1 Relation of giant cell arteritis to polymyalgia rheumatica L. A . H E A L E Y
It is evident that polymyalgia rheumatica and giant cell arteritis are related but the nature of the link between them is not known. Both syndromes occur in Caucasians almost exclusively; reports in other ethnic groups are rare. Both are diseases of older patients who are usually over age 60, and both are more common in women by a ratio of 2 or 3 : 1. The two syndromes are often seen in the same patient. Finally, giant cell arteritis has been found on biopsy of asymptomatic arteries in patients with polymyalgia. The question then arises, is polymyalgia always a manifestation of giant cell arteritis? Porsman (1951) and Paulley (1956) first pointed out the similarity between the prodromal stages of temporal arteritis and the syndrome that later came to be known as polymyalgia rheumatica. Paulley and Hughes (1960) described 76 patients with giant cell arteritis of whom 32 also had polymyalgia (then called anarthritic rheumatism). They first suggested that temporal arteritis and polymyalgia rheumatica might be two expressions of one underlying generalized giant cell arteritis. This association was confirmed by Alestig and Barr (1963) in Sweden. They biopsied temporal arteries that appeared normal to clinical examination in ten patients with polymyalgia rheumatica and found arteritis in seven. A review of the clinical histories of their patients reveals that four of them had headache or other symptoms suggestive of temporal arteritis but three did not. This finding has been confirmed many times. Terminology often leads to confusion when trying to compare reports by different authors. Polymyalgia rheumatica usually describes the rheumatic syndrome but giant cell arteritis (and its alternative terms, temporal arteritis and cranial arteritis) might refer to either a clinical syndrome, such as severe headache or blindness, or the histological finding, or to both. A useful convention was proposed by Boesen and Sorenson (1987). They used the terms polymyalgia rheumatica and temporal arteritis to define the typical clinical syndromes, whereas the term giant cell arteritis is used to denete the group as a whole, including patients with non-specific symptoms in whom the diagnosis was based on a positive biopsy. They state that it seems reasonable to assume that temporal arteritis and polymyalgia rheumatica may be two different clinical manifestations of the same generalized arteritis. Baitli~re's Clinical Rheurnatology--
Vol. 5, No. 3, December 1991 ISBN 0-7020-1537-7
371 Copyright 9 1991, by Bailli~re Tindall All rights of reproduction in any form reserved
372
L.A. HEALEY
In this chapter, their convention witl be followed in modified form. Polymyalgia rheumatica and temporal arteritis will be used to refer to clinical syndromes, and the term giant cell arteritis will be used to refer to the histological findings on biopsy. However, their assumption wilt be stated as a hypothesis that wilt be discussed with respect to three points: the nature of the two clinical syndromes: how frequently they coexist: and the time sequence of their appearance in the same patient. EPIDEMiOLOGICAL STUDIES When published series are reviewed, it is not surprising that most investigators from Scandinavia suspect that the two syndromes are part of the same disease and favour the concept, as expressed by Bengtsson (1990), that polymyalgia rheumatica is one expression of an underlying giant cell arteritis and therefore to be treated with an initial dose of 30 or 40 mg of prednisone. Since the initial paper of Alestig and Barr there have been other reports from Scandinavia on the frequency with which biopsies demonstrate giant cell arteritis. Hamrin (1972) reported a series of 93 patients, in 84 of whom temporal artery biopsy was performed. The biopsy was positive in 30 of 40 patients who had clinical symptoms of temporal arteritis, and in 18 of the 44 who had only polymyalgia rheumatica and apparently normal temporal arteries. Because of these findings, Hamrin suggested that the syndrome might more aptly be called polymyalgia arteritica. The experience of Fauchald et al (1972) from Oslo, Norway is similar. Of 94 patients sampled, the biopsy was positive in 41 of 45 patients with temporal arteritis, and also in 20 of 48 with polymyalgia alone. The authors found it difficult to make a practical clinical distinction between the two conditions. Bengtsson and Malmvall (1982) reported a series of 126 patients in G6teborg, Sweden. They found giant cell arteritis in the biopsy of 53 of 59 patients who had either temporal arteritis alone or temporal arteritis and polymyalgia, and in 21 of 67 patients with only polymyalgia. These patients were seen by the authors during a 3-year period at a referral hospital. In Boesen and Sorenson's study (1987), a prospective investigation of a Danish county, 46 new cases were diagnosed in a single year and followed for 3 years: 31 with polymyalgia alone, three with temporal arteritis, ten with both syndromes, and two with systemic symptoms and positive biopsy. Of the 31 patients with polymyalgia alone, biopsy was performed in 24 and was positive in five. In those series from Scandinavia that include a longer follow-up, more than 50% of the patients with polymyalgia had either clinical or biopsy evidence of arteritis. This has not been true in the reports from elsewhere in Europe or from North America, where the relative frequency of giant cell arteritis is significantly less. The best epidemiological information in North America is found in a series of studies performed in Olmstead County, Minnesota by investigators from the Mayo Clinic. They found an average annual incidence of giant cell
