5 large vessel vasculitis (giant cell arteritis, takayasu arteritis)

29

Click here to load reader

Upload: william-s-wilke

Post on 18-Sep-2016

223 views

Category:

Documents


2 download

TRANSCRIPT

Page 1: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

William S. Wilke MD Senior Staff Rheumatologlst Cleveland Chmc Foundation, Department of Rheumattc and Immunologic Dtseases, 9500 Euclid Avenue, Cleveland, OH 44195, USA

Giant cell arteritis and Takayasu arteritis are separate but similar idiopathic diseases clinically characterized by constitutional symptoms, shared surrogate markers of systemic inflammation and indistinguishable granulomatous pan- arteritis of large vessels. This review emphasizes and analyses changing perceptions about the diseases. Recent series suggest that aortic involvement in giant cell arteritis may be more common than was previously appreciated. The case for and against inflammatory arthritis m giant cell arteritls is discussed. Ethnic and geographical vanation in Takayasu arteritJs-dlsease expression is reviewed. New philosophies of treatment are presented for both diseases. Prognosis in giant cell arteritls and its relationship to treatment is analysed. The utdity of the laboratory for diagnosis and monitoring disease activity is appraised for each.

Key words: polymyalgia rheumatica; giant cell arteritis; Takayasu artentis.

Clinical description and diagnosis

Giant cell arteritis

Giant cell arteritis is rarely encountered in patients under 50 years of age. The mean annual incidence for the population over age 50 is approxi- mately 20-25 per 100 000 for Northern Europeans but somewhat lower for other populations (Hunder, 1990). The disease is more common In females (4:1).

Clinical signs and symptoms associated with the disease are given in Table 1. Headache is the most common symptom and is usually localized to the temporal area but may be diffuse. The pain from the involved artery is often described as sharp and throbbing and characteristically occurs daily. Most patients recognize this headache as new, more severe and more pervasive than any previous headache. Scalp tenderness often accompanies the headache and may be exacerbated by brushing or combing the hair or wearing a hat. Scalp tenderness is a very specific diagnostic symptom encountered in only 2-3% of patients without giant cell arteritis but not

Ballh#re's Chmcal Rheumatology-- Vol 11, No 2, May 1997 ISBN 0-7020-2266-7 0950-3579/97/020285 + 29 $12 00/00

285

Copynght © 1997, by Bailli~re Tmdall All rights of reproduction in any form reserved

Page 2: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

286 W S Wtlke

Table 1. Percentage of symptoms m giant cell artentts at diagnosis

First author (year) Hamilton (1971) Mowat (1974) Huston (1978) Smith (1983) Hunder (1985) N of patients 25 59 42 24 31

Headache 48 24 90 83 71 Scalp tenderness 16 3 69 62 42 Myalgia 28 100 48 25 29 Malaise 8 66 48 62 45 Fatigue 12 71 48 62 NS Anorexia 12 NS NS NS NS Wetght loss 16 54 55 21 29 Fever 16 12 21 29 3 Vision change 8 3 53 12 6 Loss vision 54 0 10 21 42 Jaw claudlcation 8 NS 67 25 NS Arthralg~a 4 25 21 NS 16 Anaemia 4 NS NS NS NS Other 16 NS 19 29* NS First symptom to diagnosis NS 6 2 months 1 month NS NS * OlZzlness

NS = not stated

very sensitive, occurring in only 40% of giant cell arteritis patients (Hunder et al, 1990).

ClaudicatIon of the muscles of mastication is another very specific symptom occurring in approximately 40% of patients with giant cell arterltis and in only 2-3% of patients with other forms of vasculins (Hunder et al, 1990). This symptom, characterized by cramping of the masseter and/or temporalis muscles most commonly occurs when the patient chews food but may occur during prolonged speaking.

Symptoms of polymyalgia rheumatica occur initially in at least 30% of patients, but may occur for the first time in the course of disease as cortico- steroids are tapered.

The onset of symptoms is often abrupt which facilitates diagnosis. Bird demonstrated that moderately abrupt onset, defined as time from first symptom to the nadir of symptoms within 14 days, differentiated panents with polymyalgla rheumatlca from patients with diseases which mimic it (Bird et al, 1979). In that series, 88% of 146 patients with polymyalgia rheumatica satisfied this criteria while only 37% of 253 patients with condmons which mimic it including rheumatoid arthritis, periarthrms of the shoulder, polymyosms, osteoarthritis, and metabolic disease did so.

Neuro-ophthalmological signs Neuro-ophthalmological signs and symptoms occur in 20-30% of patients (Caselli et al, 1988; Mehler and Rabinowich, 1988; Reich et al, 1990). The per cent frequency of important neuro-ophthalmological signs and symptoms among 166 patents with giant cell arteritis reported In a retro- spective series are given in Table 2 (Caselli et al, 1988). During the 1950s and early 1960s the frequency of visual loss was reported to be as high as 60% in patient populations reported from ophthalmological pracnce. The

Page 3: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

Large vessel vascuhtJs 287

Table 2. Neuro-ophthalmtc involvement. Major findings m 166 patients wtth grant cell artentts *

AmaurosJs fugax (10%) Permanent vtsual loss (8%) Mononeuropathy (7%) Penpheral neuropathy (7%) TIA Carottd (4%)

Vertebral bastlar (2%)

Infarct Carotid (2%) Vertebral bastlar (1%)

Vertigo (5%) Tlnnltus (1%) Organic affectwe (3%)

TIA = transient ~schaem~c attack * Casselh et al (1988)

time from first symptom to diagnosis has declined over the past 30 years probably due to heightened awareness of the condition among physicians (Hunder, 1990), which has prompted earher treatment. In addition, a high index of suspicion has facilitated the recognition of less characteristic and probably more benign disease (Turnbull, 1996). These factors favoured a decline in the frequency of visual loss, now estimated to be under 10%.

Involvement of the vertebrobasilar system can present as hearing loss, ataxia, and dementia (Wilkinson and Russell, 1972). Depression and confusion encountered in as many as one-third of patients m early series are less frequent today and may be relatively late symptoms (Russell, 1959) associated with delay of treatment. Peripheral neuropathy and mono- neuritis multiplex revolving the median, ulnar, peroneal, and sural nerves may occur when large arteries other than the superficial temporal artery are involved.

Large artery involvement in giant cell artentts

Separate reports of four patients (Gilmore, 1941) and two patients (Sproul and Hawthorne, 1937) described histopathology in the aorta or branches of the aorta consistent with a diagnosis of giant cell arteritis at autopsy after death from large artery aneurysmal rupture. These authors recogmzed that the histopathology in the involved arteries was similar to the hlsto- pathology seen in the superficial temporal arteries of patients with giant cell arteritis. Since those early reports, other case reports and series have documented the occurrence of large artery involvement in patients with giant cell arteritls (Hoyt et al, 1941; Hunder et al, 1967; Ostberg 1973; Greene et al, 1986; Sav-Soderberg et al, 1986; Nmet et al, 1990).

Selected information from a series of four reports from the Mayo Chnic published over the past 20 years is given in Table 3 (Klein et al, 1975; Evans et al, 1994, 1995; Lie, 1995). These series and other reports demonstrate that:

. Large artery involvement is present in at least 15 % of giant cell arteritis cases. In a prospective series of 28 patients with giant cell arterltis, 65% of cases assessed by Doppler echography were found to have large vessel involvement (Nlnet et al, 1990). The distribution of aneurysms from pooled autopsies of 31 patients with aortic involvement m grant

Page 4: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

288 W.S. W~lke

g

e4

E

~-~

<

o

o

o o

U.I

o I.o ~I

~o~

o~

o o m _

. ~ o'~

i1) -

g _ ~ _

I n "

Z Z

o r r LO Z

v

,,~ l.tJ

Page 5: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

.

.

Large vessel vascul i t is 289

cell artentis was reported to be 87% for thoracic and 84% for abdominal aortic segments (Greene et al, 1986). The risk of thoracic and abdominal aortic aneurysms in giant cell artemis is at least 17.3 and 2.4 times higher, respectively, than in the general population (Evans et al, 1995).

Dissection of thoracic or abdominal aortic aneurysms may be an early or late event in patients with giant cell artentis (Evans et al, 1994, 1995).

While acute phase reactants may be elevated in 92% of patients at the time of diagnosis of large vessel involvement, symptoms of clinically active disease may be absent in nearly one-half (16 of 33) (Evans et al, 1994).

Ar t i cu l a r i n v o l v e m e n t tn g i a n t cel l a r te r i t t s

Gordon (1960) and later Kogstad (1965) first described inflammatory arthritis of the sternoclavicular joints in a minority of patients with symptoms of polymyalgla rheumatica. Bruk also reported inflammatory arthritis in 80 polymyalgia rheumatica patients, 15 of whom had biopsy proven giant cell artemis (Bruk, 1967). Fifty nine (72%) had tenderness at the acromloclavlcular joint with synovial thickening in 15 (19%). In addition, in this same series, swelhng of the knee was described m 40 (50%), of the wrist in six (8%) and of the metacarpophalangeal joints in five (6%). Radiographic erosions were uncommon in peripheral joints and acromioclavicular lomts, but were common m the sacrodlac loints and at the symphysls pubis. Criteria for the dlagnosls of polymyalgia rheumatlca in this report included ' . . . finding on examination of tenderness of central joints, tendons and ligaments . . . ' which surely biased pauent selection to favour axial arthropathy and calls the diagnosis of classic polymyalgla rheumatica into quesuon. Subsequently, others have attempted to establish the frequency and characterize the nature of amcutar involvement in polymyalgia rheumatlca/glant cell arteritls (O'Duffy et al, 1976; Miller and Stevens, 1978; Chuang et al, 1982; Douglas et al, 1983; Pa~ce et al, 1983; Ginsburg et al, 1985; Kyle et al, 1990) (Table 4).

