DISTAL EXTREMITY SWELLING WITH PITTING EDEMA IN POLYMYALGIA RHEUMATICA

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1 ARTHRITIS & RHEUMATISM Vol. 39, No. 1, January 1996, pp Q 1956, American College of Rheumatology 73 DISTAL EXTREMITY SWELLING WITH PITTING EDEMA IN POLYMYALGIA RHEUMATICA Report of Nineteen Cases CARL0 SALVARANI, SHERINE GABRIEL, and GENE G. HUNDER Objective. To determine the frequency and clinical characteristics of ditruse distal extremity swelling with pitting edema occurring in polymyalgia rheumatica (PMR). Methods. Clinical features and laboratory findings were recorded for all 245 residents of Ohsted County, Minnesota who developed PMR over a 22-year period ( ). Those who exhibited 21 episode of diffuse distal extremity edema with pitting were selected for this study, and were evaluated further. Results. Thirteen women and 6 men in this incidence cohort of PMR had 21 episode of distal extremity swelling with pitting edema. Giant cell arteritis was also identified in 5 patients. In 11 patients, the swelling and edema developed concurrently with proximal PMR symptoms. In 2 patients, the distal swelling was the initial manifestation, and in 6 patients, the distal symptoms developed during relapses or recurrences of PMR. Both upper and lower extremities were affected, usually in a symmetric manner. Other peripheral manifestations were also common. The distal swelling and pitting edema responded promptly to corticosteroids, and slowly or incompletely to nonsteroidal antiinflammatory drugs; a similar response was observed in the proximal symptoms. The distal swelling appeared to represent tenosynovitis and synovitis of regional structures. Conclusion. Distal extremity swelling with pitting edema represents a manifestation of PMR that has not been well described in previous studies. Awareness of Carlo Salvarani, MD, Sherine Gabriel, MD, MPH, Gene G. Hunder, MD: Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Dr. Salvarani's current address is Arcispedale S. Maria Nuova, Reggio Emilia, Italy. Address reprint requests to Gene G. Hunder, MD, Mayo Clinic, 200 First Street Southwest, Rochester, MN Submitted for publication May 10, 1995; accepted in revised form August I, this finding will help facilitate the proper diagnosis and institution of appropriate therapy for this disease. Polymyalgia rheumatica (PMR) is a clinical syndrome that occurs in persons 250 years old (14). It is characterized by aching and morning stiffness in the proximal portions of the body, and by evidence of a systemic reaction, usually indicated by an elevated erythrocyte sedimentation rate (ESR). The cause of the musculoskeletal pain is not completely understood, but inflammation in proximal joints and penarticular structures is a likely basis for much of the discomfort. In addition to axial discomfort in PMR, musculoskeletal symptoms can commonly occur distal to the elbows and knees (I,4-7). Such distal extremity symptoms tend to be less severe and more variable than proximal pains. These distal symptoms have been less well characterized, but include aching and stiffness similar to proximal pains, synovitis in 21 joint, tenosynovitis, and carpal tunnel syndrome. We have occasionally noted patients with PMR who have diffuse swelling in the distal extremities with pitting edema. In the present report, we focus on this latter finding associated with PMR, and have determined the frequency of distal extremity swelling with pitting edema and related clinical features in a population-based cohort of patients with PMR. PATIENTS AND METHODS We recently reported incidence rates of PMR in Olmsted County, Minnesota, over a 22-year period ( ) (8). We identified 245 residents of Olmsted County (173 women and 72 men) who met diagnostic criteria for PMR. These criteria were the following: 1) age 250 years; 2) bilateral aching and morning stiffness (lasting %30 minutes) persisting for at least 1 month and involving 2 of the