373
R E L A T I O N OF GCA I'O PMR
arteritis to be 17.0 per 100 000 population aged 50 and older (Machado et al, 1988). The rate in G6teborg for the same age group was almost identical, 16.8 per 100 000 (Bengtsson and Malmvall. 1982). In Olmstead County, the annual incidence for polymyalgia rheumatica was 53.7 per 100 000 persons aged 50 and older (Chuang et al. t982) compared with an annual incidence of 28.6 per 100 000 in G6teborg. These figures suggest that the frequency of giant cell arteritis is roughly the same in Scandinavia and in Minnesota but that in Minnesota there are many more patients who have only polymyalgia without associated giant cell arteritis. i have not carried out a formal epidemiological study but in my series of 246 patients with polymyalgia rheumatica followed long term, 55 patients had temporal arteritis, which was proven by biopsy in 48 (Healey, 1984). This figure of 22% is similar to the Mayo Clinic series in which 15 of 96 patients (16%) with polymyalgia rheumatica also had temporal arteritis (Chuang et al, 1982). In striking contrast is the experience of Spiera and Davison (1982) in New York City. They see many patients with polymyalgia rheumatica but temporal arteritis is rare, having occurred in only four of 400 patients treated with low dose prednisone and followed closely for years. They disagree with the need for high dose prednisone and find that patients do well when treated with an initial dose of 5-10 mg per day. Many of their patients are of Jewish descent, and the study of Friedman et al (1982), who found a relatively low incidence of temporal arteritis in Israel, might be confirmatory. The highest annual incidence rate was found in western Jewish males (of European and American origin). This was only 1.2 per 100 000 for the population over age 50, which is strikingly different from the figure of 17 per 100 000 found in G6teborg and in Olmstead County. Another way to look at this question and eliminate any possible bias that might enter into retrospective reviews is with prospective studies in which all patients who have a diagnosis of polymyalgia rheumatica and no symptoms to suggest temporal arteritis have a temporal artery biopsy performed as a routine procedure or investigation, rather than as a clinical decision based on symptoms. There are only a few such studies and the results are shown in Table 1. In Norway and Sweden, the chance of finding giant cell arteritis in an innocuous temporal artery in a patient with polymyalgia ranges from 31 to Table 1. Positive biopsies in patients with polymyalgiarheumatiea. Location Vaxjo, Sweden G6teborg, Sweden Oslo, Norway Ribe, Denmark London, England Rochester MN, USA New York, USA
Number biopsied
Numberpositive
44 67 48 24 18 36 14
t8 (41) 21 (31) 20 (41) 5 (21) 2 (11) 2 (6) 0
Values in parentheses are percentages.
374
L. A, H E A L E Y
41%. In similar studies carried out in other countries, the numbers are small but the results are very different. Dixon et al (1966) found two positive biopsies in samples from 18 patients in London. The largest series is from the Mayo Clinic, where H u n d e r and Allen (1973) biopsied 36 consecutive patients with polymyalgia and found just two (6%) with arteritis. Spiera and Davison (1982) in New York City found no evidence of arteritis in 14 patients biopsied. Thus polymyaigia rheumatica appears to associate with giant ceil arteritis frequently in Scandinavia, more often than would be expected by chance in the rest of Europe and in North America, and rarely in Israel. In all series, there are some patients with polymyalgia who never develop temporal arteritis and who have a negative biopsy. The converse is also true. In every study, there are a significant number of patients with temporal arteritis who never have polymyalgia. Of 42 patients seen at the Mayo Clinic over a 25-year period, Huston et al (1978) found that 22 (52%) did not have polymyalgia. It is hard to be certain about the exact percentages because the two syndromes do not always present at the same time.
TEMPORAL RELATION
As mentioned, polymyalgia rheumatica was first considered to be a prodrome of temporal arteritis, but this is not always the case. The two syndromes often appear together but they may also be separated by a long interval and either one may appear first. For this reason, prolonged observation is necessary to appreciate how frequently the two occur in the same patient. The two syndromes appeared simultaneously or within 1 year of one another in 29 of 45 patients who had both polymyalgia and temporal arteritis (Healey, 1986). However, in 16, the interval was from 1 to 6 years. Polymyalgia was the initial manifestation in seven patients and temporal arteritis came first in nine. Huston et al (1978) also noted that temporal arteritis was often the initial manifestation. Subsequent to the 1986 report, I have seen a patient in whom headache, partial vision loss and biopsy-proven giant cell arteritis appeared 10 years after the polymyalgia was recognized and treated. Jones and Hazleman (1981) report a patient in whom the interval between the appearance of polymyalgia and arteritis was 9 years. Even recognizing that the interval may be tong, there are many patients with polymyalgia who have been followed for a sufficient number of years to be certain that they do not have temporal arteritis.