Analysis of these reports is difficult. Certainly stenoclavicular and acromioclavicular loint pain, synovitis, and erosions do occur in older patients with proximal muscle pain and elevated acute phase reactants. Douglas et al (1983) documented abnormal synovial histology in tissue obtained at arthroscopy of acromloclavlcular lolnts. Histological abnor- malities included mild synovial hypertrophy, perivascular oedema and peri- vascular cellular infiltrates with only variable prohferation of surface epithelium. The authors remarked that this mild synovial proliferation differentiated this h~stopathology from the more proliferative hlstopathology of rheumatoid arthrms. This is in keeping with Bruk's earlier report of the hlstopathology obtained from sternoclavicular joints in four patients with polymyalgm rheumatica and with the histopathology of six synovial biopsy

Page 6: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

290 W.S . Wilke

• .E -~

o')

E g -E

E _,&,,, o

"8

o

E

o= 12

¢.

o

~ ~ ~ ~ < ~ o o ~ ~-o =_

o ~ . "o ...o .,~ ~ o 0

• .uE ~ "o

- ~ 0 . o - ~ o

~E o - o ' ° ~ ~ ~

o ~ = . . .~ E ,.':, "6 E .c: o ~ ~ ~ ' 5

- o = ~ ~ > - o ~ o ' 5 ~ = ~

"It o < z o > o -I ° ~ 6 ~ < ,,,

8

0 O ~

_ ~ o ~ ® ~ ~ ~ o

0 t.O ~ ) 143 ~ 0

LO

Z

= 8

"5

5~

E £

E o

m

u_

o

E

II <

g E

II o CO

Page 7: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

Large vessel vasculitis 291

specimens obtained from the knees or sternoclavicular joints of classically defined polymyalgla rheumatica patients by Chou and Schumacher (Bruk, 1967; Chou and Schumacher, 1984). In the latter report, electron microscopy was also performed and &d not show ev, dence for other causes of arthrius such as calcium pyrophosphate dlhydrate crystal disease. In addmon, the controlled sclntlgraphic studies of O'Duffy suggested that loInt inflammation, especially involving the shoulders, did occur in a classically defined population with polymyalgia rheumatica (O'Duffy et al, 1976). But are all series comprised of patients who have the same syndrome called polymyalgla rheumatica that is associated with giant cell arteritls?

In fact, the percentage of patients with biopsy proven giant cell artemis in these series is low. Healey (1983) has emphasized the difficulty m differ- entiating polymyalgia rheumatlca from rheumatoid arthritis of the elderly. Furthermore, because most patients with polymyalgia rheumauca require corticosterold for disease control, successful treatment of 42% of 96 patients using non-steroidal anti-inflammatory drugs alone in one series with a high Incidence of peripheral arthritis (Chuang et al, 1982), suggests that the patients m this population experienced a heterogenous mix of musculoskeletal diseases. Some degree of dmgnostlc heterogeneity within patient populations may well explain the high frequency of articular involvement in other series.

That 2-3% of a large population of patients with giant cell arterms (Gmsberg et al, 1985) had concurrent peripheral arthritis might be explained by the background frequency of inflammatory peripheral arthritis m an elderly population. In that report, radiographic involvement was only documented in the sternoclavlcular joints, not in peripheral joints. In the best conceived prospective study of arthropathy in classically defined polymyalgia rheumatica/gmnt cell arthritis, reported by Kyle and colleagues, although 10 of 56 patients complained of peripheral joint pain, radiographic erosive changes were not seen m peripheral lomts (Kyle et al, 1990). Erosions, however, were seen in the sternoclavlcular joints of two patients, in agreement with findings of axml arthrms m prewous series (Miller et al, 1978; Palce et al, 1983). The cause-and-effect relationship between grant cell arthritis and diffuse peripheral joint involvement resembling rheumatoid arthritis is not compelhng.

Takayasu arteritis

Takayasu arterltis is an idiopathic, inflammatory disease that produces arteritls primarily of the aorta and its branches. About half of all patients experience systemic symptoms. Disease typically occurs in women (70-90%) of reproductive age, although children and individuals > 40 years old have been reported. Arteritis can produce stenosis, occlusion, dilatation and/or aneurysms of large muscular vessels.

The pattern of arterial involvement varies among ethnic populations (see Table 5) (Kerr et al, 1994; Hata et al, 1996; Hoffman, 1996). Vascular symptoms depend both on the anatomical location of the revolved artery

Page 8: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

292 W. S Wllke

Table 5. Percentage of anatomlcal dlstnbutlon of vascular lesions* In Japan, India and North America

Japan India North America

Aortic arch and branches 68 36 98 Common carotid arteries 20 7 58 Abdominal aorta 11 22 65 Renal artery a 52 38

* Hata et al (1976), Kerr et al (1994), Hoffman (1996).

and the nature of the lesion, ie stenotic or occlusive. Symptoms of dizziness, syncope, visual changes, vertigo, and arm claudication are more common in patients from Japan and the US than m patients from India due to a higher frequency of involvement of the aortic arch and its branches in the former population (Hata et al, 1996; Kerr et al, 1994). Alternatively, hypertension is more common in patients from India because of a higher frequency of abdominal aortic and renal artery stenosis compared to Takayasu arteritis patients from Japan and the US. Other vascular-related abnormalities include pulmonary hypertension, hypertensive or ischaemic cardiac disease or renal disease, and abdominal pain.

Constitutional ‘systemic’ symptoms include malaise, weight loss, fever, night sweats, myalgias, arthralgias, and arthritis. Cutaneous manifestations such as erythema nodosum, lupus-like rash, and glomerulonephritis have been described infrequently with Takayasu arteritis (Sharma et al, 1996a). Some authorities have considered constitutional symptoms to be pre- vasculitic, early symptoms implying that a pattern of staged evolution of disease occurs over time. In this scheme, symptoms due to newly develop- ing vascular stenosis, aneurysms, and vascular pam (eg carotidyma) from ongoing mflammation would be the second stage of Takayasu arteritls. Finally, m the stage of fibrosis, the disease would be considered to have ‘burned out?. Although these progressive stages of disease certainly occur m some patients (Sharma et al, 1996a);this clinical model is by no means the rule. For example, in the National Institutes of Health (NIH) series only 43% of 60 patients followed for over 20 years experienced constitutional symptoms at any time durmg the course of disease. Although the often reported ‘stages’ of Takayasu arteritis were noted in some patients, they represented a minority of this cohort (Kerr et al, 1994). Disease remission occurred in 82% of the patients but relapses occurred m 50% and Takayasu arteritis never became inactive m 18%. Clearly, constitutional ‘systemic’ symptoms and vascular symptoms may occur concurrently, and disease ‘burn-out’ is not always achieved.

Mortality during 5 year follow-up has been reported to be as low as 3% (Kerr et al, 1994) and as high as 35% (Morales et al, 1991). Approximately two-thirds of patients experienced significant disability (Kerr et al, 1994). Some authorities feel that the disease is less severe in North American patients. This might imply an inherent ethnic difference in disease. Differences in philosophy of therapy and access to medical care, however, may play a large role.

Page 9: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

Large vessel vascuht)s 293

Diagnosis of giant cell arteritis

The diagnosis of giant cell arteritis should be considered in any individual over age 50 who experiences a new headache, jaw claudication, un- explained visual symptoms, and systemic symptonqs described in the previous section. Pauents, however, do not always present classically. In a retrospective review of 48 patients w~th biopsy-proven giant cell arterms, nine (18%) lacked at least one classic criteria defined as age >50, new headache, significant elevation of erythrocyte sedimentation rate (ESR) and proximal muscle pain/temporal artery tenderness (Wilke et al, 1995). These pauents demonstrated non-specific symptoms and could be arbitrarily classified as clinical subsets previously described including peripheral vascular occlusive (four pauents), febrile (three), malignant (one), and general symptoms which included malaise and depression (one) (Healey and Wilske, 1980). This concept of occult giant cell arterms extends the clinical index of suspicion for the disease to patients over age 50 who present with sudden blindness, fever of unknown origin and/or weight loss/malaise of unknown cause.

At physical examination, abnormality of the superficial temporal artery is a very specific finding encountered in 40-50% of patients (Hunder et al, 1990). Scalp tenderness, systemic brmts and asymmetric blood pressure or pulse m all four extremities should be sought. Pain with active and passive range of motion of the hips and shoulders indicative of polymyalgm rheumatica, should lead to consideration of grant cell a r t e r l t l S .

Differential dlagnos~s and dlfferent)ahon from mimics of giant cell arter)tls.

The American College of Rheumatology (ACR) published classification criteria developed by comparing 214 patients with giant cell arterms to 593 patients with other forms of vasculitis (Hunder et al, 1990). Because of this design, these criteria are only useful for differentiating giant cell arterttls from other forms of vasculius. Five criteria proved discriminative: age _> 50 years at disease onset; onset of new or localized headache; superficial temporal artery tenderness or decreased pulsation; elevated Westergren ESR (WSR) _> 50 mm/hour; and biopsy histology that demonstrates necrouzmg arterltis characteristic of grant cell arteritis. The presence of three or more of these criteria was associated with a sensitivity of 93.5% and a specificity of 91.2%. The differential diagnosis of polymyalgia rheumatica/giant cell artentis with comments about differential points is given in Table 6.

