Polymyalgia rheumatica and giant-cell arteritis Carlo Salvarani, Fabrizio Cantini, Gene G Hunder Polymyalgia rheumatica and giant-cell arteritis are closely related disorders that aect people of middle age and older. They frequently occur together. Both are syndromes of unknown cause, but genetic and environmental factors might have a role in their pathogenesis. The symptoms of polymyalgia rheumatica seem to be related to synovitis of proximal joints and extra-articular synovial structures. Giant-cell arteritis primarily aects the aorta and its extracranial branches. The clinical ndings in giant-cell arteritis are broad, but commonly include visual loss, headache, scalp tenderness, jaw claudication, cerebrovascular accidents, aortic arch syndrome, thoracic aorta aneurysm, and dissection. Glucocorticosteroids are the cornerstone of treatment of both polymyalgia rheumatica and giant-cell arteritis. Some patients have a chronic course and might need glucocorticosteroids for several years. Adverse events of glucocorticosteroids aect more than 50% of patients. Trials of steroid-sparing drugs have yielded conicting results. A greater understanding of the molecular mechanisms involved in the pathogenesis should provide new targets for therapy. Denitions and diagnostic criteria Giant-cell arteritis mainly involves the large and medium-sized arteries, especially branches of the proximal aorta. Polymyalgia rheumatica is characterised by aching and morning stiness in the shoulder and pelvic girdles and neck. The two disorders can occur separately or together in people aged 50 years and older. The diagnosis of polymyalgia rheumatica depends on a combination of clinical symptoms, raised acute-phase reactants, exclusion of other diseases, and response to glucocorticosteroids. At least three sets of diagnostic criteria for polymyalgia rheumatica are used in clinical practice (panel). 13 The criteria formulated by Chuang and co-workers 1 and by Healey, 2 on the basis of clinical experience, are much the same. The core symptoms are proximal pain and stiness; the only dierence is the inclusion in the Healey criteria of the response to glucocorticosteroids. Criteria for the classication of giant-cell arteritis were developed by the American College of Rheumatology in 1990 (table). 4 These criteria were designed to dierentiate this disease from other vasculitides, and are not useful for making the diagnosis in individual patients. 5 Temporal artery biopsy remains the gold standard for diagnosis of giant-cell arteritis. Because of skip inammatory lesions, specimen length should be at least of 153 cm, to keep false negative results to a minimum. 6 Routine examination of temporal artery biopsy at multiple levels does not substantially increase the diagnostic yield. 7 Since negative unilateral temporal artery biopsy is associated with an extremely low frequency (13%) of subsequent positive contralateral biopsy, bilateral biopsy is not recommended as an initial routine procedure. 8,9 When possible, temporal artery biopsy should be done before treatment is started; however, specimens might show arteritis after more than 2 weeks of glucocorticosteroid therapy. 10 Achkar and colleagues 10
showed that in a consecutive cohort of 535 patients who had temporal artery biopsies, the positivity rates of temporal artery biopsy were similar in untreated and corticosteroids treated patients (31% vs 35%). Studies have assessed possible predictors of positive temporal artery biopsy. The combination of jaw claudication plus double vision predicted a positive biopsy in all patients in one study, whereas a normal ESR before treatment made giant-cell arteritis unlikely, but it does not exclude completely this diagnosis. 11,12 Epidemiology The incidence rates of giant-cell arteritis and polymyalgia rheumatica increase progressively after 50 years of age. 13
The reported rates for giant-cell arteritis are highest in northern European countries and in Minnesota (USA), which has a population of similar ethnic background, and are 20 or more per 100 000 people older than 50 years. 1416
Rates of this disease are lower in Mediterranean countries 17,18 and lowest in Arabian and Asian countries. 19,20 The lowest prevalence was reported in Japan (147 per 100 000 population older than 50 years). 20 Autopsy studies suggest that giant-cell arteritis might be more common than is clinically apparent. 21 Women are aected two to three times more commonly than are men. The incidence of giant-cell arteritis has increased over the past 2040 years, possibly because of increased awareness. Some studies have reported seasonal variations or a cyclic pattern. 22,23 Although Lancet 2008; 372: 23445 Unit of Rheumatology, Arcispedale S Maria Nuova, Reggio Emilia, Italy (C Salvarani MD); Unit of Rheumatology, Division of Medicine, Ospedale di Prato, Prato, Italy (F Cantini MD); and Mayo Clinic College of Medicine, Rochester, MN, USA (G G Hunder MD) Correspondence to: Dr Carlo Salvarani, Unit of Rheumatology, Arcispedale S Maria Nuova, V.le Risorgimento N80, 42100 Reggio Emilia, Italy salvarani.carlo@asmn.re.it Search strategy and selection criteria We searched the Cochrane Library, Medline, and EMBASE, mainly using the search terms polymyalgia rheumatica [Mesh], giant cell arteritis [Mesh], and temporal arteritis [Mesh]. We largely selected articles published in English during the past 5 years, without excluding older papers that we considered to be highly relevant to the topics discussed in this Seminar. We also searched the reference lists of articles identied by this search strategy, and selected those that we judged relevant. We also included some review papers providing insightful overviews on polymyalgia rheumatica and giant-cell arteritis. Seminar www.thelancet.com Vol 372 July 19, 2008 235 patients with this disease have an increased risk of developing aortic aneurysm and dissection, and cerebrovascular accidents, most studies of long-term survival have shown no excess mortality. 