Volume 347:261-271 - July 25, 2002 - Number 4
Polymyalgia Rheumatica and Giant-Cell Arteritis
Carlo Salvarani, M.D., Fabrizio Cantini, M.D., Luigi Boiardi, M.D., Ph.D., and Gene G. Hunder, M.D.
The first description of polymyalgia rheumatica was provided by Bruce in 1888, who called this condition "senile rheumatic gout," thus emphasizing its occurrence in the elderly.1 In 1957, Barber proposed the use of the term "polymyalgia rheumatica."2 In 1963, Bagratuni outlined the nonerosive articular nature of polymyalgia rheumatica,3 and in the 1990s, diffuse swelling of the hands and edema were reported in some patients.4
Giant-cell arteritis is a chronic vasculitis of large and medium-sized vessels. Although it may be widespread, symptomatic vessel inflammation usually involves the cranial branches of the arteries originating from the aortic arch. The first clinical description of giant-cell arteritis was presented by Hutchinson in 1890.5 However, it was not reported again until the 1930s, when Horton and colleagues6 described the histologic appearance of granulomatous arteritis of the temporal vessels. The relation between polymyalgia rheumatica and giant-cell arteritis was not widely accepted until more than 20 years later, and Paulley and Hughes were among the first to recognize the association.7
Epidemiology and Diagnostic Criteria
Polymyalgia rheumatica is a common illness in certain populations, with a prevalence of 1 case for every 133 people over the age of 50 years.8 Giant-cell arteritis is less frequent than polymyalgia rheumatica. In Olmsted County, Minnesota, the average annual incidence was 17.8 cases per 100,000 persons 50 years of age and older.9 However, autopsy studies suggest that giant-cell arteritis may be more common than is clinically apparent.10 Women are affected twice as often as men.
The incidence of polymyalgia rheumatica and giant-cell arteritis increases after the age of 50 years and peaks between 70 and 80 years of age. Population surveys show higher frequencies of polymyalgia rheumatica and giant-cell arteritis at higher latitudes.8,9,11,12,13,14,15 The incidence of polymyalgia rheumatica appears to have been relatively stable in recent years; in contrast, the incidence of giant-cell arteritis appears to have increased. In addition, there is evidence of periodic clustering of cases of giant-cell arteritis.9 The mortality rate in patients with polymyalgia rheumatica and giant-cell arteritis is similar to that expected in general populations of similar age and sex, although thoracic aortic aneurysms and dissection of the aorta are important late complications of giant-cell arteritis.16
The current diagnostic criteria for polymyalgia rheumatica were empirically formulated by Chuang et al.17 and Healey18 (Table 1). The two sets of criteria are similar, the only difference being the inclusion in the Healey criteria of responsiveness to corticosteroids. Criteria for the classification of giant-cell arteritis were formulated by the American College of Rheumatology in 1990 (Table 2).19 These criteria were designed for use ininvestigative studies to help distinguish giant-cell arteritis from other types of vasculitis; they are not useful for making the diagnosis in individual patients.20
Temporal-artery biopsy is recommended in all patients who are suspected of having giant-cell arteritis. The inflammatory involvement of affected arteries is often intermittent rather than continuous. If the temporal artery is clearly abnormal on physical examination, only a small specimen needs to be removed for histopathological review. When extracranial arteries are normal on palpation and giant-cell arteritis is suspected, it is important to obtain a biopsy of a longer segment of temporal artery (3 to 5 cm) and consider performing a contralateral biopsy if the results of the first biopsy are normal. We used this approach and found that only 10 percent of patients had negative findings on biopsy.21 When possible, temporal-artery biopsy should be performed before treatment is initiated; however, examination of temporal-artery–biopsy specimens may reveal evidence of arteritis after more than two weeks of corticosteroid therapy.22
Population-based studies of polymyalgia rheumatica have demonstrated the presence of biopsy-proved giant-cell arteritis in 16 to 21 percent of patients.8,11 Conversely, symptoms of polymyalgia rheumatica have been observed in 40 to 60 percent of patients with giant-cell arteritis in clinical series.9 Polymyalgia rheumatica may thus begin before, at the same time as, or after giant-cell arteritis.