Differentiation of giant cell artentis from polymyalgla rheumatlca is problematic. Clinically, both share numerous characterlsucs: frequent abrupt onset, same age group affected, as many as 40% of patients with simultaneous disease and dramatic improvement with cortlcosteroid therapy. In addition, both diseases share elevation of acute phase reactants, demonstrate the same low frequency of autoantibodies, share HLA-DRB1 alleles and peripheral markers of immune activation such as increased

Page 10: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

294 W. S WiIke

Table 6. Differential diagnosis of polymyalgta rheumatlca and grant cell artentm

D~fferenttal d~agnosts Comment

Other vascuhtts 0 e polyartentls nodosa, Histology and chnlcal symptoms Wegener's granulomatosts)

Maltgnancy, myeloprohferatlve dtsorders

Infection 0 e subacute bactenal endocardltls) Inflammatory arthntis 0 e rheumatoid arthntls) Polymyosltls

Prominence of weight loss and poor response to cortlcosterolds

Prominence of fever and posltwe bactenal cultures Symmetrical lomt swelling Weakness, mouth pare

interleukin-6 (IL-6) concentration, activated circulating monocytes and simdar inflammatory cytokme profiles in the temporal artery (Wagner et al, 1996; Weyand et al, 1994, 1995). This evidence strongly suggests that polymyalgia rheumatica and giant cell arteritls are not separate disease entities but constitute a spectrum of the same &sease.

Labora to ry d tagnosts of g iant cel l arteri t is

No specific serological test has been described. Non-specific abnormalities which include normochromlc, normocytic anaemia; thrombocytosis; and elevation of ubiquitous enzymes including alkaline phosphatase are con- sistent with the diagnosis. Elevation of acute phase reactants, especially the WSR support the initial chmcal diagnosis. Unfortunately, the WSR may not always be elevated at diagnosis. Ellis and Ralston reported that 18 of 80 patients (22.5%), 33 of whom had positive temporal artery biopsies presented with a WSR below 30 ram/hour (Elhs and Ralston, 1983). Other series and case reports corroborate their data (Wilke and Hoffman, 1995). In the climcal setting of characteristic signs and symptoms of giant cell arterius m a patient with normal acute phase reactants, superficial temporal artery biopsy can be very helpf~, and should be obtained. Is It always necessary?

Historically, the diagnosis of giant cell arteritls has been confirmed by biopsy. Histological confirmation was considered to be crucml m order to dlfferennate it from polymyalgia rheumat~ca because treatment was different. Patients with polymyalgia rheumatica experienced prompt remission when gwen prednisone eqmvalent to 15 rag/day. Giant cell arterius patients, alternatively, experienced amelioration of symptoms more slowly and required treatment with 40-60 mg of prednisone per day. If such dichotomy of treatment is necessary, biopsy is also necessary. Pauents w~th polymyalgia rheumauca should not be exposed to the potential toxicity of high dose corticosteroid therapy; but patients with giant cell arterms must be protected from bhndness with high dose cortico- steroid therapy. If the daily dose of treatment is, however, similar for both diseases, the need for superficial temporal biopsy xs less critical. In fact, as will be shown in the treatment section, th~s may be the case. Following dlscusson of treatment, recommendations about the role of superficial biopsy will be gwen.

Page 11: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

Large vessel vascuhtls 295

Diagnosis of Takayasu arteritis

Because Takayasu arteritis is a rare disease and disease mamfestauons may be vague and non-specific, delay m diagnosis is common. The median time from the first symptom to diagnosis in the prospective NIH series was 10 months (Kerr et al, 1994). The diagnosis should be considered in any young pauent with large vessel ischaemlc symptoms and hypertension. The index of suspicion is increased when systemic symptoms are also present. Physical examination should focus on identifying vascular brmts, asymmetric pulses and blood pressure determination in both arms and both legs. Obtaining tissue from large vessels to estabhsh an uneqmvocal histological diagnosis is rarely feasible. Angiography remains the procedure of choice to provide the best circumstantial evidence to support the diagnosis.

Angiographlc abnormalities include at least four lesions. The most common is smooth, concentric arterial or aortic narrowing, which occurs m approximately 85% of cases. Complete occlusion of vessels or irregular contour of the aortic wall occurs with less frequency (Figures 1 and 2). Fusiform or saccular aneurysms are less common, occurring in 10-33% of cases (Virmani et al, 1986; Kerr et al, 1994; Hata et at, 1996).

Classification of disease based on anatomical involvement has been described. The classification adopted after reports given at international conferences m 1993 and 1994 is given in Figure 3 (Hata et al, 1996). Because patterns of disease may vary among d~fferent ethnic populanons, such classification schemes are useful as a framework for cohort com- parison.

o

. . " - " ~ . i ~ h . . . . J " " "

Figure 1. Artenography demonstrates smooth, concentric narrowing of the abdominal aorta

Page 12: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

296 W S. Wilke

I

i ' " I . ~ I

Figure 2. Artenography demonstrates irregular contour of the aortic wall in Takayasu arteritls

Figure 3. Arteriographtc patterns of involvement In Takayasu artentls Adapted from Hata et al (1996)

Page 13: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

Large vessel vascuhtls 297

Differential diagnosis and differentiation of Takayasu artentis from mimics

Because the constitutional 'systemic' symptoms are non-specific, diagnosis of Takayasu arteritis depends upon symptoms and signs arising from arterial stenosis/occlusion. The ACR (1990) criteria are given in Table 7 (Arend et al, 1990). The presence of three or more criteria yielded a sensitivity of 90.5% and a specificity of 97.8%. These criteria are not perfect.

Table 7. Amencan College of Rheumatology (1990) cntena for the classification fo Takayasu artentls *

Cntenon Definition

Age at disease onset <40 years

Claudlcation of extremRles

Decreased brachlal artery pulse

BP difference >10 mmHg

Bruit over subclavian arteries or aorta

Arterlogram abnormahty

Development of symptoms or findings related to Takayasu artent~s at age 40 years

Development and worsening of fatigue and discomfort in muscles of one or more extremities whde ~n use, especially the upper extremities

Decreased pulsation of one or both brachial artenes

Difference of > 10 mmHg In systohc blood pressure between arms

Bruit audtble on auscultation over one or both subclawan arteries or abdominal aorta

Arter~ograph~c narrowing or occlusion of the entire aorta, ~ts pnmary branches, or large artenes m the proximal upper or lower extremities, not due to artenoscterosis, fibromuscular dysplasla or s~mdar causes, changes usually focal or segmental

* Arend et al (1990) BP = blood pressure

The ACR (1990) criteria have been established in a population of North American patients whose disease differs in some ways from patients in other parts of the world. Takayasu arteritls appears to be the most common cause of renovascular hypertension in India, China, and South East Asia (Sharma et al, 1996b). Not one case of Takayasu arteritis was discovered among a population of 880 North American patients with renovascular hypertension reported in the early 1970s (Maxwell et al, 1972). A high Incidence of fibromuscular dysplas]a (35% of 502 surgical patients) and lack of histological description and analysis weakens this prospective study. Without tissue diagnosis m the setting of renovascular hypertension, an initial erroneous diagnosis of fibromuscular dysplasia may precede the correct diagnosis of Takayasu arteritis (Hoffman, 1994). Even among populations of patients with Takayasu arterms, the frequency of hyper- tension differs. Seventy s~x per cent of 237 adult patients reported with Takayasu arterltiS from Mexico since 1956 experienced hypertension at some time during the course of their disease (Dabaque, 1996). Only 33% of North American patients in the NIH cohort experienced hypertension during a mean follow-up period of 5.3 years (Kerr et al, 1994). These data suggest that differences in clinical disease expression clearly exists among different ethnic populations.

Page 14: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

298 W. S W~lke

The arbitrary restriction excluding the diagnosis of Takayasu artentis to patents over age 40 has not been generally accepted. For example, 13% of the NIH cohort and 15% of Japanese patients with typical features of Takayasu artentis were at least 40 years old (Kerr et al, 1994; Sharma et al, 1996b). Alternatively, if age was not an ACR (1990) criterion for the diagnosis of Takayasu arterttis, 15-50% of patients with giant cell artentis and large vessel ,nvolvement might be reclassified as having the former. A recent report suggested that the majority of patients with giant cell arterins could be differentiated from Takayasu arteritis (Michel et al, 1996). Because the patient populations of both diseases were arbitrarily defined by a priori chmcal characteristics which mcluded age restricnons, selection bins may have accounted for between group &fferences. These observations emphastze the overlapping features of these two diseases and raise questions about whether they are truly distinct from one another.

Finally, the ACR (1990) criteria for Takayasu arteritis were only tested for sensinvity and specificity versus other vasculindes. They have not been vahdated in patients with other causes of large vessel &sease such as fibro- muscular dysplasia, arteriosclerosis obliterans, or other causes. The differ- entml diagnosis with comments about differential points is given in Table 8 (Hoffman, 1995).