CLINICAL COURSE It now seems evident from arthroscopy and biopsy studies (Douglas et at, 1983; Chou and Schumacher, 19841 that the symptoms of polymya!gia are due to synovitis, which is located primarily in shoulder and hip joints. While this is very responsive to steroid, it is not always self-limited and may persist,
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375
relapse or recur (Chuang et al, 1982; Healey, 1984). Conversely, temporal arteritis is almost always a single episode; documented instances of late recurrence are rare. Huston et al (1978) found temporal arteritis to be a self-limited illness, lasting less than a year, but they noted that recurrences of polymyalgia were frequent. Most reported recurrences of temporal arteritis prove to be either polymyalgia rheumatica, an elevation of the sedimentation rate without symptoms, or non-specific headache. There are only a few documented instances of recurrent temporal arteritis; these seem to be the exceptions to the rule. Blumberg et al (1980) report a patient with headache, elevated sedimentation rate and a biopsy demonstrating granulomatous arteritis, who had another headache 9 years later. A biopsy on the other side showed inflammation in the adventitia of the artery rather than the usual medial and intimal layers, a sedimentation rate over 100, and again a response to prednisone. Beevers et al (1973) report a woman with headache, high sedimentation rate and positive biopsy who was treated with steroid in unknown dose. Six months later she had a return of symptoms. Biopsy of the contralateral artery showed "dense round cell infiltration', but not what was regarded as active giant cell arteritis. Such documented cases are difficult to find, particularly if the initial episode is treated with at least 40 mg of prednisone a day for a month, a dose that is considered sufficient to suppress the inflammation. Polymyalgia rheumatica and giant cell arterics differ clinically in ways that suggest that they are separate syndromes. Polymyalgia is a synovitis that tends to run a prolonged or recurring course. Temporal arteritis is a vasculitis that almost always appears as a single episode. This episode may either precede, coincide with, or follow the appearance of polymyalgia. Even if the clinical episode of temporal arteritis is self-limited and does not coincide with the duration of the polymyalgia, it is still theoretically possible that the histological giant cell arteritis might persist. We know from the biopsy studies of normal arteries in patients with polymyalgia that it can be present without symptoms, but there is little experience with repeat biopsy to know if it persists. Rynes et al (1977) have reported a case that provides some information. A 70-year-old woman with polymyalgia rheumatica had a normal temporal artery biopsy and a good response to low dose prednisone. Two months later, she developed headache and a tender contralateral temporal artery; biopsy demonstrated giant cell arteritis. Hall et al (1983) describe one similar patient in a review of their experience with temporal artery biopsy at the Mayo Clinic. Since the inflammation is randomly distributed, rather than involving the arterial wall uniformly, it is possible to speculate that the initial biopsy failed to locate an involved area. This cannot be disproved but the report of Hall et al (1983) makes it unlikely. They reviewed the records of t34 patients who had undergone temporal artery biopsy: 46 biopsies were positive and 88 were negative. In the follow-up period, which extended to 192 months (mean of 70 months), only eight of the 88 patients with negative biopsy developed clinical temporal arteritis. The most extensive experience with serial biopsies is in the report of Fauchald et al (1972). They obtained repeat biopsies in 20 patients following
376
L . A . HEALEY
completion of treatment for temporal arteritis. Two samples showed active arteritis, two years and 10 years after treatment was completed. The patient biopsied two years later still showed clinical signs of disease. Four patients had what the authors called residual infiltration, i.e. a few small infiltrates of lymphocytes in the media or intima. In 14 patients, the picture was that of healed arteritis, showing fibrosis and disruption of the internal elastic lamina without any inflammation. This report indicates that when temporal arteritis is treated with high dose prednisone, active inflammation is usually suppressed and does not persist in the arterial wall.
