in their knee synovial flaidl aspirates, 7 (7%) had MSU crystals bilaterally, and 6 (2%) had no crystals in either knee. The clinical characteristics of the 5 patients from whom synovial fluid was aspirated are shown in Table 1. There was no difference in the average age of the patients in the crystal-positive and crystal-negative gtoups. Neither the duration of known gout nor the - ~ MSU crystal-positive MSU crystal-negative Characteristic (n = 29) (n = 21) Age Duration of t 5.7 arthritis (years) Duration since last 7.7 t attack (months) Alcohol abuse Kidney stones 6 Obesity 6 11 Hypertension Congestive heart failurekoronar y artery disease Diabetes mellitus * Values are expressed as mean? SD or as the percentage. There were no significant differences between the 2 groups (by Student s 2-tailed r-test). duration of the asymptomatic period since the last gouty attack (intercritical period) was statistically significantly different, although patients with crystals tended to have a slightly longer disease duration and slightly more recent attacks. The presence or absence of conditions associated with gout, such as alcohol abuse, hypertension, congestive heart failure, obesity, or diabetes mellitus, did not help to distinguish between the 2 groups (Table 1). Two patients had had tophi noted at the time of a previous physical examination ( clinically tophaceous ); both of these patients were MSU crystal-positive. Table 2. Sites of previous gouty attacks in 5 patients with asymptomatic nontophaceous gout whose knee synovial fluid was examined for the presence of monosodium urate (MSU) crystals* MSU crystal- MSU crystal- MSU crystal- positive positive negative unilaterally Site (n = 29) (n = 21) (n = 6) Metatarsophalangeal joint Midfoot Ankle Knee Elbow 1 Wrist Hand Total sites * The total sites of prior attacks exceed the total numbers of patients because some patients had attacks in multiple sites.

3 1482 BOMALASKI ET AL The knee and MTP joints were the most common sites at which MSU crystals were originally identified. There were no differences between those patients in whom MSU crystals were found in the current study and those in whom they were not found. Other sites of initial involvement included the midfoot, ankle, elbow, and wrist. However, many patients had symptoms consistent with a diagnosis of gout in joints other than the knee or MTP joint before intraarticular MSU crystals were documented. In the interval between the documentation of crystals and entry into the study, multiple joints were involved (Table 2). Again, the knee and MTP joints were the most common sites of involvement. The treatment regimens were similar in both groups (Table ). Allopurinol therapy, at a dosage of at least mg/day, was used in 46% of the MSU crystal-positive patients and in 52% of the MSU crystal-negative patients. The duration and dosage of allopurinol therapy varied. Two patients had previously received injections of long-acting corticosteroids into the knee joint. Both of these patients were MSU cry stal-positive. There was no significant difference in the mean serum uric acid values in the patients with and those without MSU crystals (Table 4). Fifty percent of both groups had serum uric acid values <7.1 mg/dl. The mean serum creatinine values were also similar in the 2 groups. The volume of fluid obtained from the crystal- Table. Drug therapy in 5 patients with asymptomatic nontophaceous gout whose knee synovial fluid was examined for the presence of monosodium urate (MSU) crystals* MSU crystal- MSU crystal- MSU crystal- positive positive negative unilaterally Treatment (n = 29) (n = 21) (n = 6) Colc hicine Colchicine and Probenecid and Allopurinol Allupurinol and colc hicine Allupurinol and Allupurinol,, and colc hicine None 2 * = nonsteroidal antiinflammatory drug Table 4. Laboratory characteristics of 5 patients with asymptomatic nontophaceous gout whose knee synovial fluid was examined for the presence of monosodium urate (MSU) crystals* MSU crystal-positive MSU crystal-negative Characteristic (n = 29) (n = 21) Synovial fluid 4.9 f volume (cc) White blood ,418 1 f 65 cells/mm Serum uric acid (mg/dl) Serum creatinine (mg/dl) * Values are mean