Patients with polymyalgia rheumatica who do not have symptoms of claudication or abnormalities of temporal arteries on examination have a very high probability of having normal findings on biopsy.23 Consequently, we perform temporal-artery biopsy only in patients with polymyalgia rheumatica who present with cranial symptoms or signs.
Polymyalgia rheumatica and giant-cell arteritis are probably polygenic diseases in which multiple environmental and genetic factors influence susceptibility and severity. The increased incidence at higher latitudes and in Scandinavian countries and U.S. communities with a strong Scandinavian ethnic background and the occasional familial cases support the evidence suggesting environmental and genetic causes.8,9,11,12,13,14,15
A viral cause has been suspected but not confirmed in polymyalgia rheumatica and giant-cell arteritis. An increased prevalence of antibodies against parainfluenza virus type 1 was reported in patients with polymyalgia rheumatica and giant-cell arteritis.24 A close temporal relation between the observed incidence peaks of polymyalgia rheumatica and giant-cell arteritis and epidemics of Mycoplasma pneumoniae, parvovirus B19, andChlamydia pneumoniae infections has been found.14 However, other studies were unable to find any association between infection and the onset of polymyalgia rheumatica and giant-cell arteritis.25 The epidemiologic evidence that there is a similar cyclic fluctuation (every six to seven years) in the incidence of giant-cell arteritis and parvovirus B19 infection suggests that this virus has a role.9 A significant association between histologic evidence of giant-cell arteritis and the presence of parvovirus B19 DNA in temporal-artery specimens has been reported.26
The most commonly studied genetic association is with the genes of the HLA complex. As is the case in rheumatoid arthritis, HLA-DRB1*04 and DRB1*01 alleles are associated with susceptibility to polymyalgia rheumatica and giant-cell arteritis.27,28 These alleles may influence the severity of disease.29
A model for the pathogenesis of giant-cell arteritis has been proposed by Weyand and Goronzy.30 Antigen is recognized in the adventitia by T cells that enter the artery through the vasa vasorum, undergo clonal expansion, and are stimulated to produce interferon-. This results in the differentiation and migration of macrophages and the formation of giant cells. In the adventitia macrophages produce the inflammatory cytokines interleukin-1 and interleukin-6, whereas in the media and intima, they contribute to arterial injury by producing metalloproteinases and nitric oxide, respectively. This destructive mechanism of the arterial wall is associated with a repair mechanism that includes the secretion of growth and angiogenic factors (platelet-derived growth factor and vascular endothelial growth factor) through the infiltration of mononuclear cells and multinucleated giant cells. These changes ultimately lead to the degradation of the internal elastic lamina and to occlusive luminal hyperplasia.
Variations in the clinical presentation of giant-cell arteritis may be correlated with the expression of cytokine messenger RNA (mRNA) in the affected temporal arteries. Patients with ischemic symptoms have higher concentrations of interferon- mRNA and interleukin-1 mRNA, fever is correlated with low concentrations of interferon-, and polymyalgia rheumatica and large-vessel giant-cell arteritis are correlated with the up-regulation of interleukin-2 mRNA.30
In situ production of cytokines can be documented in the temporal arteries of patients with polymyalgia rheumatica who do not have histologic evidence of arteritis, even though these patients do not produce interferon-, unlike those with giant-cell arteritis.31 These data suggest that a subclinical vasculitis may be present in the temporal arteries of patients with polymyalgia rheumatica and that the production of interferon- may be crucial for the development of overt vasculitis.