Table 8. Dtfferenttal diagnosis of Takayasu arteritls

Dtfferentzal diagnosts Comment

Tuberculous, mycottc, or syphd~tlc artenes Ehlers-Danlos syndrome Marfan syndrome Spondyloarthrepathtes Vascuhtldes Cogan's syndrome, Behget's dtsease,

g~ant cell artent~s of elderly, and Kawasak~s' d~sease Sarcold vasculopathy Ftbromuscular dysplasla

Aneurysms, stenoses rare Aneurysms Aorttc root dtlatatton Aortic root dilatation (uncommon) Untque disease features

Aneurysms and stenoses, vessels of any size Stenoses more common than aneurysms,

non-mflammatoTy

Reproduced from Hoffman (1995, Rheumattc Disease Chmcs of North America 21: 73-80) wtth permission

Laboratory diagnosis in Takayasu arteritis

Laboratory abnormahtles in Takayasu arterins are non-specific. Autoantibodies encountered in other connective tissue diseases including rheumatoid factor, ann-nuclear factor, anti-cardiolipin annbodies and anti- neutrophll cytoplasmic antibodms (ANCA) are no more common in Takayasu arteritls than in the general population. Acute phase reactants such as the WSR are elevated in at least 50% of patients and are thought by some to correlate with signs and symptoms of disease activity (Hall and Buchblnder, 1990). Circulating anti-endothelial annbodies in sigmficantly higher ntre than in controls have been recently reported in 17 of 18 Takayasu arteritis patients (Slma et al, 1994). These annbodies however have been spora&cally and inconsistently described m a variety of other

Page 15: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

Large vessel vascuhtls 299

connective nssue &seases as well as in angfitlS obliterans, are non-specific, and should not be used to estabhsh diagnosis (Bacon, 1991).

Pathology and pathogenesis of giant cell arteritis and Takayasu arteritis

Pathology

Advanced lesions in large and medium vessels in giant cell arterins and Takayasu artemis demonstrate a panarterltis with intimal prohferanon. Fibrmoid necrosis may occur but is only seen m a minority of cases. Acute inflammanon in both diseases is characterized by infiltration of the adventitla and media by CD4 and CD8 lymphocytes with some macrophages. Giant cells, eoslnophils and plasma cells are sometimes encountered. B-cells are rarely seen. In giant cell arterins, the histology can be differentiated from that of scenescent arteries by the presence of mflam- matory cells, frequent multmucleated giant cells, extensive fragmentation of the internal elastic lamina, and dramatic endothelial proliferanon (Lie et al, 1970). A stage of healed fibrosls has been best characterized in Takayasu arteritis in whmh elasnc tissue is replaced with fibrous tissue, the vaso- vasorum are obhterated and the mnma undergoes irregular thickening. Skip lesions occur in grant cell arteritlS and may result in sampling error at biopsy.

Pathogenesis

A comprehensive discussion of the pathogenesls of giant cell arterins and Takayasu arteritis is beyond the scope of this manuscript. Nmther the triggering mechanisms nor the ulnmate contributxon of T-lymphocytes, macrophages, humeral mechanisms, or cytoklnes are entirely understood in rather &sease. Increasing numbers of reports suggest that vascular inflam- mation is first encountered in the adventltia and then extends to the me&a and endothehum m both (Seko, 1994; Weyand et al, 1994; Wagner, et al, 1996).

Treatment

Giant cell artentis

Initial dose corticosterold therapy for giant cell arteritis has been &scussed (Wilke and Hoffman, 1995). Five prospective series that employed accept- able diagnosnc criteria, applied predefined treatment protocols and included substantial numbers of giant cell arterltis patients were analysed

Page 16: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

300 W S Wflke

(Hunder et al, 1975; Bengtsson et al, 1981; Behn et al, 1983; Kyle et al, 1989; Myles et al, 1992). Of interest, an initial dose of 11 to 25 mg of prednisolone controlled symptoms m 95-97% of cases (Behn et al, 1983; Myles et al, 1992). Among three series which employed initial dose prednlsolone of approximately 20mg/day, only one of 196 panents experienced bhndness (Behn et al, 1983; Kyle et al, 1989; Myles et al, 1992). This unfortunate patient had been treated with prednisone 60 mg/day for 4 weeks prior to visual loss calhng the initial diagnosis of giant cell arteritls into question (Myles et al, 1992). We were unable to make firm recommendations about initial corticosteroid therapy but felt that doses ranging from 20-60mg/day were appropriate in individual clinical circumstances (Wllke and Hoffman, 1995).

Duration of therapy was also analysed (Wllke and Hoffman, 1995), and the authors agreed with most authorities who suggest that treatment should be continued for at least 2 years. The analysis also showed that main- tenance corticosteroid dose in excess of 15-20 mg of prednlsone per day 2 months after initiation of therapy was rare, occurring in approximately 20% of patients, and indicated cortlcosteroid resistance.

Treatment, prognos~s and the need for corticosterold-spanng drugs

The vahd characterization of prognosis in giant cell arteritls must consider more than mortality compared with aged matched controls. Consideration of morbidity from active disease and treatment tomcity are also important outcome measures.

Debate remains concerning survivorshlp. Many series suggest that survivorship among patients with giant cell arteritis is not significantly &fferent from that of the general population (Hauser et al, 1971; Houston et al, 1978; Jonasson et al, 1979; Godeau et al, 1982; Barrier et al, 1983; Andersson et al, 1986; Gouet et al, 1985; Boesen et al, 1987; Matteson et al, 1996). A recent retrospective review of 205 patients followed for a mean of 7.1 years computed standardized mortality ratios and found no differ- ence in survivorshlp in patients wltb giant cell arterltis versus the general populanon (Matteson et al, 1996). Mortality was not increased by factors such as gender, older age at onset, disease duration or specific clinical features. The authors, however, did not analyse the subset of patients with aneurysms of the aorta which occurred in 17% of cases reported by the same group and resulted in death in 50% (Evans et al, 1995). The high mortality rate m the aged control population in this study raises questions about whether the number of giant cell arteritls patients included in this study were adequate to detect significant differences in causes of death. Whether comparison of early mortahty (i.e. first year after diagnosis) to late mortality rates (see below) would reveal sigmficant differences was also not explored m this study.

Other series have reported increased mortality associated with giant cell arterms (Graham et al, 1981; Rubinow et al, 1984; Nordberg and Bengtsson, 1989; Biscard et al, 1991; Nesher et al, 1994). The causes of death in these series appeared to be dichotomous. Vascular death exceeded

Page 17: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

Large vessel vasculitis 301

expected estimates during the first year after diagnosis (Nordberg and Bengtsson, 1989; Graham et al, 1991). These deaths were presumed to be linked to inappropriately low doses of cortlcosterold which failed to suppress disease activity. However, it is not possible to know whether these deaths would have been prevented even if the disease was better controlled. In one series, clinical disease was active as measured by symptoms and/or acute phase reactants at the time of vascular death m 13 of 17 patients (Nordberg and Bengtsson, 1989).

Later deaths were largely due to adverse effects of corticosteroids. In a recent prospective series in which 43 biopsy proven patients were followed during treatment for a mean of 3 years, the standardized mortality rate for giant cell arterltis pauents was 2.12 × greater than expected in an age/sex matched population (Nesher et al, 1994). In this and other series, the frequency of morbidity which included vertebral fractures, diabetes, and infection, directly correlated with both the initial and the maintenance dose of corticosteroid (Graham et al, 1981; Rubinow et al, 1984; Nesher et al, 1994). Twenty five of 43 (58%) consecutive patients in the prospective series of Nesher were still receiving a mean dose of 22 mg prednisone or the equivalent per day 6 months after initiation of therapy (Nesher et al, 1994). Although a critical review of treatment studies in giant cell arterms suggested that only 5-10% of patients have 'resistant' disease defined as a daily corticosteroid requirement of _ 15-20 mg predmsone 2 months after initiation (Wilke and Hoffman, 1995), some studies suggest that 5-10% may be too conservative (Kyle and Hazleman, 1989). In addition, the upper limit of maintenance dose of cort~costeroid therapy associated with mortality/morbidity may be lower than 15 mg of prednisone equivalent per day. In an older retrospective series, excess mortality, often due to infection was associated with a dady maintenance dose of prednisone _> 10 rag/day (Graham et al, 1981).

This information establishes the need for a safe, effective additional agent which might be effective to reduce corticosterold requirements m these more resistant patients. Only four series address the addition of a 'corticostero~d-sparing drug' for giant cell arteritis patients who require high dose corticosteroid maintenance therapy for disease control (Utsinger, 1982; Doury et al, 1983; Spiera and Swerdlow, 1987; Krall et al, 1989). The small number of patients m each study, lack of controls treated with only corucosterold, and non-uniform diagnostic and disease activity criteria make interpretation of these small series difficult.

Four prospective series have been published which studied imtial therapy of giant cell arterit~s with corucosteroid combined with another agent (deSdva and Hazleman, 1986; Settas et al, 1991; Hernandez-Garcia et al, 1994; van der Veen et al, 1996). In a controlled double-bhnd study that com- pared azathloprme (AZA) plus cortxcosterold to cortlcosterold alone for 31 patients, AZA proved to be cortlcosterold-sparing at 52 weeks (deSflva and Hazleman et al, 1986). Methotrexate (MTX) 7.5 rag/week was not shown to be significantly corncosteroid-sparing xn another double-blind controlled trial of 40 patients (34 with polymyalgia rheumatlca and six with grant cell arteritis) followed for at least i year (van der Veen et al, 1996). An open trial

Page 18: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

302 W. S Wilke

of MTX (Hernandez-Garcia et al, 1994) and a trial comparing either AZA or MTX added to corticosterold as inmal therapy (Settas et al, 1991) suggested that MTX may be corticosterold-sparing and superior to AZA. The lack of corticosteroid-only controls in this trial makes conclusions tenuous.