2 74 SALVARANI ET AL following areas: neck or torso, shoulders or proximal regions of the arms, and hips or proximal aspects of the thighs; 3) ESR (Westergren) elevated to 240 mdhour; and 4) the absence of another disease that would explain the findings. Information about the ascertainment of these cases of PMR in Olmsted County residents over the period of study was outlined in previous reports (1,8). We used a standardized data collection form to record information on each patient s age, sex, location of the aching and morning stiffness, joint abnormalities, the presence of systemic manifestations, onset and duration of disease, the presence of giant cell arteritis (GCA), results of temporal artery biopsy if performed, type of treatment used, along with dosage and duration, and the development of relapses or recurrences. Laboratory and radiologic data were recorded as available. Relapse was defined as an increase of articular symptoms or signs of PMR that occurred < 1 month after reduction or discontinuation of therapy, as well as regression of these symptoms or signs when the dosage of medication was increased or therapy was resumed. Recurrence was defined as the return of musculoskeletal symptoms of PMR >1 month after the discontinuation of therapy. The end of the disease was the date of permanent discontinuation of therapy without a relapse or recurrence. The end point of patient followup was the date of the last clinic visit or the date of death. Using this population incidence cohort, we collected data for the present study on patients who had episodes of distal extremity swelling. We recorded information on the presence of swelling of the joints and periarticular structures, synovitis, tenosynovitis, and diffuse swelling with and without pitting edema. For patients with diffuse distal extremity swelling with pitting edema, we recorded its location, duration, response to therapy, and any recurrences. RESULTS Nineteen of the 245 patients in the population cohort with PMR (8%) manifested 21 episode of diffuse distal extremity swelling with pitting edema during the course of the illness. The clinical features of these 19 patients compared with the overall group of 245 are shown in Table 1. Although some differences between the groups were present, none were statistically significant. Five of the patients (patients 1, 2, 13, 16, and 19) also had biopsy-proven GCA. Characteristics of the swelling with pitting edema. Table 2 lists the 19 patients and describes the site of the swelling and pitting edema, the relationship to the stage of the disease, and the influence of therapy on the swelling and edema. In 18 patients, 1 episode of swelling with edema of the distal extremity occurred. In the other patient (patient 18), 3 episodes occurred. In 2 patients (patients 4 and 18), the distal swelling with pitting edema was the initial manifestation. These 2 patients were treated with nonsteroidal antiinflammatory drugs (NSAIDs) and the swelling persisted as Table 1. Clinical features at diagnosis of polymyalgia rheumatica, in 19 patients with distal extremity pitting edema, compared with total cohort Patients with Total edema population Feature (n = 19) (n = 245) Age, years, median (range) Sex. F/M Aching and stiffness, % Shoulders/arms Hips/thighs Nec Wtorso Giant cell arteritis, no. Hemoglobin, gddl, median (range) Erythrocyte sedimentation rate, mm/hour, median (range) 75 (54-86) 13/ ( ) 73 (42-120) 74 (5 1-95) 173/ ( ) 69 (40-131) symptoms of PMR gradually developed over the following months. In 11 patients, the swelling with pitting edema and the symptoms of PMR developed concurrently. In 2 patients (patients 10 and 14), this manifestation was noted during a relapse of PMR, and in 4 patients, the episode occurred at a time of a recurrence of PMR after the initial course of therapy had been stopped (Table 2). In those patients with single episodes, 6 episodes involved the upper extremities, 8 episodes the lower extremities, and, in 4 episodes, both upper and lower extremities were involved. In patient 18, who had multiple episodes, both the upper and lower extremities were affected. In 5 patients, 1 extremity was involved, and in 14 patients, multiple extremities were involved. Fourteen episodes involved upper or lower extremities in a symmetric manner. The episodes of soft tissue swelling with pitting edema developed either subacutely or gradually over several days or longer. The area involved was reported to be painful, and the pain was made worse by moving the joints in the affected area. The tissues affected were usually tender to palpation and sometimes warm, but erythema was not prominent. The swelling and pitting edema usually occurred at the time PMR developed, relapsed, or recurred, indicating a connection with disease activity. In some cases, the areas of swelling and edema conformed to underlying joints or tendons, such as the posterior tibial tendon in patient 5 and Achilles tendons in patient 14. However, in most instances, the swelling was more diffuse and articular in location, but it extended beyond specific joint margins or other structures. The swelling and pitting