24 Polymyalgia rheumatica is two to three times more common than is giant-cell arteritis, although the distribution is similar. 16,17,2527 In Olmsted County, Minnesota, the average yearly incidence was 525 cases per 100 000 people aged 50 years and older. 25
Population-based studies have shown a fairly stable incidence of polymyalgia rheumatica in recent years. Relation between giant-cell arteritis and polymyalgia rheumatica The clinical connections between polymyalgia rheumatica and giant-cell arteritis have suggested that they are dierent manifestations of the same disease process. These connections include their frequent occurrence together, the older age at onset with progressively increasing incidence rates after 50 years, similar sex ratio, substantial increase of acute-phase reactants before treatment, and rapid responsiveness to glucocortico- steroids and outcome. 13 Population-based studies have shown that 1621% of patients with polymyalgia rheumatica have giant-cell arteritis, and polymyalgia rheumatica is present in 4060% of patients with giant-cell arteritis. 22,25,26 Polymyalgia rheumatica might begin before, appear simultaneously with, or develop after clinical manifestations of giant-cell arteritis. A few patients with polymyalgia rheumatica without ndings of giant-cell arteritis at diagnosis have a positive temporal artery biopsy or develop giant-cell arteritis during follow-up. 28,29 PET- evidence of vascular uorodeoxyglucose uptake, predominantly at subclavian arteries, was noted in 30% of patients with isolated polymyalgia rheumatica at diagnosis, 30 despite a negative biopsy sample of temporal artery.
This study conrms that most patients with isolated polymyalgia rheumatica do not have evidence of vasculitis; however large artery vasculitis may be present in polymyalgia rheumatica even in absence of temporal arteries involvement. Pathology and pathogenesis In giant-cell arteritis, inammation mainly aects the large and medium-sized muscular arteries, especially the proximal aorta and its branches. 13,31 These arteries have a prominent internal elastic membrane and vasa vasorum. As the cervical arteries penetrate the dura they become thinner, have much less elastic tissue, and no vasa vasorum. Intracranial arteries are rarely associated with the vasculitic process. 32 The classic histological picture of giant-cell arteritis is characterised by a granulomatous inammatory inltrate with lymphocytes, macrophages, and multinucleated giant cells, which are usually located at the intima-media junction (gure 1). However, only about 50% of routine biopsy samples show all these typical features. The others manifest a chronic inammatory reaction, featuring lymphomononuclear cells and sparse neutrophils and eosinophils, but no giant cells (gure 1). Inammation tends to aect the arteries in a segmental fashion, and the inammatory process is usually most severe in the inner portion of the media adjacent to the disrupted internal elastic lamina. 33,34 In some cases the inammation is restricted to the vasa vasorum or to periadventitial small vessels, or both (gure 1). 35 In such instances, the diagnosis of giant-cell arteritis might not be straightforward. Denition Age at disease onset 50 years Development of symptoms or ndings beginning at 50 years or older New headache New onset of or new type of localised pain in the head Temporal artery abnormality Temporal artery tenderness to palpation or decreased pulsation, unrelated to arteriosclerosis of cervical arteries Increased ESR ESR 50 mm/h by the Westergren method Abnormal artery biopsy Biopsy specimen with artery showing vasculitis characterised by a predominance of mononuclear cell inltration or granulomatous inammation, usually with multinucleated giant cells *For purposes of classication, a patient with vasculitis is said to have giant-cell (temporal) arteritis if at least three of these ve criteria are present. The presence of any three or more criteria yields a sensitivity of 935% and a specicity of 912%. Adapted from reference 4. Table: 1990 criteria for the classication of giant-cell (temporal) arteritis (traditional format)* Panel: Diagnostic criteria for polymyalgia rheumatica Chuang et al 1 1 Patients 50 years or older 2 Bilateral aching and stiness persisting for 1 month or more involving two of the following areas: neck or torso, shoulders or proximal regions of the arms, and hips or proximal aspects of the thighs 3 ESR greater than 40 mm/h 4 Exclusion of other diagnoses except giant-cell arteritis The presence of all these criteria denes diagnosis of polymyalgia rheumatica. Healey 2 1 Persistent pain (for at least 1 month) involving two of the following areas: neck, shoulders, and pelvic girdle 2 Morning stiness lasting more than 1 h 3 Rapid response to prednisone (20 mg/day) 4 