All of these studies documented the often prompt and complete response of symptoms in most giant cell arterins patients when initially treated with prednisone 20-40 mg/day alone. If an additional lmmunosuppressive/anti- inflammatory agent is tested m unselected giant cell arterins patients, any measurable benefit experienced by the small percentage of patients with corticostermd-resistant disease will be diluted and possibly obscured by the excellent response to corticosteroids experienced by the majority of patients. This phenomenon has obvious implications for the design of future drug trials in giant cell arterins. Large cohorts will be likely to Identify appropriate patients. Such a study should ideally enroll biopsy- proven giant cell artentis patients who require predmsone in doses _>15rag/day as chronic maintenance therapy after at least 2 months of remission and subsequent corticosteroid tapering. In addition, a standard corticosteroid tapering protocol should be used for all patients, and disease activity and toxicity parameters should be clearly defined to objectively identify relapses and second drug toxicity. Because relapses most often occur during the first 2 years after diagnosis and treatment, long-term follow-up is essential to estimate treatment efficacy and recurrences even after treatment has been discontinued.

Definitive proof of the value of adding cytotoxm agents to corticosteroid therapy in giant cell artentis is still lacking. However, in the significant subset of patients who experience relapses if prednisone is tapered below 15 mg/day, we favour MTX as the additional agent. Factors that have influenced this choice includes its relative long-term safety in rheumatoid arthritis and its effecnveness in other forms of systemic vasculitis such as Wegener's granulomatosis and Takayasu arteritis (Hoffman et al, 1994; Hoffman, .1995). Careful selection of patients for treatment with MTX is necessary. They should have serum~creatimne values that are normal or at least less than 2.0 mg/dl, not have liver disease, abstain from alcoholic beverages, comply with medication instructions, and refrain from taking simultaneous medications which might potentiate MTX such as probenecld.

Treatment of Takayasu arteritis

Corticosteroids, whmh include prednisone or prednisolone, are the recom- mended initial agents of choice for the treatment of Takayasu artentis. The Systemm Vascular Disorders Research Committee, Ministry of Health and Welfare of Japan suggested treatment guidelines (Ito, 1992). When evidence of vascular inflammation was present, defined as fever and elevated acute phase reactants, an initial dose of predmsone 30 mg/day was recommended. This dose was continued for at least 2 weeks after sublective symptoms were controlled and acute phase reactants normalized.

Page 19: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

Large vessel vascuhtis 303

Thereafter, prednisolone was tapered over approximately 4 months and &scontinued. Alternative medications such as AZA, 6-mercaptopurine or cyclophosphamide (CP) were only recommended if disease did not respond to corticosteroM.

The NIH protocol employed higher dose corncosteroid, I mg/kg prednisone given for 1-3 months, before tapering to an alternate day regimen (Kerr et al, 1994; Hoffman, 1995). If patients failed to respond to corticosteroid or could not be tapered to an alternate day programme, a cytotoxic drug was in&cared.

Response to corticosteroid was often mcomplete (Table 9). Initial overall response has been reported to be as high as 100% (Hall et al, 1985) and as low as 31% (Jam et al, 1996). When present, constitutional 'systemic' symptoms such as fever, malaise, and headache, and the serological measures of inflammation such as acute phase reactants, respond most promptly and do so m at least 50% of panents (Nakao et al, 1967; Fraga et al, 1972; Ito, 1974; Inada and Ito, 1976; Waern et al, 1983; Hall et al, 1985; Shelhamer et al, 1985; Kerr et al, 1994; Jam et al, 1996). Occlusive/stenotic symptoms due to active vasculins, including claudication and extremity pain, respond less well, usually in <20-25% (Nakao et al, 1967; Fraga et al, 1972; Ito, 1974; Inada and Ito, 1976; Hall et al, 1985; Shelhamer et al, 1985; Kerr et al, 1994). Initial higher dose corncosteroid (30 mg/day versus i mg/kg per day) may have been a factor in some authors reporting better response. The NIH experience illustrated the remitting, relapsing nature of disease in some patients (Kerr et al, 1994). Although lmtlal remission was achieved in approximately 60% of panents, 50% of responders eventually relapsed when corticosterold was tapered.

Inadequate initial response of corticosteroid, or relapse when moderate dose corticostermd was employed during tapermg, mandated consideration of additional treatment. The ad&tlon of AZA, cytoxan (CTX) or 6-mercaptopurme improved response in approximately 60% of a retro- specnve cohort of Japanese pat, ents who initially responded poorly to corticosteroid (Ito, 1992). Slmdarly, 25 of 60 patients from the NIH cohort eventually required an additional agent which produced remission at least once in 40% {Kerr et al, 1994). Relanvely severe short- and long-term adverse effects associated with CTX resulted in the use of MTX which was

Table 9. Response of Takayasu artentls to mlhal cortlcosterold from selected series

N of % Response % Response Dally dose First author (year) treated patients 'systemJc' symptoms vascular symptoms$ CS (mg)

Nakao (1967) 29 'Most' 17 NR Fraga (1972) 12 1 O0 -45 30* Ito (1992) 45 70-1 O0 20 20-30* Inada (1976) 150 50-98 -25 -30* Hall (1985) 29 1 O0 50 30-1001- Shellhammer (1985) 16 N R 56 1 mg/kgt Kerr (1994) 48 NR 50 1 mg/kg1-

NR = not reported, * prednrsolone, 1- prednlsone, :~ response defined as lessened claudmatlon, return of pulse for improved artenographtc tmagmg

Page 20: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

304 W S. Wllke

reported in a prospective study of 18 pauents (Hoffman, 1995). Thirteen of 16 pauents who remained in the study experienced control of constitutional 'systemic' symptoms, stabdlzauon of vascular lesions by symptomauc and arteriographic criteria, and abdlty to discontinue corucosteroid.

Surgical treatment is required m up to 50% of patients (Kerr et al, 1994). Indicauons noted in the NIH series included: 1) hypertension associated with renal artery stenos~s; 2) extremity ischaemm which hmits acuvities of dally living; 3) severe (> 70%) stenosls of at least three cerebral vessels; 4) symptoms of CNS ischaemia; 5) moderate aoruc regurgitauon; and 6) cardiac lschaemia with proven coronary artery stenosls. Comphcauons of surgery included restenosis, thrombosis, haemorrhage and infection in 36% of patients receiwng syntheuc grafts versus 9% of patients who received autologous grafts (Kerr et al, 1994). Most authormes agree that it is best to ume surgery with disease remission (Hall and Buchbmder, 1990; Kerr et al, 1994; Hoffman et al, 1996). Five-year patency rates following grafts were improved in patients whose disease was reactive compared to rates m pauents whose disease was active at the time of surgery (Pagan et al, 1986). In th~s series, 29 patients underwent a total of 36 grafts. The 5-year patency rate was 53% for pauents with acuve disease at the ume of surgery and 88% when performed during inacuve disease.

Angmplasty also has a role. Fifty six per cent of 20 transluminal angio- plasty procedures m 11 patients were successful at first attempt m the NIH population (Kerr et al, 1994). Restenosis occurred m these patients within 3.5 to 13.6 months. Results of two other series are given m Table 10 (Dong et al, 1987; Takagl et al, 1993).

Table 10. Ang,oplasty for renal artery stenosls ,n Takayasu artent,s

F,rst author (year) N of lesions % Improved % Cured F/U (mos)

Takagl (1993) 75 (54) 48% 44% 3-70 M=26

Dong (1987) ' 32 (22) . 27% 59% 6-53 M=25 5

Measuring disease activity during therapy

Giant cell arteritis

Just as acute phase reactants are not always elevated inmally at the time of diagnosis, they do not always predict or concur with the climcal diagnosis of disease flare during corucosteroid treatment and tapering. Many published series have attempted to correlate acute phase reactants and the degree of disease activity (Wllke and Hoffman, 1995). Only one of these studies was prospective, used accepted diagnostic criteria and the standard treatment protocol, provided a priori criteria for disease flare and included a sufficient number of patients (55) who were followed for as long as 44 months (Kyle et al, 1989). At diagnosis, the WSR was >30 ram/hour in all

Page 21: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

Large vessel vascuht)s 305

patients and the CRP level was elevated m 49 (89%). The WSR was elevated m nine (45%) and the CRP in two (10%) of 20 patients judged to be in remission during the first month. When chnical relapses occurred during corticosteroid tapering, the WSR was elevated in only 43% of patients and the CRP in 35%. Furthermore, there was discordance between CRP and WSR in 19%. These data demonstrate that neither CRP nor WSR can be depended on to diagnose clinical exacerbation. The history and find- ings at clinical examination remain the gold standard.

Takayasu arteritis

The current criteria used to characterize disease activity have been derived by consensus and tradition and have not been validated in prospectxve, comparative trials (Ito, 1992; Hoffman et al, 1995). The patients followed in the NIH series were reqmred to undergo sequential angiography whether disease was considered to be active or inactive (Kerr et al, 1994). S~tzone per cent of patients demonstrated new angiograph~c lesions despite apparent p~olgnged remission by criteria which included normal acute phase reactants, absent constitutional 'systemic' symptoms and absence of new claudicatory/occluslve symptoms. Whether this finding represents clinically silent continued vascular inflammation or evolving fibrotic and atherosclerotic shrinkage is not absolutely clear. Strong evidence however for continued inflammation despite clinical remission comes from the surgical literature. Forty two per cent of Takayasu arteritis patients under- going vascular bypass surgery were discovered to have active histological inflammation despite apparent chnical and serological laboratory remission (Lagneau et al, 1987).