3 DISTAL EXTREMITY SWELLING WITH PITTING EDEMA IN PMR 75 Table 2. Characteristics of 19 patients with polymyalgia rheumatica and distal extremity pitting edema* Response to therapy Sexlage Patient (years) Site of swelling with edema Stage of disease NSAID Corticosteroids 1 FI84 Hands and wrists 0 2 Fl76 Hands and wrists Recurrence 7 years after onset 0 3 Fl69 Hands, wrists, ankles, feet 0 4 Fl82 Left ankle and foot, medial calf 3 months prior to onset 0 5 Fl54 Left ankle, especially along Recurrence 3% years after onset 0 + course of posterior tibia1 tendon 6 Fl70 Feet and pretibial areas - 7 Fl75 Right foot Recurrence 1 l/2 years after onset FI80 Left hand and wrist MI73 Left hand and wrist 0 t 10 M/86 Hands and wrists Relapse 9 months after onset - 11 MI82 Hands and wrists 0 12 FI84 Ankles and dorsum of feet - 13 MI72 Ankles, feet, pretibial region + 14 Fl57 Achilles tendons and distal calves Relapse 8 months after onset - + I5 MI57 Hands, wrists, ankles, feet Recurrence 13 years after onset Fl79 Ankles, feet, left hand ~n5 Hands, wrists, ankles, feet MI74 Left ankle 5 months prior to onset - - Right hand, both ankles + - Right hand, ankles, feet Relapse 14 months after onset Fno Ankles and feet + - * 0 indicates lack of response; + indicates response to therapy. NSAlD = nonsteroidal antiinflammatory drug. edema were most visible and prominent over the dorsum of the hands and wrists, the ankles, and the tops of the feet. The swelling and edema usually responded promptly to corticosteroids, and more slowly or incompletely to NSAIDS. In some cases, NSAID therapy resulted in no improvement and, when corticosteroids were substituted, the symptoms promptly improved (Table 2). In patients 3 and 9, carpal tunnel syndrome was also present at the time the dorsa of the hands and wrists were swollen and edematous (Tables 2 and 3). In both patients, carpal tunnel release surgery was performed and histologic examination of the tenosynovial membranes in the carpal tunnel showed evidence of lymphocytic synovitis. Other peripheral joint manifestations. In addition to the episodes of swelling and pitting edema, 17 of the 19 patients also had other peripheral findings distal to the arms and thighs during the course of the illness (Table 3). These included an additional episode of diffuse swelling of the hands, wrists, or feet in 6 patients, with pitting edema not recorded as being present (Table 3). Other musculoskeletal findings were generally diagnosable as synovitis of joints or tenosynovitis. Thirteen patients had further single episodes, 2 patients had 2 episodes (patients 2 and lo), and 2 others had 3 episodes (patients 18 and 19). None of the patients developed these other manifestations prior to the onset of PMR. However, 9 patients developed the symptoms concurrently with disease onset, and 6 developed them later during a relapse or recurrence of PMR (Table 3). Patients 18 and 19 developed these manifestations at onset and also later in the course of the disease. Patients 2, 5, and 18 developed transient peripheral symptoms in the absence of proximal aching and stiffness. Overall, these other musculoskeletal manifestations included synovitis of the knees in 11 patients, of the wrists in 1 patient, and of the rnetacarpophalangeal (MCP) joints or proximal interphalangeal (PIP) joints in 3 patients. Tenosynovitis developed in 6 patients (Table 3). As noted above, carpal tunnel syndrome occurred in 2 patients. These manifestations resolved completely after corticosteroid therapy was started. In 2 instances, synovial fluid was aspirated from a swollen joint when the pitting edema was also present, although the fluid was aspirated from a different extremity in each instance. In patient 16, the left knee yielded fluid with a leukocyte count of 10.0 x 109/liter, with 83% neutrophils. Right knee fluid from patient 7 yielded a leukocyte count of 1.2 X lo Aiter, with 17% neutrophils. In an additional patient (patient