Recently, studies involving positron-emission tomography have provided evidence of vascular involvement in patients with polymyalgia rheumatica who do not have clinical signs of vasculitis.32
Arthroscopic, radioisotopic, and magnetic resonance imaging (MRI) studies of patients with polymyalgia rheumatica all have indicated the presence of a synovitis in proximal joints and periarticular structures.33,34,35 The synovitis associated with polymyalgia rheumatica is histologically mild and is characterized by a predominance of macrophages and T cells, mostly CD4+ helper T cells33 (Figure 1A and Figure 1B). These features are verysimilar to those of the vascular lesions of giant-cell arteritis.36
In giant-cell arteritis, arteries originating from the aortic arch are usually affected by an inflammatory infiltrate associated with marked disruption of the internal elastic lamina. This infiltrate is usually focal and segmental. The classic histologic picture of giant-cell arteritis, observed in 50 percent of the cases, is one of granulomatous inflammation in which giant cells are usually located at the junction between the intima and media (Figure 1C). The other 50 percent have panarteritis with a mixed-cell inflammatory infiltrate that is predominantly composed of lymphomononuclear cells, with occasional neutrophils and eosinophils but without giant cells (Figure 1D).37 In rare patients the only histologic abnormality may be a small-vessel vasculitis surrounding a normal temporal artery.38
The combination of persistent pain for at least one month with aching and morning stiffness in the neck, shoulder girdle, and pelvic girdle that lasts at least 30 minutes and an increase in the erythrocyte sedimentation rate to at least 40 mm per hour is strongly suggestive of polymyalgia rheumatica.17,18
On examination, limitation of active and, often, passive movements of the shoulders due to pain is present. Shoulder pain is the presenting finding in the majority of patients (70 to 95 percent). The hips and neck are less frequently involved (between 50 and 70 percent). In both the shoulder and pelvic girdles the pain usually radiates distally toward the elbows and knees. The discomfort may begin on one side, but it soon becomes bilateral. Systemic symptoms and signs are present in approximately one third of patients and include fever, malaise or fatigue, anorexia, and weight loss. The diagnosis is usually made within two to three months after the onset of symptoms.17,39,40
The prominent and diffuse shoulder discomfort may be due more to periarticular structures than to the glenohumeral joint itself. Physical examination reveals little evidence of swelling or tenderness of proximal joints that could account for the patients' often marked symptoms. An MRI study of patients with polymyalgia rheumatica identified subdeltoid and subacromial bursitis as more prominent and common than joint synovitis and bicipitaltenosynovitis35 (Figure 2).
4,8,41,42 They include nonerosive, self-limited, asymmetric peripheral arthritis (predominantly affecting the knees and wrists), carpal tunnel syndrome, and swelling and pitting edema of the dorsum of the hands and wrists (Figure 3A), as well as of the ankles and the tops of the feet.
The onset of giant-cell arteritis tends to be gradual, but it can be abrupt. Systemic symptoms are present in about half of patients.39,43 Although the fever is usually low grade, it can reach 39° to 40°C in about 15 percent of patients and may be the presenting clinical manifestation.44
39,45 The pain is frequently marked and tends to be located over the temporal or occipital areas but may be less well defined. Scalp tenderness is usually confined to the temporal and, less commonly, the occipital arteries, but it may be diffuse. It is seen most often in those with headaches.
On physical examination, the frontal or parietal branches of the superficial temporal arteries may be thickened, nodular, tender, or occasionally erythematous (Figure 4A). Pulses may be decreased or absent. The occipital arteries and, less often, the postauricular or facial arteries may be enlarged or tender. Nearly half of patients suffer from jaw claudication.43 Occasionally, intermittent claudication may occur in the muscles of the tongue or those involved in swallowing. In rare cases, more marked vascular narrowing may lead to infarction of the scalp or the tongue.
43,45,46,47 Affected patients typically report partially obscured vision ("a shade covering one eye"), which may progress to total blindness. If untreated, the other eye is likely to become affected within one to two weeks. Once established, visual impairment is usually permanent. Amaurosis fugax is an important visual symptom that precedes permanent visual loss in 44 percent of patients.47 Diplopia or visual hallucinations occur less frequently.46,47,48 Visual loss is caused by ischemia of the optic nerve or tracts as a result of arteritis of the branches of the ophthalmic or posterior ciliary arteries and, less commonly, by occlusion of the retinal arterioles. The early funduscopic findings consist of ischemic optic neuritis with a slight pallor and edema of the optic disk and scattered cotton-wool patches and small hemorrhages. These retinal changes usually follow the loss of vision.