CONCLUSIONS Based on observations cited, it seems more accurate to regard the two syndromes as associated, rather than to state that one, polymyalgia rheumatica, is a manifestation of the other, an underlying giant celt arteritis. The two frequently do not appear in the same patient at the same time. The more chronic synovitis of polymyalgia may be clinically active long before the temporal arteritis presents, or it may come on after the episode of temporal arteritis has been treated and no active inflammation remains in the artery. Some patients have only temporal arteritis or only polymyalgia rheumatica and never develop the other illness. As to the question of how frequently the two are associated, there are conflicting answers which range from 'most of the time' in Scandinavia to 'almost never' in Israel. The figures for the rest of Europe and North America are somewhere between these two extremes. The conflicting studies seem to be accurate and the discrepancies are not explained by errors of ascertainment or selection bias. It is probable that all investigators are correct for the populations they have tested. These observations naturally lead to speculation as to probable causes. The available evidence is consistent with either hereditary or environmental factors or a combination of both, but the initial suspicion leans toward a genetic explanation. There may be separate populations with different genetic susceptibilities. In Scandinavia, the older patient reacts to an unknown stimulus with the development of both polymyalgia and temporal arteritis. In Israel, the putative stimulus leads to polymyalgia rheumatica alone. In other locations in the rest of Europe and North America, the two populations are mixed in varying percentages. Since the incidence of polymyalgia rheumatica in Olmstead county is almost twice that in G6teborg (53.7 versus 28.6), this suggests that there are many people in Minnesota with the same genetic tendency toward giant cell arteritis as the Scandinavian patients, plus an additional group who respond with polymyalgia rheumatica alone. Thus the total number with polymyalgia rheumatica is greater but the percentage of them who also have temporal arteritis is less than in Scandinavia. The information from H L A typing studies to date has not been helpful. Most studies have used serological testing methods and the results with class I antigens has been variable and shown no consistent relationship. Several
RELATION OF GCA TO PMR
377
studies have shown the f r e q u e n c y of the class 11 antigen H L A - D R 4 to be increased to a b o u t twice the f r e q u e n c y f o u n d in control populations. H o w ever, these studies have not carefully separated patients with polymyalgia rheumatica f r o m those with giant cell arteritis. A s H u n d e r (1990) has pointed out, tests with mixed l y m p h o c y t e cultures which divide the H L A - D R 4 into its subtypes D w l 0 , D w l 3 , D w l 4 and D w l 5 m a y well provide further information, particularly if care is taken to segregate the patients into the groups identified clinically as having both s y n d r o m e s or just polymyalgia rheumatica.
SUMMARY Polymyalgia rheumatica and t e m p o r a l arteritis a p p e a r to be separate syndromes rather than two manifestations of an underlying giant cell arteritis. Polymyalgia r h e u m a t i c a is a synovitis that m a y be persistent or recurrent, while t e m p o r a l arteritis is almost always a single episode; d o c u m e n t e d recurrences are rare. T h e two s y n d r o m e s frequently occur in the same patient although not necessarily at the same time and t h e y m a y be separated by a long interval. I n some patients with polymyalgia rheumatica, giant cell arteritis is f o u n d on biopsy o f an a s y m p t o m a t i c t e m p o r a l artery. T h e frequency of this concurrence is variable in different populations. It is high in Scandinavia, low in Israel and intermediate b e t w e e n these extremes in other populations that have b e e n studied.
REFERENCES Alestig K & Barr J (1963) Giant cell arteritis. Lancet i: 1228-1230. Beevers DG, Harpur JE & Turk KAD (1973) Giant cell arteritis: the need for prolonged treatment. Journal of Chronic Diseases 26: 571-584. Bengtsson B-A (1990) Giant cell arteritis. Current Opinion in Rheumatology 2: 60-65. Bengtsson B-A & Malmvall B-E (1982) Giant cell arteritis. Acta Medica Scandinavica, Supplement 658: 18-28. Blumberg S, Giansiracusa DF, Docken WP & Kantrowitz FG (1980) Recurrence of temporal arteritis. Journal o f the American Medical Association 244: 1713. Boesen P & Sorenson SF (1987) Giant cell arteritis, temporal arteritis, and polymyalgia rheumatica in a Danish county. Arthritis and Rheumatism 30: 294--299. Chou C-T & Schumacher HR (1984) Clinical and pathologic studies of synovitis in polymyalgia rheumatica. Arthritis and Rheumatism 27: 1107-1118. Chuang TY, Hunder G, Ilstrup DM & Kurland LT (1982) Polymyalgia rheumatica. A 10-year epidemiologic and clinical study. Annals of Internal Medicine 97: 672-680. Dixon A StJ, Beardwell C, Kay A, Wanka J & Wong YT (1966) Polymyalgia rheumatica and temporal arteritis. Annals o f the Rheumatic Diseases 25: 203-208. Douglas WAC, Martin BA & Morris JH (1983) Polymyalgia rheumatica: an arthroscopic study of the shoulder joint. Annals of the Rheumatic Diseases 42:311-316. Fauchald P, Rygvold O & Oystese B (1972) Temporal arteritis and polymyalgia rheumatica: clinical and biopsy findings. Annals o f Internal Medicine 77: 845-852. Friedman G, Friedman B & Benbasset J (1982) Epidemiology of temporal arteritis in Israel. Israel Journal o f Medical Sciences 18: 241-244.