f SD. There were no significant differences between the 2 groups (by Student s 2-tailed t-test). positive group ranged from.1-15 cc. In the crystalnegative group, the range was.5-15 cc. The synovial fluid white blood cell count in the crystal-positive group ranged from 5 cells/mm to 7,6 cells/mm, with a median value of 25 cells/mm. The range of white blood cells in the crystal-negative group was 5-, cells/mm, with a median value of 1 cells/mm. Of those patients with MSU crystals in their synovial fluid, 65% had intracellular crystals in mononuclear and/or polymorphonuclear leukocytes. Calcium pyrophosphate dihydrate crystals were noted in the knee synovial fluid of 2 patients, 1 of whom had no prior documentation of such crystals. DISCUSSION Fifty-eight percent of the asymptomatic patients with nontophaceous gout had demonstrable MSU crystals in the synovial fluid of the knee. No clinical or laboratory characteristics, including serum uric acid levels, drug therapy, or time since the last gouty attack, served to adequately identify the MSU crystal-positive group. Previous studies by investigators at this institution have noted the presence of MSU crystals in asymptomatic first MTP joints (1,2). Agudelo et a1 (1) found MSU crystals in the asymptomatic MTP joints of 1 of 14 patients (14 of 15 MTP joints [9%]). All of these patients had a history of podagra, but only 1 had had the diagnosis of gout confirmed by the demonstration of MSU crystals. Although all MTP joints were asymptomatic at the time of aspiration, the number of patients experiencing a gouty attack in other joints at the time of the MTP joint aspiration was not noted. Similarly, Weinberger et a1 (2) noted MSU crystals in 6 of 9 asymptomatic MTP joints (67%); 2 of

4 MSU CRYSTALS IN GOUT patients (22%) were experiencing an acute attack in another joint at the time of the MTP aspiration but were still negative for MSU crystals in the MTP joint. Rouault et a1 () also examined synovial fluid from asymptomatic MTP joints; they found MSU crystals in 16 of 2 patients (7%). The presence of MSU crystals did not correlate with the duration of gout, the presence of tophi, or the history of podagra in the patients they studied. Thus, our findings of MSU crystals in 29 (58%) of 5 patients with asymptomatic nontopha- C~OUS gout and the lack of correlation with the duration of gout are consistent with the results of other studies in which MTP joints were examined for MSU crystals. One previous study examined MSU crystals in asymptomatic knee joints of patients with tophaceous gout (4). Eleven of 1 patients (85%) had MSU crystals. Both extracellular and intracellular crystals were noted. Sixty-five percent of our population with MSU crystals had intracellular crystals, which were found in both mononuclear and polymorphonuclear leukocytes. Thus, as has been noted in the studies of MTP joints, leukocyte ingestion of crystals does not invariably provoke an acute gouty attack. Furthermore, crystal shape and size are not clearly associated with MSU crystal virulence (6). The MTP and knee joints were the most commonly affected sites at the time of initial documentation of intraarticular MSU crystals. These were also the joints most commonly involved during the period before entry into the study (Table 2). This finding correlates with that noted by other investigators who have reported that toe and knee joints are the most common sites of gouty arthritis (7-9). Treatment with allopurinol had been prescribed in approximately 5% of each group of our patients (Table ). It was of interest that there was no significant difference in the mean serum uric acid levels in the group of patients who had MSU crystals versus those who did not have MSU crystals. Studies are in progress to determine whether further lowering of serum uric acid levels or longer duration of lowered serum uric acid levels will result in lower numbers of joints with persistent crystals. Asymptomatic patients may have severe joint destruction (1,ll); such destruction might predict longer persistence of MSU crystals. The data presented here suggest some trends in Clinical and SynOVial fluid characteristics Of patients with MSU