4 76 SALVARANI ET AL Table 3. Peripheral musculoskeletal findings other than swelling with pitting edema in 19 patients with polymyalgia rheumatica (PMR)* Patient Finding Stage of disease PMR present Synovitis of wrists, MCPs, PIPs Synovitis, left knee Synovitis of MCPs, PIPs; extensor carpi ulnaris tendinitis Bilateral CTS Synovitis, left knee; left thumb extensor tendinitis Tenosynovitis, right posterior tibial tendon None Swelling, right wrist and hand; no pitting noted Synovitis, left knee Bilateral CTS Synovitis, right knee; tenosynovitis, right third palmar flexor tendon Swelling, both hands; pitting not noted None Swelling, right hand; pitting not noted; synovitis of both knees Swelling, dorsum left hand, especially over middle finger extensor tendon Swelling, left hand; pitting not noted; synovitis, right knee Swelling, dorsum left wrist; synovitis of both knees, wrists, MCPs, PIPs Synovitis, right knee; left carpi ulnaris tendinitis with swelling Swelling, dorsum right foot Relapse 4 months after onset Recurrence 7 years after onset 9 years after onset Relapse 3 years after onset - Relapse 9 months after onset 2 years after onset - Relapse 16 months after onset Recurrence 13 years after onset Relapse 5 months after onset Relapse 1% years after onset Relapse 11 months after onset Relapse 13 months after onset * MCPs = metacarpophalangeal joints; PIPs = proximal interphalangeal joints; CTS = carpal tunnel syndrome. No No - - No No 9), synovial fluid leukocytes were aspirated from the right knee at a time when PMR was present, but without swelling with pitting edema. The leukocyte count was 1.4 x lo iliter, with 11% neutrophils. Findings of rheumatoid factor tests were negative in all 17 patients tested. Fluorescent antinuclear antibody tests gave negative results in 10 patients, had a positive result with a serum titer of 1:20 in 1 patient, and had 1 negative and 1 positive result with a titer of 1:40 in 2 testings in another patient. Joint radiography was performed in all patients at some time point during the course of the illness. The radiographs showed either normal joints or evidence of osteoarthritis in all patients; none showed erosions or changes associated with rheumatoid arthritis (RA). CASE REPORTS Swelling with pitting edema near the onset of PMR. Patient 12, an 84-year-old woman, developed gradual onset of aching and morning stiffness in the shoulder and hip girdles. She felt tired, became anorectic, and had a weight loss of 3 kg. The symptoms became worse, and she was unable to function independently. Two months after onset, she developed pain, swelling, and pitting edema in the ankles and mid-dorsal areas of both feet. The ESR was 47 mm/ hour. A diagnosis of PMR was made. Prednisone, 15 mg/day, was started, with rapid resolution of joint pain within 48 hours after treatment. When she was seen for followup 18 days later, the aching and pain were absent and the foot swelling was nearly gone. The ESR was 12 mdhour. The prednisone dosage was gradually decreased, and was discontinued at the end of 1 year. The patient died of a myocardial infarction 7 years later, without a recurrence of PMR or foot swelling. Swelling with pitting edema at onset of PMR. Patient 1, an 84-year-old woman, developed dif use swelling in the dorsum of the right hand and wrist over a 1-2-week period. Shortly thereafter, she noted sim-

5 DISTAL EXTREMITY SWELLING WITH PITTING EDEMA IN PMR 77 ilar swelling in the left hand and wrist, as well as marked aching and morning stiffness of the neck, shoulders, and proximal regions of the arms. She developed marked fatigue, anorexia, and had a weight loss of 7 kg. Physical examination revealed tenderness and pitting edema in the dorsa of both hands. The patient s fingers were not affected, but she could not make complete fists. The ESR was 54 mdhour. Indomethacin, 25 mg 3 timedday, was started. Two weeks later, her condition had not improved, and the ESR was 82 mm/hour. Prednisone, 40 mg/day, was given. When she was seen 10 days later, the patient s symptoms had resolved. Four months later, the prednisone dosage had been reduced to 5 mg/day, and the proximal symptoms and diffuse