Approximately 30 percent of patients have neurologic manifestations.49 The most common are neuropathies (14 percent), including mononeuropathies and peripheral polyneuropathies of the arms or legs.50 Less common neurologic findings are transient ischemic attacks or strokes in the territory of the carotid or vertebrobasilar artery.
Respiratory tract findings, including cough with or without sputum, sore throat, and hoarseness, occur in about 10 percent of patients.51 Musculoskeletal manifestations are common in patients with giant-cell arteritis. Polymyalgia rheumatica is the most frequent, occurring in around 40 percent of patients, but distal symptoms, such as peripheral arthritis and swelling and pitting edema of the hands and feet, may occur in 25 percent of patients.52
In approximately 10 to 15 percent of patients, the branches of the aortic arch, particularly the subclavian and axillary arteries, become narrowed and result in claudication of the arms.53 Bruits may be heard on auscultation over the carotid, subclavian, axillary, and brachial arteries. Pulses in the neck or arms may be decreased or absent. Patients with such symptoms may have few of the usual symptoms of giant-cell arteritis, so the diagnosis may initially be overlooked.
Thoracic aortic aneurysm is 17 times as likely in patients with giant-cell arteritis as in those without the disease.16 This complication occurs as a late event, usually several years after the diagnosis and often after other symptoms have subsided. The aneurysm may rupture and result in death. A yearly chest radiograph is adequate to screen for thoracic aortic aneurysm.
An erythrocyte sedimentation rate of at least 40 mm per hour is considered an important diagnostic finding in patients with polymyalgia rheumatica. Some studies have reported that 7 to 20 percent of patients with polymyalgia rheumatica have a normal erythrocyte sedimentation rate at the time of diagnosis.54 A markedly elevated erythrocyte sedimentation rate is also a hallmark of giant-cell arteritis. The criteria of the American College of Rheumatology include an erythrocyte sedimentation rate of at least 50 mm per hour as one of the five criteria found to be useful in the classification of giant-cell arteritis.19 However, up to 22.5 percent of patients with giant-cell arteritis have a normal erythrocyte sedimentation rate before treatment.21
A recent population-based study from the Mayo Clinic has reported that 5.4 percent of patients had an erythrocyte sedimentation rate of less than 40 mm per hour at diagnosis and that 10.8 percent had an erythrocyte sedimentation rate of less than 50 mm per hour.21
54,55,56 Levels of interleukin-6 appear to be a sensitive indicator of active disease, but most clinical laboratories do not yet have the means to measure these levels.56 Most patients have a mild-to-moderate anemia of chronic disease, and approximately one third of patients have mildly abnormal liver-function tests. Tests for rheumatoid factor and antinuclear antibodies are usually negative.17,39,45
Scintigraphy, MRI, and ultrasonography are all useful in identifying proximal synovitis in patients with polymyalgia rheumatica.34,35,57 Ultrasonography and MRI studies have shown that subacromial and subdeltoid bursitis is the most frequent lesion, present in almost all patients with polymyalgia rheumatica (Figure 2A and Figure 2B), and that these two techniques are equally effective in confirming the presence of bilateral subacromial and subdeltoid bursitis in such patients.57 We have found that ultrasonography of the shoulders is sometimes useful to confirm the diagnosis in patients with atypical cases.58
MRI has demonstrated that tenosynovitis is the prominent lesion in patients with polymyalgia rheumatica who have swelling and pitting edema of the hands and feet59 (Figure 3B). A role for color duplex ultrasonography in the diagnosis of giant cell arteritis has been proposed by Schmidt et al.,60 who found that a dark halo around the lumen of temporal arteries was specific for the diagnosis of giant-cell arteritis (Figure 4B). However, we found that ultrasonography does not increase the diagnostic accuracy of a careful physical examination61; therefore, we do not routinely use this technique.