crystals, but none of the differences between this group and the group without MSU crystals were significant. However, a greater volume of fluid was aspirated from the knees of the MSU crystalpositive group. Although 5 patients were included in this study, a beta error might be present, and some trends could, perhaps, become statistically significant if a much larger patient cohort were studied. Six of 19 patients (2%) who had both knees aspirated had unilateral knee MSU crystals. This result confirms the importance of aspirating more than 1 joint (12) and of examining the second synovial fluid if the first specimen does not show MSU crystals (1,14). Also, 6 asymptomatic patients presented with a synovial fluid bulge sign, and in 5 of these patients (8%), MSU crystals were present. Therefore, asymptomatic patients with synovial fluid accumulation evident on physical examination may be more likely to have crystals. These findings suggest that some local factors, in addition to systemic features, might be important. Clinical factors, such as diabetes mellitus and alcohol abuse, did not help to identify the MSU crystal-positive patients (Table 1). However, these factors do appear to predispose one to the development of gout (15). In conclusion, knee joint aspiration is a sensitive method for demonstrating MSU crystals in patients with nontophaceous gout and can provide a definite diagnosis in some patients, even in the interim between attacks. Clinical characteristics, drug therapy, and serum uric acid levels do not differentiate MSU crystal-positive patients from those without crystals. Aspirating more than 1 joint may be necessary to confirm the presence of MSU crystals. The implications of the persistence of intracellular MSU crystals despite normalization of serum uric acid levels should be determined. ACKNOWLEDGMENTS We thank Susan Rothfuss, Marie Sieck, and Gilda Ciayburne for their technical assistance and Mary Ellen Maguire for her help in preparation and typing of the manuscript. REFERENCES 1. Agudelo CA, Weinberger A, Schumacher HR, Turner R, Molina J: Definitive diagnosis of gout by identification of urate crystals in asymptomatic metatarsophalangeal joints. Arthritis Rheum , Weinberger A, Schumacher HR, Agudelo CA: Urate crystals in asymptomatic metatarsophalangeal joints. Ann Intern Med 91:5657, 1979

5 1484 BOMALASKI ET AL. Rouault T, Caldwell DS, Holmes EW: Aspiration of the asymptomatic metatarsophalangeal joint in gout patients and hyperuricemic controls. Arthritis Rheum 25:29-212, Gordon TP, Bertouch JV, Walsh BR, Brooks PM: Monosodium urate crystals in asymptomatic knee joints. J Rheumatol9: , Wallace SL, Robinson H, Masi AT, Decker JL, Mc- Carty DJ, Yii T-F: Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum , Antommattei, Schumacher HR, Reginato AJ, Clayburne G: Prospective study of morphology and phagocytosis of synovial fluid monosodium urate crystals in gouty arthritis. J Rheumatol 11: , Grahame R, Scott JT: Clinical survey of 54 patients with gout. Ann Rheum Dis 29:461468, Hadler NM, Franck WA, Bress NM, Robinson DR: Acute polyarticular gout. Am J Med 56: , Mody GM, Naidoo PD: Gout in South African blacks. Ann Rheum Dis 4:9497, Barthelemy CR, Nakayama DA, Carrera GF, Lightfoot RW Jr, Wortmann RL: Gouty arthritis: a prospective radiographic evaluation of sixty patients. Skeletal Radio1 11~1-8, Nakayama DA, Barthelemy C, Carrera G, Lightfoot RW Jr, Wortmann RL: Tophaceous gout: a clinical and radiographic assessment. Arthritis Rheum 27:46&471, Abeles M, Urman JD: Acute gouty arthritis: the diagnostic importance of aspirating more than one involved joint. JAMA 28:2526, Schumacher HR, Jimenez SA, Gibson T, Pascual E, Traycoff R, Donvart BB, Reginato AJ: Acute gouty arthritis without urate crystals identified on initial examination of synovial fluid: report on nine patients. Arthritis Rheum 18:6-612, Romanoff NR, Canoso JJ, Rubinow A, Spark EC: Gout without crystals on initial synovial fluid analysis. Postgrad Med J 54:95-97, Kelley WN, Fox IH: Gout and related disorders of purine metabolism, Textbook of Rheumatology. Second edition. Edited by WN Kelley, ED Harris Jr, S Ruddy, CB Sledge. Philadelphia, WB Saunders, 1985, pp