swelling of the hands had returned. Pitting edema was not identified at this time. On this examination, however, it was believed that synovitis was present in the wrists, MCP joints, and PIP joints. The prednisone dosage was increased to 10 mglday, and joint symptoms and swelling resolved. Three months later, the patient stopped the prednisone treatment on her own. The proximal aching returned without hand or wrist swelling. She developed headache and jaw claudication. A temporal biopsy showed changes associated with GCA. Swelling with pitting edema on recurrence of PMR. Patient 2, a 76-year-old woman, developed aching and morning stiffness in the neck, torso, and shoulders. The ESR was 62 mmhour. Prednisone, 45 mg/day, was begun, and her symptoms resolved within 72 hours. Five months later, the prednisone was stopped after the dosage was gradually reduced. After an additional 3 months, her proximal aching and stiffness returned, and the ESR was 47 mm/hour. Prednisone was reinstituted, and her condition improved again. Six months later, the prednisone was discontinued without recurrence of symptoms. Seven years later, at age 83, the patient experienced the same aching and stiffness in the neck, shoulders, and hips. At the same time, she also developed painful swelling and pitting edema in both hands and a left knee effusion. The ESR was 86 mm/hour. She was started on a regimen of ibuprofen, but the symptoms did not improve. She was then given prednisone, 20 mg/day, and the proximal aching, as well as the hand and knee swelling, resolved. The ESR remained at 60 mdhour. When the prednisone dosage was lowered to 15 mg/day, she noted headache and jaw claudication. A temporal artery biopsy showed changes associated with partially treated GCA. Additional similar cases. In the cohort of 245 patients with PMR (8), there were 5 other patients who had diffuse swelling of 21 distal extremity, similar to the cases outlined above, except that pitting edema was not described in these 5 patients. This group included 3 men and 2 women, ages 67-80, with a median pretreatment ESR of 74 mmhour (range ). In 3 patients, dif use swelling in both hands and wrists was present. In the fourth patient, the dorsum of the right hand and wrist was swollen. In the fifth patient, the dorsum of the left hand and wrist was affected. Each of these 5 patients had 1 episode of distal extremity swelling. In 4 patients, the swelling of the hands and wrists began early in the course of the disease, in conjunction with proximal symptoms of PMR, and resolved along with the other symptoms when treatment with corticosteroids was started. In the fifth patient, diffuse swelling of both hands and wrists developed during a recurrence of PMR 1 year after the original onset of the disease. This last patient had a pretreatment ESR of 106 mmhour, and the symptoms showed a typical rapid response to treatment with prednisone, 20 mg/day. The prednisone was reduced and discontinued completely after 1 year. About 5 weeks later, the proximal aching and stiffness, and also diffuse swelling of the dorsal aspects of the hands, recurred. It was also noted that the digits and PIP joints in both hands appeared swollen. All symptoms resolved with administration of 10 mg of prednisone per day. The ESR, which had risen again to 82 mm/hour, dropped to 27 mm/hour after reinstitution of the prednisone. The prednisone was later reduced and eventually stopped without recurrence of PMR or hand swelling. One additional resident of Olmsted County, seen during the same period of time, developed typical manifestations of PMR, and also pitting edema of the hands and wrists, but was not included in the study cohort because the ESR did not reach the criterion of 40 mmhour (8). The patient was a 59-year-old man who developed aching in the shoulders, proximal aspects of the arms, hips, and proximal regions of the thighs and neck, with 2-3 hours of morning stiffness. The ESR rose from 9 mmhour before disease onset, to 27 mm/hour at the time of the diagnosis. The patient began treatment with 40 mg of prednisone/day and all the symptoms resolved rapidly, including the swelling of the hands and wrists. However, when the prednisone was reduced to 15 mg/day, the proximal aching and stiffness and bilateral hand pitting edema returned.