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Hall S, Lie JT, Kurland LT et al (1983) The therapeutic impact of temporal artery biopsy. Lancet ii: 1217-1220. Hamrin B (1972) Polymyalgia arteritica. Acta Medica Scandinavica, Supplement 533: 1-164. Healey LA (1984) Long-term follow-up of polymyalgia rheumatica: evidence for synovitis. Seminars in Arthritis and Rheumatism 13: 322-328. Healey LA (1986) The relationship of polymyalgia rheumatica to giant cell arteritis--single or separate syndromes? Journal o f Rheumatology 13: 1190. Hunder G (1990) Immunogenetics and polymyalgia rheumatica (editorial). British Journal of Rheumatology 29: 321-324. Hunder G & Allen GL (1973) The relationship between polymyalgia rheumatica and temporal arteritis. Geriatrics 28: 134-142. Huston KA, Hunder G, Lie JT, Kennedy RH & Elveback LR (1978) Temporal arteritis: a 25 year epidemiologic, clinical and pathologic study. Annals of Internal Medicine 88:162-167. Jones JG & Hazleman BL (1981) Prognosis and management of polymyalgia rheumatica. Annals of the Rheumatic Diseases 40: 1-5. Machado EBV, Michet C J, Ballard DJ et al (1988) Trends in incidence and clinical presentation of temporal arteritis in Olmstead County, Minnesota, 1950-1985. Arthritis and Rheumatism 31: 745-749. Paulley JW (1956) Anarthritic rheumatoid disease. Lancet ii: 946. Paulley JW & Hughes JP (1960) Giant cell arteritis, or arteritis of aged. British Medical Journal 2: 1562-1567. Porsman VA (1951) Proc 11 Congress European Rheum Editorial Scientia, Barcelona p. 479. Rynes RI, Mika P & Bartholomew LE (1977) Development of giant cell (temporal) arteritis in a patient 'adequately' treated for polymyalgia rheumatica. Annals of the Rheumatic Diseases 36: 88-90. Spiera H & Davison S (1978) Long term follow-up of polymyalgia rheumatica. Mount Sinai Journal o f Medicine 45: 225-229. Spiera H & Davison S (1982) Treatment of polymyalgia rheumatica. Arthritis and Rheumatism 25: 120.
It is evident that polymyalgia rheumatica and giant cell arteritis are related but the nature of the link between them is not known. Both syndromes occur in Caucasians almost exclusively; reports in other ethnic groups are rare. Both are diseases of older patients who are usually over age 60, and both are more common in women by a ratio of 2 or 3 : 1. The two syndromes are often seen in the same patient. Finally, giant cell arteritis has been found on biopsy of asymptomatic arteries in patients with polymyalgia. The question then arises, is polymyalgia always a manifestation of giant cell arteritis? Porsman (1951) and Paulley (1956) first pointed out the similarity between the prodromal stages of temporal arteritis and the syndrome that later came to be known as polymyalgia rheumatica. Paulley and Hughes (1960) described 76 patients with giant cell arteritis of whom 32 also had polymyalgia (then called anarthritic rheumatism). They first suggested that temporal arteritis and polymyalgia rheumatica might be two expressions of one underlying generalized giant cell arteritis. This association was confirmed by Alestig and Barr (1963) in Sweden. They biopsied temporal arteries that appeared normal to clinical examination in ten patients with polymyalgia rheumatica and found arteritis in seven. A review of the clinical histories of their patients reveals that four of them had headache or other symptoms suggestive of temporal arteritis but three did not. This finding has been confirmed many times. Terminology often leads to confusion when trying to compare reports by different authors. Polymyalgia rheumatica usually describes the rheumatic syndrome but giant cell arteritis (and its alternative terms, temporal arteritis and cranial arteritis) might refer to either a clinical syndrome, such as severe headache or blindness, or the histological finding, or to both. A useful convention was proposed by Boesen and Sorenson (1987). They used the terms polymyalgia rheumatica and temporal arteritis to define the typical clinical syndromes, whereas the term giant cell arteritis is used to denete the group as a whole, including patients with non-specific symptoms in whom the diagnosis was based on a positive biopsy. They state that it seems reasonable to assume that temporal arteritis and polymyalgia rheumatica may be two different clinical manifestations of the same generalized arteritis. Baitli~re's Clinical Rheurnatology--
Vol. 5, No. 3, December 1991 ISBN 0-7020-1537-7
371 Copyright 9 1991, by Bailli~re Tindall All rights of reproduction in any form reserved
372
L.A. HEALEY