Current markers of active disease are imperfect, including ang~ography. Unfortunately, the angiographic image only allows visuahzation of the vascular lumen; a p~cture of disease outcome, not of disease process. Imaging modalitles designed to study vessel wall characteristics have recently been reported. B-mode ultrasonography was employed in 16 patients with Takayasu arteritis and compared to 16 control patients (Raninen et al, 1996). Thickening of the wall of the carotid and subclavian arteries and of the abdominal aorta was apprecmted in 100% of patients w~th Takayasu arteritls and differentiated these patients from controls suggesting that ultrasonography might be used for &agnosls. The usefulness of this modality to estabhsh disease activity, however, was not reported.

Indmm-111-mixed leukocyte scans were performed in 10 patients with Takayasu arterltis and correlated with other measures of chnlcal, laboratory and radiographic activity (Chen et al, 1995). Although eight patients were known to have active disease by previous criteria, only two scans demonstrated vessel uptake. The low sensitivity of this modahty for active disease was disappointing.

Spiral computed tomography was demonstrated to show high attenuation m the wall in pre-contrast transverse ~mages, circumferential wall thickness, and a concentric flow-attenuation ring inside the aortic wall

Page 22: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

306 W.S. Wflke

in active disease (Park, 1996). The author felt that the high-attenuation aortic wall in the delayed phase might correlate with florid inflammation and vasculanzation of the tumca media and tunica adventitm, suggesting that this modality has potentml to differenuate active from inactive disease. Controlled, comparative studies are lacking.

The usefulness of magnetic resonance imaging (MRI) continues to be examined. A high frequency of false positive and false negative findings in 10 consecutive patients, using angiography as the gold standard, suggested that th~s technique might be an insensitive tool for diagnostic screening (Miller et al, 1986). Neither histology nor response to therapy over time was assessed in this study. Ahernat~vely, MRI of the abdominal aorta revealed thickening of the aomc wall which thinned to normal following treatment with corticosteroids (Tanigawa et al, 1992). In this case report, symptoms were also controlled by corncosteroid therapy. Very recent prehmmary findings in three patients suggests that MRI employing T2- weighted techniques, which are sensinve to ussue water content associated with oedema, m~ght be a sensmve, non-mvasive study that is useful to monitor patients with Takayasu arteritis (Flamm et al, 1996). The authors now have experience with their techmque in 24 patients w~th giant cell artentis and Takayasu arterius. Findings have been consistent with the chnical impression and response to treatment in > 90% of cases.

Because symptoms and signs of active disease may be absent in up to 50% of patients who continue to have vascular inflammauon/progression, new surrogate markers and/or other dmgnostlc modahties are needed. Sequential angiography is expensive, does not reveal vessel wall inflam- mation and carries a significant risk of morbidity. Better imaging techmques to detect inflammation in the vascular wall and more sensinve in&cators of endothelialhmmune acuvation markers are urgently needed.

Summary

Clinical description and diagnosis

Large artery involvement very s~mflar to Takayasu arterms occurs m at least 15% of patients with giant cell arterius and blurs the clinical dlstlncnon between the two diseases.

Pr acSice points

• Blood pressure should be regularly obtained m all four extremities m pauents w~th polymyalgia rheumat~ca, g~ant cell artentis and Takayasu arterins to monitor for possible large vessel involvement

• This pracuce should be continued even after remission off therapy

• Patients >age 40 develop Takayasu artentis

Page 23: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

Large vessel vascuht~s 307

Polymyalgia rheumatica and grant cell arterltis are not separate diseases, but constitute a spectrum of disease. Because the former is a syndrome which can also indicate inflammatory arthritis, infection, and malignancy, care must be taken in assigning the diagnosis. The case for the occurrence of axial arthritis, especially in the sternoclavlcular joint in some patients with polymyalgia rheumatica symptoms and even in giant cell arteritis is weak; and the case for polyartlcular peripheral joint involvement In giant cell arterltIS is weaker still.

Practice point

The presence of inflammatory arthritis in a patient with polymyal- gia rheumatica/giant cell arteritis should produce healthy scepticism about common pathogenesis and trigger a diagnostic search for other causes

Diagnosis and treatment

Initial dose corticosterold treatment for polymyalgia rheumanca and giant cell arterins may be similar. Mandatory superficial temporal artery biopsy for all patients with symptoms of either condition might be reconsidered.

Practice points

• Superficial temporal artery biopsy should be obtained m:

--Panents with signs and symptoms of polymyalgia rheumatica or giant cell arteritis who fall to respond to prednisone dose of at least 20 mg/day

--Patients with unexplained visual symptoms, malaise, weight loss, and elevated acute phase reactants in whom a diagnosis of infection, malignancy, or other connective tissue disease IS lacking

• Superficial temporal artery biopsy might be 'held' in panents with a classic history of polymyalgia rheumatlca or giant cell arteritis who respond promptly and appropriately to initial corticosterold therapy

Agents other than cortlcosterold alone are necessary to control disease in a minority (5-10%) of giant cell arteritis patients and in at least 50% of Takayasu arteritis patients.

Page 24: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

308 W.S. Wdke

Practice point

Consider the use of an ad&tional agent such as methotrexate for patients w~th giant cell arteritis or Takayasu arteritis who require moderate (15-20 mg) predmsone per day as chromc maintenance therapy to control disease

Acute phase reactants are only moderately helpful for the initial diagno- sis of giant cell arterltis and Takayasu arteritis. Clinical signs and symptoms remain the gold standard. In addinon, acute phase reactants are often un- reliable measures of disease activity during therapy m both conditions. Furthermore, angiography in Takayasu artentis allows visuahzation of the vascular lumen, but does not allow study of the vascular wall in order to determine whether disease is acnve or 'burned-out'.

Research agenda I I I

• .\re markers .~uch as th rombomodu l in , and-cndothehal annbodie% I yon Wd[eb~and factor or others more sen~ti~e/specffic marker,, ot I s~tcmtc/vascular intlammanon m grant cell arterttn, and Takavasu I arterltv,? I I

• I.~ thcn'e a role for tnorc soplu~tLcatcd nlllagLLlg rnodahtncs de.,,igucd [ i

to ~rud) ~cs~el \~ all ch:lr:~.tertsuc~ m Taka)a,u arterins? I I

Acknowledgement

The author wishes to thank Gary S. Hoffman, MD for expert advice m preparing this manuscript.

R e f e r e n c e s

Andersson R, Malmvall BE & Bengtsson BA (1986) Long-term survwal m giant cell arterxns including temporal arterms and polymyalgla rheumatlca Acta Medtca Scandinavia 220: 361-364. ~,

* Arend WP, Michel BA, Bloch DA et al (1990) The American College of Rheumatology 1990 Criteria for the Classification of Takayasu's Arterms. Arthrzt~s and Rheurnatzsrn 33: 1129-1134.

Bacon PA (1991) Vascuhnc syndromes associated with other rheumatic condmons and un- classified systemic vascuhns. Current Opinion m Rheumatology 3: 56-61.

Barrier J, Tourmemame N, Maulaz D et al (1983) Evolunon, traltement et pronosnc de [a mala&e de Horton Anna[es de Medecme Interne (Paris) 34: 428-435.

Behn AR, Perera T & Myles AB (1983) Polymyalgla rheumanca and corncosterolds: how much for how long~ Annals of Rheumatic Disease 42: 374-378.

Page 25: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

Large vessel vascuhtls 309

Bengtsson BA & Malmvall BE (1981) An alternate-day corttcosterold regimen m maintenance therapy of giant cell arterms. Acta Medtca Scandinavia 209: 347-350.

Bird HA, Essehncks W, Dixon AS et al (1979) An evaluation of criteria for polymyalgla rheumatlca. Annals of Rheumatm Dzsease 33:434-439

Biscard C, Sloth H, Kedlng N & Juel K (1991) Excess mortahty in giant cell arterltls. Journal of Internal Medicine 30:119-123.

Boesen P & Sorensen SS (1987) Giant cell arteritlS, temporal arterlttS, and polymyalgla rheumatlca in a Damsh county: a prospective investigation, 1982-1985. Arthrms and Rheurnattsrn 30: 294-299.

Bruk MI (1967) Amcular and vascular manifestations of polymyalgta rheumatlca Annals of Rheumauc Disease 26: 103-116.

Caselli RJ, Hunder GG & Whtsnant JP (1988) Neurologlc disease m biopsy-proven giant cell (temporal) arterms. Neurology 38: 352-359.

Chen CC, Kerr GS, Carter CS et al (1995) Lack of sensmvtty of lndmm-111 mixed leukocyte scans for active disease in Takayasu's arterms. Journal of Rheurnatology 22:478-481.

Chou CT & Schumacher HR Jr (1984) Clinical and pathologic studies of synovms m polymyalgla rheumatlca. Arthrttzs and Rheumatism 27:1107-1117.

Chuang TY, Hunder GG, Ilstrup DM & Kurland LT (1982) Polymyalgla rheumatica. A ten- year epldemiologic and chnlcal study. Annals of Internal Medtczne 97: 672-680.