If a diagnosis of extracranial giant-cell arteritis is suspected, arteriography, computed tomography (CT), and magnetic resonance angiography are the required diagnostic tests. On arteriography, the typical finding is bilateral stenosis or occlusion of the subclavian, axillary, and proximal brachial arteries, and these arteries have a smooth, tapered appearance (Figure 5A). Femoral arteries and their branches are less commonly involved. The best imaging technique to detect aortic aneurysms or dissections is CT (Figure 5B) or MRI (Figure 5C). The finding of a thickened aortic wall on CT or MRI is a direct indication of inflammation of the aortic wall (Figure 5C) and thus of active disease.62
Treatment and Course
Corticosteroids are the drug of choice to treat polymyalgia rheumatica and giant-cell arteritis. Initial pulsed intravenous doses of methylprednisolone (1000 mg every day for three days) may be given to patients with recent or impending visual loss. Corticosteroids may prevent but usually do not reverse visual loss.
Regular assessment of clinical symptoms, the erythrocyte sedimentation rate, or the C-reactive protein value is the most useful way of monitoring the patients.39,54 An isolated finding of an increased erythrocyte sedimentation rate during therapy is not a valid reason to increase the dose of corticosteroids. A treatment course of one to two years is often required. However, some patients have a more chronic, relapsing course and may require low doses of corticosteroid for several years.39,54,63,64 No consistently reliable predictors of the duration of corticosteroid therapy have been found. One study suggested that measurement of interleukin-6 levels after four weeks of therapy was helpful in identifying patients with more severe disease.56 Corticosteroid-related adverse events are common. A long-term follow up study found that 65 percent of patients with polymyalgia rheumatica had at least one adverse event.65 The risks of diabetes mellitus and osteoporotic fractures were two to five times as great among patients with polymyalgia rheumatica as among persons of similar age from the same population. Increasing age at diagnosis, a cumulative dose of prednisone of at least 2 g, and female sex independently increased the risk of adverse events. 66
Calcium and vitamin D supplementation should be given with corticosteroid therapy in all patients with polymyalgia rheumatica or giant-cell arteritis. In patients with reduced bone mineral density, bisphosphonates are indicated.67
In studies of cytotoxic agents, methotrexate has been used as a corticosteroid-sparing drug in patients with polymyalgia rheumatica and giant-cell arteritis, with conflicting results.68,69 However, this drug may be given to patients who need high doses of corticosteroids to control active disease and who have serious side effects. Alternate-day oral corticosteroid therapy is generally less effective in suppressing symptoms of polymyalgia rheumatica and giant-cell arteritis than is daily administration.70
A wide variety of conditions may mimic polymyalgia rheumatica.71 When present, distal-limb symptoms may initially make it difficult to differentiate polymyalgia rheumatica from rheumatoid arthritis or other, similar syndromes. Pronounced symmetric involvement of peripheral joints, seropositivity for rheumatoid factor, and the development of joint erosions and extra-articular manifestations clearly differentiate rheumatoid arthritis from polymyalgia rheumatica. It may be difficult to differentiate polymyalgia rheumatica with swelling and edema of the hands and feet from the uncommon syndrome of remitting seronegative, symmetric synovitis with pitting edema (RS3PE).4,59,72 The latter condition is characterized by the acute onset of bilateral, diffuse, symmetric swelling of the wrists and hands associated with marked, pitting edema of the dorsum of the hands and, less frequently, of the feet.72 Affected patients are persistently seronegative for rheumatoid factor and do not have rheumatoid arthritis. Articular symptoms of RS3PE respond rapidly to small doses of corticosteroid. MRI of the hands and feet has shown tenosynovitis to be the cause of diffuse swelling in some cases of RS3PE.59 Some studies have suggested that polymyalgia rheumatica and RS3PE are part of the clinical spectrum of the same disease.42
In the elderly, systemic lupus erythematosus may sometimes present as polymyalgia rheumatica.73 The presence of pleuritis or pericarditis (which are common in late-onset systemic lupus erythematosus), leukopenia or thrombocytopenia, and antinuclear antibodies should raise the clinical suspicion of systemic lupus erythematosus. The predominant proximal muscular weakness demonstrated with movement, rather than pain and an increase in muscular enzyme levels, differentiate polymyositis from polymyalgia rheumatica.74
The presence of peripheral enthesitis, dactylitis, anterior uveitis, and radiologic evidence of sacroiliitis differentiate late-onset spondyloarthropathy from polymyalgia rheumatica.75 The younger age at the onset of symptoms, the presence of other, related conditions, such as irritable bowel syndrome, the presence of multiple, small, localized areas of muscle tenderness ("trigger points"), and a normal erythrocyte sedimentation rate clearlydifferentiate fibromyalgia from polymyalgia rheumatica.