In this chapter, their convention witl be followed in modified form. Polymyalgia rheumatica and temporal arteritis will be used to refer to clinical syndromes, and the term giant cell arteritis will be used to refer to the histological findings on biopsy. However, their assumption wilt be stated as a hypothesis that wilt be discussed with respect to three points: the nature of the two clinical syndromes: how frequently they coexist: and the time sequence of their appearance in the same patient. EPIDEMiOLOGICAL STUDIES When published series are reviewed, it is not surprising that most investigators from Scandinavia suspect that the two syndromes are part of the same disease and favour the concept, as expressed by Bengtsson (1990), that polymyalgia rheumatica is one expression of an underlying giant cell arteritis and therefore to be treated with an initial dose of 30 or 40 mg of prednisone. Since the initial paper of Alestig and Barr there have been other reports from Scandinavia on the frequency with which biopsies demonstrate giant cell arteritis. Hamrin (1972) reported a series of 93 patients, in 84 of whom temporal artery biopsy was performed. The biopsy was positive in 30 of 40 patients who had clinical symptoms of temporal arteritis, and in 18 of the 44 who had only polymyalgia rheumatica and apparently normal temporal arteries. Because of these findings, Hamrin suggested that the syndrome might more aptly be called polymyalgia arteritica. The experience of Fauchald et al (1972) from Oslo, Norway is similar. Of 94 patients sampled, the biopsy was positive in 41 of 45 patients with temporal arteritis, and also in 20 of 48 with polymyalgia alone. The authors found it difficult to make a practical clinical distinction between the two conditions. Bengtsson and Malmvall (1982) reported a series of 126 patients in G6teborg, Sweden. They found giant cell arteritis in the biopsy of 53 of 59 patients who had either temporal arteritis alone or temporal arteritis and polymyalgia, and in 21 of 67 patients with only polymyalgia. These patients were seen by the authors during a 3-year period at a referral hospital. In Boesen and Sorenson's study (1987), a prospective investigation of a Danish county, 46 new cases were diagnosed in a single year and followed for 3 years: 31 with polymyalgia alone, three with temporal arteritis, ten with both syndromes, and two with systemic symptoms and positive biopsy. Of the 31 patients with polymyalgia alone, biopsy was performed in 24 and was positive in five. In those series from Scandinavia that include a longer follow-up, more than 50% of the patients with polymyalgia had either clinical or biopsy evidence of arteritis. This has not been true in the reports from elsewhere in Europe or from North America, where the relative frequency of giant cell arteritis is significantly less. The best epidemiological information in North America is found in a series of studies performed in Olmstead County, Minnesota by investigators from the Mayo Clinic. They found an average annual incidence of giant cell
373
R E L A T I O N OF GCA I'O PMR
arteritis to be 17.0 per 100 000 population aged 50 and older (Machado et al, 1988). The rate in G6teborg for the same age group was almost identical, 16.8 per 100 000 (Bengtsson and Malmvall. 1982). In Olmstead County, the annual incidence for polymyalgia rheumatica was 53.7 per 100 000 persons aged 50 and older (Chuang et al. t982) compared with an annual incidence of 28.6 per 100 000 in G6teborg. These figures suggest that the frequency of giant cell arteritis is roughly the same in Scandinavia and in Minnesota but that in Minnesota there are many more patients who have only polymyalgia without associated giant cell arteritis. i have not carried out a formal epidemiological study but in my series of 246 patients with polymyalgia rheumatica followed long term, 55 patients had temporal arteritis, which was proven by biopsy in 48 (Healey, 1984). This figure of 22% is similar to the Mayo Clinic series in which 15 of 96 patients (16%) with polymyalgia rheumatica also had temporal arteritis (Chuang et al, 1982). In striking contrast is the experience of Spiera and Davison (1982) in New York City. They see many patients with polymyalgia rheumatica but temporal arteritis is rare, having occurred in only four of 400 patients treated with low dose prednisone and followed closely for years. They disagree with the need for high dose prednisone and find that patients do well when treated with an initial dose of 5-10 mg per day. Many of their patients are of Jewish descent, and the study of Friedman et al (1982), who found a relatively low incidence of temporal arteritis in Israel, might be confirmatory. The highest annual incidence rate was found in western Jewish males (of European and American origin). This was only 1.2 per 100 000 for the population over age 50, which is strikingly different from the figure of 17 per 100 000 found in G6teborg and in Olmstead County. Another way to look at this question and eliminate any possible bias that might enter into retrospective reviews is with prospective studies in which all patients who have a diagnosis of polymyalgia rheumatica and no symptoms to suggest temporal arteritis have a temporal artery biopsy performed as a routine procedure or investigation, rather than as a clinical decision based on symptoms. There are only a few such studies and the results are shown in Table 1. In Norway and Sweden, the chance of finding giant cell arteritis in an innocuous temporal artery in a patient with polymyalgia ranges from 31 to Table 1. Positive biopsies in patients with polymyalgiarheumatiea. Location Vaxjo, Sweden G6teborg, Sweden Oslo, Norway Ribe, Denmark London, England Rochester MN, USA New York, USA
Number biopsied
Numberpositive
44 67 48 24 18 36 14
t8 (41) 21 (31) 20 (41) 5 (21) 2 (11) 2 (6) 0
Values in parentheses are percentages.