Cullen JF (1972) Temporal artentms: occurrence of ocular complications 7 years after diag- nosis British Journal of Ophthalmology 56: 504-588.

Dabague J & Reyes PA (1996) Takayasu's arterms in Mexico: A 38-year clinical perspective through literature review. International Journal of Cardiology 54 (supplement): S 103-S 109.

deSdva M & Hazleman BL (1986) Azathloprme m giant cell arterms/polymyalgla rheumatlca: a double-bhnd study. Annals of Rheurnatzc Disease 45: 136-138.

Dong Z, LI S & Lu X (1987) Percutaneous translummal angloplasty for reno-vascular hyper- tension in arterms: experience in China. Radiology 162: 477-479.

Douglas WAC, Martin BA & Morris JH (1983) Polymyalgia rheumatlca: an arthroscoplc study of the shoulder lomt. Annals ofRheumatm Dmease 42: 311-316.

Doury P, Pattin S, Dulry F & Thabout A (1983) The use of dapsone in the treatment of giant cell arterms and polymyalgla rheumatlca. Arthritis and Rheumatzsrn 30: 689-690.

" Elhs ME & Ralston S (1983) The ESR in the diagnosis of polymyalgla rheumauca/glant cell arterms syndrome. Annals of Rheumatm Disease 42: 168-170.

Evans JM, O'Fallon M & Hunder GG (1995) Increase incidence of aortic aneurysm and dissection in giant cell (temporal) arterms. Annals of Internal Medicine 122: 502-507.

Evans JM, Bowles CA, Blornsson Je t al (1994) Thoracic aortic aneurysm and rupture in giant cell arterms. A descriptive study of 41 cases. Arthritis and Rheumattsrn 37:1539-1547

Flamm SD, Van Dyke C, White RD & Hoffman GS (1996) Novel magnetic resonance imaging (MRI) techniques for evaluating active arterial inflammation in Takayasu's disease (TD). Arthritis and Rheumatism 39 (supplement): $201.

Fraga A, Mmtz G, Valle L & Flores-Izqulerdo G (1972) Takayasu's artentlS: frequency of systemic manifestations (study of 22 patients) and favorable response to maintenance steroid therapy with an adrenocortlcosterosteroId (12 patients). Arthr*tss and Rheumatism 15: 617-624.

Gilmour JR (1941) Giant-cell chronic arterms. Journal of Pathology and Bacteriology 8: 263-277.

Gmsburg WW, Cohen MD, Hall SB et al (1985) Seronegatwe polyarthrltiS in giant cell arterms. Arthritis and Rheumatism 28: 1362-1366.

Godeau P, Aubert L, Gmllevm L e t al (1982) Aspect chmque, evolution et pronosltlC de la maladie de Horton. Annales de Medecme Interne (Parts) 133: 393-400.

Gordon I (1960) Polymyalgia rheumatlca A clinical study of 21 cases. Quarterly Journal of Medicine 29: 473-488.

Gouet D, Marechaud R, Alcalay M e t al (1985) Survival in giant cell arterltls: a 14-year survey of 87 patients. Journal of Rheumatology 12: 1209-1210.

Graham E, Holland A, Avery A & Russell RWR (1981) Prognosis in giant cell arterms. Bntzsh Medical Journal 282: 269-271.

Greene GM, Lain D, Sherwln RM et al (1986) Giant cell arterltiS of the legs. Clinical isolation of severe disease with gangrene and amputation. Amerman Journal of Medmme 81: 727-733.

Page 26: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

310 W S. Wflke

Hall S, Barr W, Lie JT et al (1985) Takayasu's arterms: a study of 32 North American panents. Medzcme 64: 89-99.

Hall S & Buchbmder R (1990) Takayasu's arterms. Rheurnauc D~sease Chines of North America 16: 411-422.

Hamilton CR Jr, Shelley WM & Tumulty TA (1971) Giant cell arterms: including temporal arterms and polymyalgla rheumatlca. Medicine 50: 1-27.

Hata A, Noda M, Monwakl R & Numano F (1996) Anglographlc findings of Takayasu's arterms: new classification. Internatmnal Journal of Cardiology 54 (supplement): S155-$163.

Hauser WA, Ferguson RH, Holley KE & Kurland LT (1971) Temporal arterms m Rochester, Minnesota, 1951 to 1957. Mayo Chmc Proceedings 46: 597-602.

Healey LA (1983) Polymyalgia rheumanca and the ARA criteria for rheumatoid arthrms. Arthrms and Rheumatism 26: 1417-1418.

Healey LA & Wllske KR (1980) Presentation of occult giant cell arterms. Arthrzt~s and Rheumatism 23: 641-643.

Hernandez-Garcia, Soriano C, Morado C et al (1994) Methotrexate treatment m the manage- ment of giant cell artentis. Scandmawan Journal of Rheumatology 23:295-298

Hoffman GS (1994) Hypertensive encephalopathy m a young man with undetectable upper extremity blood pressure. Journal of Vascular Medicine and Bmlogy 5: 69-73.

"Hoffman GS (1995) Treatment of resistant Takayasu's arterms. Rheumatic D~sease Chines of North America 21:73-80

Hoffman GS (1996) Takayasu's arterms- lessons from the American National Insntutes of Health experience. International Journal of Cardmlogy 54 (supplement): $83-$86.

"Hoffman GS, Leavltt RY, Kerr GS & Faucl AS (1992) The treatment of Wegener's granulo- matosis with glucocomcmds and methotrexate. Arthritis and Rheumatism 35: 1322-1329

Hoffman GS, Leavitt RY, Kerr GS et al (1994) Treatment of glucocomcold-resistant or relaps- ing Takayasu's arterms with methotrexate. Artbrzt~s and Rheumatism 37: 578-582.

Houston KA, Hunder GG, Lie JT et al (1978) Temporal arterms: a 25-year epldemlologlc, chmcal and pathologic study. Annals of Internal Medicine 88: 162-167.

Hoyt LH, Perera GA & Kauvar AJ (1941) Temporal arterms New England Journal of Medicine 225: 283-386.

"Hunder GG (1990) Grant cell (temporal) arterms. Rheumatic D~sease Chmcs of North America 16: 399-409.

Hunder GG, Ward LE & Burbank MK (1967) Grant cell arterltls producing an aortic arch syndrome. Annals of Internal Medicine 66: $78-582.

Hunder GG, Sheps SG, Allen GL & Joyce JW (1975) Dally and alternative day comcosterold regimens m treatment of giant ceil arterms: comparison in a prospective study. Annals of Internal Medicine 82: 613-618.

Hunder GG, Bloch BA, M,chel BA et al (1990) The American College of Rheumatology 1990 criteria for the classlficanon of grant ceil arterms. Arthritis and Rheumatism 33: 1122-1128.

Inada K & Ito I (1976) Steroid therapy of aortltlS syndrome. Annual report of the Aortms Syndrome Research Committee of the Mlmstrv of Health and Welfare of Japan (in Japanese): 174-178.

Ito I (1974) Chmcal observations of 85 patients with aort,tlS syndrome (m Japanese). N~ppom Egzgz Shmpo Japanese Medical Journal 2612: 3-9.

Ito I (1992) Medical treatment of Takayasu's arterms. Heart and Vessels 7 (supplement): 133-137.

Jam S, Kuman S, Ganguly NK & Sharma DK (1996) Current status of Takayasu's arterms in In&a Internatmnal Journal of Cardmlogy 54 (supplement): Sl11-S116.

Jonasson F, Cullen JF & Elton RA (1979) Temporal arterms. A 14-year epldemmloglcal, chmcal and prognostic study. Scothsh MedzcalJournal 24: 111-117.

Kerr GS, Hallahan CW, G,ordano J e t al (1994) Takayasu's arterms. Annals of lnternal Medlcme 120:919-929

Klein RG, Hunder GG, Stanson AW & Shets SG (1975) Large artery involvement from giant cell (temporal) artent,s. Annals of Internal Medzcme 83: 806-812.

Kogstad OA (1965) Polvmyalgla rheumanca and Its relation to arterms temporahs Acta Medlca Scandinavia 178: 591-598.

Page 27: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

Large vessel vascul~t~s 311

Krall PL, Mazanec DJ & Wllke WS (1989) Methotrexate for corncostermd-reslstant polymyalgla rheumanca and giant cell arterms. Cleveland Chmc Journal of Medicine 56: 253-257.

Kyle B, Tudor J, Wralght DP et al (1990) Rarity of synovlUs m polymyalgla rheumatlca. Annals of Rheumatic Dzsease 49: 155-157.

*Kyle V, Casston TE & Hazleman BL (1989) Erythrocyte sedimentation rate and C-reacnve protein m the assessment of polymyalgla rheumatlca/glant cell arterms on presentanon and during follow-up. Annals of Rheumatic Disease 48: 667-671.

Kyle V & Hazleman BL (1989) Treatment of polymyalgla rheumatlca and giant cell arterms. II. Relationship between steroid dose and steroid associated side effects. Annals of Rheumatzc Disease 48: 662-666.

Lagneua P, Michel JP & Vuong PN (1987) Surgical treatment of Takayasu's &sease. Annals of Surgery 205: 157-166.

Lie JT (1995) Aortic and extracramal large vessel giant cell arterms: a review of 17 cases with h~stopatholog~c documentation. Seminars m Arthrms and Rheumausm 24:422-431.