Bacterial endocarditis and solid-organ cancers (of the kidneys, ovaries, or stomach) or hematologic (myeloma) cancers may also cause conditions mimicking polymyalgia rheumatica.71 The lack of an adequate response to prednisone and the presence of atypical features (the absence of the accentuation of symptoms with motion, the absence of morning stiffness or the presence of minimal stiffness, and a diffuse pattern of aches) should suggest the need for further investigations. In patients with typical signs and symptoms of polymyalgia rheumatica, a systemic search for occult cancer or infection is not routinely advised.
Primary systemic amyloidosis may have features mimicking polymyalgia rheumatica, giant-cell arteritis, or both.76 In patients with a monoclonal band on immunoelectrophoresis who have no response to corticosteroid therapy, staining of temporal-artery specimens for amyloid should be performed.
Generally, there is little difficulty in distinguishing giant-cell arteritis from other types of vasculitis, because of the difference in the distribution of lesions, histopathological findings, and organ involvement. The histopathological and radiographic findings of giant-cell arteritis may sometimes be indistinguishable from those observed in Takayasu's arteritis or isolated angiitis of the central nervous system. The age at onset and the distribution of lesions allow the proper diagnosis to be made.
Standardized diagnostic and classification criteria are needed for polymyalgia rheumatica. We believe that ultrasonographic evidence of bilateral shoulder bursitis and elevated C-reactive protein levels could be included as diagnostic criteria. Some studies have shown that serum levels of interleukin-6 are persistently increased in patients with polymyalgia rheumatica or giant-cell arteritis after months of corticosteroid treatment, despite the rapid control of symptoms. Future studies will clarify whether this marker of inflammation can be used to monitor disease activity and to gauge the rate of reduction in the corticosteroid dose.
Large, multicenter, randomized, double-blind, placebo-controlled studies are required to define the role of methotrexate or other immunosuppressants as corticosteroid-sparing drugs in polymyalgia rheumatica and giant-cell arteritis. A recent pilot study found that infliximab was efficacious in patients with corticosteroid-resistant giant-cell arteritis.77 Finally, a better understanding of the molecular mechanisms involved in the pathogenesis of polymyalgia rheumatica and giant-cell arteritis should provide targets for therapy as well as help determine whether there is a relation between these two conditions and an infectious cause or triggering mechanism.
We are indebted to Italo Portioli for his continuous support of the study of polymyalgia rheumatica and giant-cell arteritis; to Miguel Angel Gonzalez-Gay, PierLuigi Macchioni, and Ignazio Olivieri for their collaboration in studying polymyalgia rheumatica and giant-cell arteritis; to Libero Barozzi and Pietro Pavlica for providing MRI documentation; to Alberto Cavazza for providing histologic documentation; and to Andrea Facchini, Riccardo Meliconi, and Lia Pulsatelli for their help with the immunohistochemical characterization of polymyalgia rheumatica synovitis.
From the Rheumatology Service, Arcispedale S. Maria Nuova, Reggio Emilia, Italy (C.S., L.B.); the Unit of Rheumatology, Division of Medicine, Ospedale di Prato, Prato, Italy (F.C.); and the Mayo Clinic, Rochester, Minn. (G.G.H.).
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