374
L. A, H E A L E Y
41%. In similar studies carried out in other countries, the numbers are small but the results are very different. Dixon et al (1966) found two positive biopsies in samples from 18 patients in London. The largest series is from the Mayo Clinic, where H u n d e r and Allen (1973) biopsied 36 consecutive patients with polymyalgia and found just two (6%) with arteritis. Spiera and Davison (1982) in New York City found no evidence of arteritis in 14 patients biopsied. Thus polymyaigia rheumatica appears to associate with giant ceil arteritis frequently in Scandinavia, more often than would be expected by chance in the rest of Europe and in North America, and rarely in Israel. In all series, there are some patients with polymyalgia who never develop temporal arteritis and who have a negative biopsy. The converse is also true. In every study, there are a significant number of patients with temporal arteritis who never have polymyalgia. Of 42 patients seen at the Mayo Clinic over a 25-year period, Huston et al (1978) found that 22 (52%) did not have polymyalgia. It is hard to be certain about the exact percentages because the two syndromes do not always present at the same time.
TEMPORAL RELATION
As mentioned, polymyalgia rheumatica was first considered to be a prodrome of temporal arteritis, but this is not always the case. The two syndromes often appear together but they may also be separated by a long interval and either one may appear first. For this reason, prolonged observation is necessary to appreciate how frequently the two occur in the same patient. The two syndromes appeared simultaneously or within 1 year of one another in 29 of 45 patients who had both polymyalgia and temporal arteritis (Healey, 1986). However, in 16, the interval was from 1 to 6 years. Polymyalgia was the initial manifestation in seven patients and temporal arteritis came first in nine. Huston et al (1978) also noted that temporal arteritis was often the initial manifestation. Subsequent to the 1986 report, I have seen a patient in whom headache, partial vision loss and biopsy-proven giant cell arteritis appeared 10 years after the polymyalgia was recognized and treated. Jones and Hazleman (1981) report a patient in whom the interval between the appearance of polymyalgia and arteritis was 9 years. Even recognizing that the interval may be tong, there are many patients with polymyalgia who have been followed for a sufficient number of years to be certain that they do not have temporal arteritis.
CLINICAL COURSE It now seems evident from arthroscopy and biopsy studies (Douglas et at, 1983; Chou and Schumacher, 19841 that the symptoms of polymya!gia are due to synovitis, which is located primarily in shoulder and hip joints. While this is very responsive to steroid, it is not always self-limited and may persist,
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relapse or recur (Chuang et al, 1982; Healey, 1984). Conversely, temporal arteritis is almost always a single episode; documented instances of late recurrence are rare. Huston et al (1978) found temporal arteritis to be a self-limited illness, lasting less than a year, but they noted that recurrences of polymyalgia were frequent. Most reported recurrences of temporal arteritis prove to be either polymyalgia rheumatica, an elevation of the sedimentation rate without symptoms, or non-specific headache. There are only a few documented instances of recurrent temporal arteritis; these seem to be the exceptions to the rule. Blumberg et al (1980) report a patient with headache, elevated sedimentation rate and a biopsy demonstrating granulomatous arteritis, who had another headache 9 years later. A biopsy on the other side showed inflammation in the adventitia of the artery rather than the usual medial and intimal layers, a sedimentation rate over 100, and again a response to prednisone. Beevers et al (1973) report a woman with headache, high sedimentation rate and positive biopsy who was treated with steroid in unknown dose. Six months later she had a return of symptoms. Biopsy of the contralateral artery showed "dense round cell infiltration', but not what was regarded as active giant cell arteritis. Such documented cases are difficult to find, particularly if the initial episode is treated with at least 40 mg of prednisone a day for a month, a dose that is considered sufficient to suppress the inflammation. Polymyalgia rheumatica and giant cell arterics differ clinically in ways that suggest that they are separate syndromes. Polymyalgia is a synovitis that tends to run a prolonged or recurring course. Temporal arteritis is a vasculitis that almost always appears as a single episode. This episode may either precede, coincide with, or follow the appearance of polymyalgia. Even if the clinical episode of temporal arteritis is self-limited and does not coincide with the duration of the polymyalgia, it is still theoretically possible that the histological giant cell arteritis might persist. We know from the biopsy studies of normal arteries in patients with polymyalgia that it can be present without symptoms, but there is little experience with repeat biopsy to know if it persists. Rynes et al (1977) have reported a case that provides some information. A 70-year-old woman with polymyalgia rheumatica had a normal temporal artery biopsy and a good response to low dose prednisone. Two months later, she developed headache and a tender contralateral temporal artery; biopsy demonstrated giant cell arteritis. Hall et al (1983) describe one similar patient in a review of their experience with temporal artery biopsy at the Mayo Clinic. Since the inflammation is randomly distributed, rather than involving the arterial wall uniformly, it is possible to speculate that the initial biopsy failed to locate an involved area. This cannot be disproved but the report of Hall et al (1983) makes it unlikely. They reviewed the records of t34 patients who had undergone temporal artery biopsy: 46 biopsies were positive and 88 were negative. In the follow-up period, which extended to 192 months (mean of 70 months), only eight of the 88 patients with negative biopsy developed clinical temporal arteritis. The most extensive experience with serial biopsies is in the report of Fauchald et al (1972). They obtained repeat biopsies in 20 patients following
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completion of treatment for temporal arteritis. Two samples showed active arteritis, two years and 10 years after treatment was completed. The patient biopsied two years later still showed clinical signs of disease. Four patients had what the authors called residual infiltration, i.e. a few small infiltrates of lymphocytes in the media or intima. In 14 patients, the picture was that of healed arteritis, showing fibrosis and disruption of the internal elastic lamina without any inflammation. This report indicates that when temporal arteritis is treated with high dose prednisone, active inflammation is usually suppressed and does not persist in the arterial wall.