Lie JT, Brown AL & Carter ET (1970) Spectrum of aging changes in temporal arteries. Its s~gmficant, in mterpretatmn of b~opsy of temporal artery. Archives of Pathology 90: 278-285,

Matteson EL, Gold KN, Bloch DA & Hunder GG (1996) Long-term survival of pauents with grant cell arterms m the American College of Rheumatology grant cell arterms classifi- cation cnterm cohort. American Journal of Medicine 100: 193-196.

Maxwell MH, Blelfer KW, Frankhn SS & Varady PD (1972) Cooperative study of reno- vascular hypertensmn:demographlc analysis. Journal of the Amertcan Medical Assoclatzon 220:1195-1204

Mehler MF & Rabmowlch L (1988) The chmcal neuro-ophthalmologlc spectrum of temporal artentls. Amerzcan Journal of Medicine 85: 839-844.

Michel BA, Arend WP & Hunder GG (1996) Chmcal dlfferennatmn between giant cell (temporal) artentis and Takayasu's artenns. Journal of Rheumatology 23:106-111.

Miller DL, Remlg JW & Volkman VJ (1986) Vascular mmgmg with MRI inadequacy m Takayasu's arterms compared with anglography. American Journal of Radzology 146: 949-954.

Miller LD & Stevens MB (1978) Skeletal manffestatmns of polymyalgia rheumatlca Journal of the Amerzcan Medzcal Assoctatlon 240: 27-29.

Morales E, Pmeda C & Martmez-Lawn M (1991) Takayasu's arterms ,n children Journal of Rheumatology 18: 1081-1084.

Myles AD, Perera T & Rldley MG (1992) Prevention of bhndness m grant cell arterms by cortlcosterold treatment. B rittsh Journal of Rh eumatology 31: 103-105.

Nakao K, Ikeda M, Klmata Set al (1967) Takayasu's arterlttS: chmcal report of 84 cases and immunologic studies of seven cases. Czrculatzon 35:1141-1155.

Nasu T (1982) Takayasu's truncoartenns-pulseless disease on aortms syndrome. Acta PatboIogzca Japomca 32 (supplement 1): 117-131.

Nesher G, Sonnenbhck M & Frledlander Y (1994) Analysis of steroid related comphcatlons and mortality m temporal arterms a 15-year survey of 43 patients. Journal of Rheumatology 21: 1203-1286.

Ninet JP, Bachet P, Dumontet CM et al (1990) Subclavmn and axfllary mvolvement m temporal arteritis and polymyalgla rheumatlca. American Journal ol c Medicine 88: 13-20.

Nordborg E & Bengtsson BA (1989) Death rates and causes of death in 284 consecutive patients with grant cell arterms confirmed by biopsy. Brztlsh Medical Journal 299: 549-550.

O'Duffy JD, Wahner HW & Hunder GG (1976) Joint imaging m polymyalgm rheumat,ca Mayo Ckmc Proceedings 51: 519-524.

Ostberg G (1973) On artentls with reference to polymvalgia artermca. Acta Pathologlca et Mtcrobzologlca Scandmawca [A] 237 (supplement): 159.

Palce EW, Wright FW & Hill AGS (1983) Sternoclavlcular erosions m polymyalgm rheumatlca. Annals of Rheurnatic Dtsease 42:379-383

Palarl R, Hekah P & Haqola PT (1986) Treatment of Takayasu's arterltls:an analysis of 29 operated panents. Thoraczc and Cardiovascular Surgery 34: 176-181.

Park JH (1996) Conventional and CT anglographlc dmgnosls of Takayasu's artentls Internauonal Journal of Cardtology 54 (supplement): S 165-S 171.

Page 28: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

312 W S Wilke

Park JR, Jones JD & Hazleman BL (1981) Relationship of the erythrocyte sedlmentanon rate to acute phase proteins m polymyalgla rheumanca and giant cell artenns. Annals of Rheumatic Disease 40: 493-495.

Raninen RO, Kupan MM, Pamllo MS et al (1996) Arterial wall thickness measurement by B-mode ultrasonography m panents with Takayasu's artertns. Annals of Rheumatic Disease 55: 461-465.

Reich KA, Glanslracusa DS & Strongwater SL (1990) Neurologlc mamfestanons of giant cell arterms. American Journal of Medzclne 89: 67-72.

Rubinow A, Brandt KD, Cohen AS & Sach B (1984) Iatrogemc morbidity accompanying suppression of temporal arterms by adrenocorncostermds. Annals of Ophthalmology 16: 258-265

Russell RWR (1959) Giant cell arterlns-a review of 35 cases. Quarterly Journal of Medicine 28: 471-489.

Sav-Soderberg HJ, Malmvall B-E, Andersson R & Bengtsson BA (1986) Giant cell artenns as a cause of death. Report of 9 cases. Journal of the American Medical Association 255: 493-496.

Seko Y, Mmota S, Kawasakl A et al (1994) Perform-secreting killer cell infiltration and expres- sion of a 65-KD heat-shock protein m aortic tissue of patients with Takayasu's artenns. Journal of Ckmcal Investlgauon 93: 750-758.

Settas L, Dmltnadls G, Sfetsms T et al (1991) Methotrexate versus azathloprme m poly- myalgla rheumanca~glant cell artenns:a double-bhnd, cross-over trial. Arthritis and Rheumahsm 34 (supplement) $72.

Sharma DK, Jam S & Sagar S (1996a) Systemic mamfestanons of Takayasu's artenns: the expanding spectrum. International Journal of Cardmlogy 54 (supplement): $149-$154.

Sharrna DK, Jam S, Sun S & Numano F (1996b) Dlagnosnc crlterm for Takayasu's arterms. International Journal of Cardiology 54 (supplement): $141-$147

Shelhamer JH, Volkman BJ, Parrfllo JE et al (1985) Takayasu's artenns and its therapy. Annals of Internal Medicine 103: 121-126.

Sima D, Thlele D, Turowskl A et al (1994) Annendothehal annbodles m Takayasu's arterms. Arthrzt~s and Rheumatism 37: 441-442.

Smith CA, Fldler WJ & Pmals RS (1983) The epldemlology of grant cell arterlns. Report of a 10-year study m Shelby County, Tennessee. Arthritis and Rheumatism 26: 1214-1219.

Spiera H & Swerdlow F (1987) Dapsone as a steroid-sparing agent m giant cell arterms (GCA) Arthr~tis and Rheumatism 30 (supplement): $62.

Sproul EE & Hawthorne JJ (1937) Chronic diffuse mesaornns report of 2 cases of unusual type. American Journal of Pathology 13: 311-323.

Takagi A, Tada Y, Sato O & Mlyata T (1993) Surgical treatment for Takayasu's artenns. Journal of Cardzovascular Surgery 30:553-558

Tamgawa K, Eguchl K, Kltamura Y e t al (1-992) Magnenc resonance imaging detecnon of aornc and pulmonary wall thickening m the acute stage of Takayasu's artenns. Improve- ment of chmcal and radLologlc findings after steroid therapy. Arthritis and Rheumatzsm 35:476--480

"Turnbull J (1996) Temporal arterms and polymyalgla rheumanca (nosographlc and nosologlc conslderatmns). Amertcan Academy of Neurology 46: 901-906.

Utsmger (1982) Treatment of steroid non-responsive giant cell arterlns (GCA) with cytoxan. Arthritis and Rheumatism 25 (supplement): $31.

van der Veen MJ, Dmat HJ, van Booma-Frankfort et al (1996) Can methotrexate be used as a steroid sparing agent m the treatment of polymyalgla rheumanca and grant cell artenns) Annals of Rheumatic Dzsease 55: 218-223.

Virmam R, Lande A & McAlhster HA Jr (1986) Pathological aspects of Takayasu's arterms. In. Lande A Berkman YM, McCalhster HA |r, (eds) Aortltls: Ckmcal, Pathologic and Radiographic Aspects pp. 55-99. New York. Raven Press.

Waern AU, Andersson P & Hemmmgsson A (1983) Takayasu's arterms- a hospital-region based study on occurrence, treatment and prognosis. Anglology 34: 311-320.

Wagner AD, Blornsson J, Bartley GB et al (1996) Interferon-gamma-producing T-cells m giant cell vascuhns represent a minority of nssue-mfiltratmg cells and are located distant from the site of pathology. Amerzcan Journal of Pathology 148: 1925-1933.

Weyand CM, Goronzy JJ & Hunder GG (1995) Response to cytokmes in polymyalgm rheumanca and giant cell artenns (letter). Annals of Iuternal Medicine 122: 634.

Page 29: 5 Large vessel vasculitis (giant cell arteritis, Takayasu arteritis)

Large vessel vascuhtls 313

'~ Weyand CM, Hicok KC, Hunder GG & Goronzy JJ (1994) Tissue cytokme pattern in patients with polymyalgla rheumatlca and giant cell arterms. Annals of Internal Medmme 21: 484-491.

"Wdke WS & Hoffman GS (1995) Treatment of cortlcosterold-resistant giant cell arterms. Rheumatm Dtsease Chinas of North Amerma 21: 59-71.

Wilke WS, Wysendeek AJ, Crall P & Segal AM (1995) Masked presentation of giant-cell arterltlS. Cleveland Clmw Quarterly 52: 155-159.

Wdkmson IMS & Russell RWR (1972) Arteries of the head and neck m giant cell arterms: a pathological study to show the pattern of arterial involvement. Archwes of Neurology 27: 278-391.