6 78 SALVARANI ET AL Sulindac was then added to the treatment regimen (prednisone maintained at 15 mglday). The symptoms gradually improved and eventually resolved, and did not recur 6 months later when the prednisone was discontinued completely. DISCUSSION This study was performed to determine the clinical characteristics of distal extremity swelling with pitting edema that may be seen in PMR. In an effort to provide an accurate clinical picture of the frequency and clinical spectrum of this manifestation, and to reduce selection and referral bias, we evaluated our community cohort of 245 patients with PMR. Among this patient cohort, 19 were observed to have had an episode of distal swelling with pitting edema. Five of the 19 patients also had GCA. Although there are no pathognomonic findings in PMR, the patients in the cohort fulfilled the preset diagnostic criteria, and none have developed another disease since onset that would explain the findings. None of the patients developed persistent synovitis, as seen in RA, that may occasionally occur in patients who initially develop PMR or GCA (9). All patients in this study cohort had 1 episode of swelling with pitting edema, except patient 18, who had 3 episodes. The episodes were observed during all phases of the disease, but occurred most often (in 11 patients) at the onset of PMR. In 2 other patients, the swelling with edema was the first manifestation; in 2 patients, it developed initially during a relapse of PMR; and in 4 patients, it occurred during a recurrence. Patient 18 had an episode at onset and during 2 relapses. In different members of the group, the upper and lower extremities were aeected singly or together. There was a tendency toward symmetric involvement. We observed no instances, in this group, in which the distal swelling and edema episodes occurred distinctly separate from the proximal symptoms of PMR. Six of the 19 patients had an additional episode of diffuse distal extremity swelling in which pitting edema was not described. It is possible that pitting may have been present in some of these instances, but not recorded by the examiner. Alternatively, the absence of pitting edema in these episodes, and in the 5 other patients, may simply indicate that the manifestation of diffuse swelling occurs in varying degrees. The nature of the episodes of swelling with pitting edema was not completely defined. However, they appeared to be part of the inflammatory processes of PMR, based on the location over or nearjoints, the association with the development of other articular symptoms of this syndrome, and the rapid response to corticosteroid therapy. The areas affected conformed best to the distribution of tenosynovial membranes. The swelling was also most prominent in areas where subcutaneous tissues are most distensible, such as the dorsum of the hand, foot, and ankle. The palmar and plantar surfaces, and the fingers and toes were also noted to be swollen in some instances, but without pitting. The swollen tissues were painful and tender and often warm, but erythema was seldom described. Motion of the joints in the region of the swollen tissues was painful and limited. For example, patients with swelling of the dorsum of the hand and wrist were unable to move the wrist through a full range of motion or make a complete fist. No biopsies of the obviously edematous tissues were obtained. But, in patients 3 and 9, flexor tenosynovitis of the wrist was observed in specimens that were obtained during surgery for carpal tunnel syndrome at the same time the dorsum of the hands were swollen. In patients 5 and 14, swelling and edema clearly conformed to the courses of tendons. There was no evidence of venous obstruction to account for the swelling. Lymphedema was not excluded. However, the distribution of soft tissue swelling appeared less extensive in an extremity, and more reversible in response to treatment, than would seem likely if the findings were secondary to lymphedema. Seventeen of the 19 patients also had other evidence of peripheral joint inflammation (Table 3). In some instances, these findings were more clearly recognizable as synovitis because soft tissue swelling occurred either in the anatomic location of the synovium or in the tenosynovial membranes, or joint effusions were present. The diffuse swelling without definite pitting edema may represent a spectrum of manifestations of a single pathologic process. Synovial fluid was aspirated from 3 joints, and the leukocyte count was moderately elevated in 1, and minimally elevated in 2 other patients. We conclude that the episodes of swelling and pitting edema were peripheral manifestations of the inflammatory processes associated with PMR and, most likely, secondary to a vigorous tenosynovitis. Synovitis of underlying joints also may be a component in some instances. The tenosynovitis with pitting edema may be one end of a spectrum of musculoskeletal manifestations of PMR. The 5 additional patients with PMR and diffuse swelling who were not described to have pitting edema may have had less marked