CONCLUSIONS Based on observations cited, it seems more accurate to regard the two syndromes as associated, rather than to state that one, polymyalgia rheumatica, is a manifestation of the other, an underlying giant celt arteritis. The two frequently do not appear in the same patient at the same time. The more chronic synovitis of polymyalgia may be clinically active long before the temporal arteritis presents, or it may come on after the episode of temporal arteritis has been treated and no active inflammation remains in the artery. Some patients have only temporal arteritis or only polymyalgia rheumatica and never develop the other illness. As to the question of how frequently the two are associated, there are conflicting answers which range from 'most of the time' in Scandinavia to 'almost never' in Israel. The figures for the rest of Europe and North America are somewhere between these two extremes. The conflicting studies seem to be accurate and the discrepancies are not explained by errors of ascertainment or selection bias. It is probable that all investigators are correct for the populations they have tested. These observations naturally lead to speculation as to probable causes. The available evidence is consistent with either hereditary or environmental factors or a combination of both, but the initial suspicion leans toward a genetic explanation. There may be separate populations with different genetic susceptibilities. In Scandinavia, the older patient reacts to an unknown stimulus with the development of both polymyalgia and temporal arteritis. In Israel, the putative stimulus leads to polymyalgia rheumatica alone. In other locations in the rest of Europe and North America, the two populations are mixed in varying percentages. Since the incidence of polymyalgia rheumatica in Olmstead county is almost twice that in G6teborg (53.7 versus 28.6), this suggests that there are many people in Minnesota with the same genetic tendency toward giant cell arteritis as the Scandinavian patients, plus an additional group who respond with polymyalgia rheumatica alone. Thus the total number with polymyalgia rheumatica is greater but the percentage of them who also have temporal arteritis is less than in Scandinavia. The information from H L A typing studies to date has not been helpful. Most studies have used serological testing methods and the results with class I antigens has been variable and shown no consistent relationship. Several
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studies have shown the f r e q u e n c y of the class 11 antigen H L A - D R 4 to be increased to a b o u t twice the f r e q u e n c y f o u n d in control populations. H o w ever, these studies have not carefully separated patients with polymyalgia rheumatica f r o m those with giant cell arteritis. A s H u n d e r (1990) has pointed out, tests with mixed l y m p h o c y t e cultures which divide the H L A - D R 4 into its subtypes D w l 0 , D w l 3 , D w l 4 and D w l 5 m a y well provide further information, particularly if care is taken to segregate the patients into the groups identified clinically as having both s y n d r o m e s or just polymyalgia rheumatica.
SUMMARY Polymyalgia rheumatica and t e m p o r a l arteritis a p p e a r to be separate syndromes rather than two manifestations of an underlying giant cell arteritis. Polymyalgia r h e u m a t i c a is a synovitis that m a y be persistent or recurrent, while t e m p o r a l arteritis is almost always a single episode; d o c u m e n t e d recurrences are rare. T h e two s y n d r o m e s frequently occur in the same patient although not necessarily at the same time and t h e y m a y be separated by a long interval. I n some patients with polymyalgia rheumatica, giant cell arteritis is f o u n d on biopsy o f an a s y m p t o m a t i c t e m p o r a l artery. T h e frequency of this concurrence is variable in different populations. It is high in Scandinavia, low in Israel and intermediate b e t w e e n these extremes in other populations that have b e e n studied.
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