7 DISTAL EXTREMITY SWELLING WITH PITTING EDEMA IN PMR 79 tenosynovitis. The findings in these 5 patients, and the 1 other with typical PMR symptoms plus peripheral swelling and pitting edema but with an ESR <40 mmhour, further indicate that the manifestation of diffuse distal swelling in PMR is not rare. We are uncertain if these patients represent a specific subset of PMR. The relatively high frequency of other peripheral joint findings may suggest this, but further study is needed. Although peripheral joint involvement in PMR has been previously described (1,4-6), swelling with pitting edema in this condition has been poorly recognized. The most characteristic symptoms in PMR are proximal, and distal symptoms, when they occur, are usually mild. Thus, prominent distal swelling may focus attention away from the proximal symptoms. However, at least a few cases of PMR with pitting edema have been described previously (10-13). In some instances, the authors were uncertain about the link between the 2 conditions. Distal extremity swelling with pitting edema has been reported occasionally in various other rheumatic diseases. Conditions that most closely resemble our cases of PMR include late-onset seronegative RA, remitting seronegative symmetric synovitis with pitting edema, and late-onset peripheral seronegative spond ylarthropathy. Seronegative RA is considered as a diagnosis most clearly when distal polyarthritis persists chronically over years, with eventual destructive changes in joints. When limb edema occurs in RA, it is usually associated with destructive joint changes at the site of edema, and a rapid and complete or near-complete response to corticosteroid therapy is unusual (10,14-15). The swelling in all our patients resolved completely after corticosteroids were started, and eventually remained absent when treatment was reduced or discontinued. None of our patients experienced a course of prolonged and persistent synovitis. In remitting, seronegative, symmetric synovitis with pitting edema, described by McCarty et a1 (16,17), older patients had an acute onset of symmetric synovitis predominantly affecting the flexor digitorum tendon sheaths in the extremities, with pitting edema of the hands and feet. A high ESR was present, and symptoms responded promptly to small doses of prednisone. A remission was achieved without relapse within 3-36 months. However, many of the patients also were reported to have pain and stiffness and restricted motion in the shoulders, suggesting some similarity to PMR. Yet, some differences were also present. The patients in the McCarty et a1 study (16,17), as well as those in other studies, have been predominantly male, not all have had proximal limbgirdle symptoms, and residual flexor contraction of the fingers and wrists may have developed, which was not seen in our patients. HLA-B7 was positive in 15 of 23 patients tested by McCarty et al, whereas levels of HLA-DR4 are increased in patients with PMR (18,19). In addition, patients in our study also had unilateral or single lower extremity involvement, and the distal swelling and edema occurred during relapses or recurrences in some instances. However, some cases of the RS3PE syndrome have recently been reported to have unilateral involvement (13,20,21). Until more is understood about the etiology and pathogenetic factors in PMR, late-onset seronegative RA, and the syndrome described by McCarty and colleagues, the exact nature of the interrelationships among them will remain uncertain. In diseases of unknown etiology, without pathognomonic findings, categorization of all patients is unlikely to be achieved. Healey (11) noted 2 patients who had 3 steroidresponsive episodes, which, at different times, were typical of PMR, remitting, seronegative, symmetric synovitis with pitting edema, and seronegative RA. He has speculated that these 3 syndromes, at least in some cases, may be variants of the same process. Dubost and Sauvezie reported 10 patients with late-onset peripheral spondylarthropathy (22). All were men over the age of 50 with mild involvement of the axial skeleton, but who had lower limb oligoarthritis with swelling and pitting edema. They had prominent systemic symptoms and a high ESR. The conditions did not respond well to corticosteroids. All were HLA-B27 positive. Five patients were found later to have sacroiliitis. Olivieri et a1 (23) have described 2 similar cases. Compared with our cohort, these patients appeared different in several ways, including the response rate to corticosteroids, which we observed to be rapid in our patients. All 19 patients with PMR and pitting edema in our study, and the 5 additional similar cases, fulfilled the criteria for PMR, as defined by Bird and coworkers (24). In summary, we have described 13 women and 6 men with PMR from a population cohort of 245 patients who had 21 episode of distal extremity swelling with pitting edema, in conjunction with the characteristic proximal symptoms seen in this condition. The distal swelling with pitting edema responded favorably to therapy, as did the proximal symptoms. We conclude that the distal swelling with pitting edema in these patients, and the diffuse swelling without pitting

8 SALVARANI ET AL edema in others, are likely due to tenosynovitis, and represent a manifestation of this syndrome that has been poorly recognized previously. Awareness that distal swelling may occur in PMR will help reduce diagnostic confusion and facilitate institution of appropriate therapy. REFERENCES 1. Chung T-Y, Hunder GG, Ilstrup DM, Kurland LT: Polymyalgia rheumatica: a 10-year epidemiologic and clinical study. Ann Intern Med 97:672480, Healey LA: Long-term follow-up of polymyalgia rheumatica: evidence for s novitis. Semin Arthritis Rheum 13: , Bengtsson B- K, Malmvall B-E: The epidemiology of giant cell arteritis including temporal arteritis and polymyalgia rheumatica: incidences of different clinical presentations and eye complications. Arthritis Rheum 24: , Salvarani C, Macchioni PL, Tartoni PL, Rossi F, Baricchi R, Castri C, Chiaravalloti F, Portioli I: Polymyalgia rheumatica and giant cell arteritis: a 5-year epidemiologic and clinical study in Reggio Emilia, Italy. Clin Exp Rheumatol 5: , O Day JD, Hunder GG, Wahner HW: A follow-up study of polymyalgia rheumatica: evidence of chronic axial synovitis. J Rheumatol7: , Chou C-T, Schumacher HR Jr: Clinical and pathologic studies of synovitis in polymyalgia rheumatica. Arthritis Rheum 27: , Ahmed T, Braun AI: Carpal tunnel syndrome with polymyalgia rheumatica. Arthritis Rheum 21: , Salvarani C, Gabriel SE, O Fallon WM, Hunder GG: Epidemiology of polymyalgia rheumatica in Olmsted County, Minnesota, Arthritis Rheum 38: , Ginsburg WW, Cohen MD, Hall SB, Vollertsen RS, Hunder GG: Seronegative polyarthritis in giant cell arteritis. Arthritis Rheum 28: , Kiely PDW, Joseph AEA, Mortimer PS, Bourke BE: Upper limb lymphedema associated with polyarthritis of rheumatoid type. J Rheumatol 21: , Healey LA: RS3PE syndrome (letter). J Rheumatol 17:414, Marce S, Schaeverbeke T, Bannwarth B, Dehais J: Seronegative symmetrical polyarthritis with pitting oedema associated with antinuclear antibodies and a past history of giant cell arteritis (letter). Br J Rheumatol 33: , Salvarani C: Upper limb lymphedema in inflammatory arthropathy (letter). J Rheumatol 22:370, De Silva RTD, Grennan DM, Palmer D: Lymphatic obstruction in rheumatoid arthritis: a cause for upper limb edema. Ann Rheum Dis 39: , Dacre JE, Scott DL, Huskisson EC: Lymphoedema of the limbs as an extra-articular feature of rheumatoid arthritis. Ann Rheum Dis 49: , McCarty DJ, O Duffy JD, Pearson L, Hunter JB: Remitting seronegative symmetrical synovitis with pitting edema: RS3PE syndrome. JAMA 254: , Russell EB, Hunter JB, Pearson L, McCarty DJ: Remitting, seronegative, symmetrical synovitis with pitting edema: 13 additional cases. J Rheumatol 17:633439, Richardson JE, Gladman DD, Fam A, Keystone EC: HLA- DR4 in giant cell arteritis: association with polymyalgia rheumatica syndrome. Arthritis Rheum 30: , Weyand CM, Hunder NNH, Hicok KC, Hunder GG, Goronzy JJ: HLA-DRBl alleles in polymyalgia rheumatica, giant cell arteritis, and rheumatoid arthritis. Arthritis Rheum , Parisier KM, Canoso JJ: Remitting, seronegative (a) symmetrical synovitis with pitting edema: two cases of RS,PE syndrome. J Rheumatol 18: , Olivieri I, Padula A, Favaro L, Oranges GS, Fem S: RS3PE syndrome with unilateral involvement (letter). J Rheumatol 21: , Dubost J-J, Sauvezie B: Late onset peripheral spondyloarthropathy. J Rheumatol 16: , Olivieri I, Oranges CS, Sconosciuto F, Padula A, Ruju GP, Pasero G: Late onset peripheral seronegative spondyloarthropathy: report of two additional cases. J Rheumatol 20: , Bird HA, Esselinckx W, Dixon AS, Mowat AG, Wood PHN: An evaluation of criteria for polymyalgia rheumatica. Ann Rheum Dis 38: , 1979