Absence of other diseases capable of causing the musculoskeletal symptoms 5 Age over 50 years 6 ESR greater than 40 mm/h The diagnosis of polymyalgia rheumatica is made if all the above criteria are satised. Bird 3 1 Bilateral shoulder pain and/or stiness 2 Onset of illness within 2 weeks 3 Initial ESR higher than 40 mm/h 4 Morning stiness exceeding 1 h 5 Age older than 65 years 6 Depression and/or loss of weight 7 Bilateral upper arm tenderness A diagnosis of probable polymyalgia rheumatica is made if any three or more of these criteria are fullled. The presence of any three or more criteria yields a sensitivity of 92% and a specicity of 80%. Seminar 236 www.thelancet.com Vol 372 July 19, 2008 In polymyalgia rheumatica, pathological ndings are much less prominent than they are in giant-cell arteritis. A mild synovitis characterised by a predominance of macrophages and CD4+ T-lymphocytes has been described in specimens of shoulder synovial membranes and other involved joints. 36 The cause of both disorders remains unknown. Their decreasing incidence with a northsouth gradientthe highest incidence being in Scandinavian countries and in US communities with a Scandinavian ethnic backgroundand the occasional familial cases lend support to a role for both environmental and genetic risk factors. 1416,25,26 The cyclic pattern of yearly incidence rates and the seasonal variations reported by some studies might suggest an environmental-infectious aetiology. 22,23,37 Several viruses have been investigated as possible triggers in a susceptible host, with inconclusive results. 38 With regard to cardiovascular risk factors, casecontrol studies have reported an increased risk of giant-cell arteritis in heavy smokers, and in patients with previous atherosclerotic disease. 3941 A wide variety of immunogenetic factors have been studied in giant-cell arteritis and polymyalgia rheumatica. In patients with giant-cell arteritis, the most commonly identied genetic association is with HLA-DRB1*04 alleles. However, the strength of the HLA-DRB1 association with polymyalgia rheumatica varies between dierent populations. 17,42,43 Knowledge of mechanisms of the inammation has advanced in recent years. Weyand and Goronzy 44 and co-workers 45 have suggested that dendritic cells located at the adventitia-media border of the artery have a crucial role in initiation of vasculitis. The dendritic cells in the wall can be activated by toll-like receptor ligands (or perhaps an unknown antigen entering via the vasa vasorum). The activated dendritic cells become chemokine-producing eector cells, which recruit CD4 T-cells into the vascular wall through the vasa vasorum. Macrophages are also recruited. The activated dendritic cells provide the necessary costimulatory signals to trigger T-cell activation. The recruited and activated CD4+ T cells in the artery wall undergo clonal expansion and begin secreting cytokines including interferon-, which has a pivotal part in regulation of the dierentiation and function of macrophages. In the adventitia, macrophages produce the inammatory cytokines interleukin 1 and interleukin 6, whereas in the media they release metalloproteinases and reactive oxygen intermediates. These inammatory mediators lead to the fragmentation of the internal elastic lamina and trigger repair mechanisms such as intimal hyperplasia and neoangiogenesis, which are regulated by platelet-derived growth factor and vascular endothelial growth factor. Platelet-derived growth factor seems to be crucial in induction of intimal hyperplasia and vessel occlusion. 46 In patients with polymyalgia rheumatica who do not have histological evidence of arteritis, adventitial dendritic cells are in an activated state, and both interleukin 1 and interleukin 6 are detectable in the so-called histologically normal temporal arteries. However, interferon--producing T cells are not recruited into vascular tissue. Without interferon-, arterial inammation in polymyalgia rheumatica remains Ref number Editor Author Created by Section Text retyped Image redrawn Special Characters Palette Urgent Special instructions $ +<> 07tl6309_1 Editor name: HC Author name Illustrator name Section name Tick Marks Axis break Error bar Shaker 65 roman Subscript 123456789 Superscript 1 2 3 4 5 6 7 8 9 Superiors (GLYPHS) Inferiors Key 1 Key 2 Key 3 Key 4 Key 5 Key 1 Key 2 Key 3 Key 4 Key 5 Key 4 Key 5 Key 4 Key 5 D E F G H I J K L Shaker 85 bold A B C A B C Figure 1: Histopathological features of giant-cell arteritis Transverse sections of temporal artery from patients with untreated giant-cell arteritis are shown. (A) Granulomatous inammation and multinucleated giant cells (arrows) at junction of media and intima (haematoxylin and eosin, 100). (B) A mononuclear transmural inltrate without giant cells (haematoxylin and eosin, 40). (C) Vasculitis involving small vessels (arrows) close to a non-inamed temporal artery (haematoxylin and eosin, 40). Seminar www.thelancet.com Vol 372 July 19, 2008 237 subclinical. 47 The systemic manifestations of giant-cell arteritis and polymyalgia rheumatica are caused by the production of inammatory cytokines derived from macrophages. Several studies have suggested that patients with a lower inammatory response have a higher risk of developing ischaemic manifestations than do other patients. 48,49 Interleukin 6 expression in the temporal artery, circulating concentrations of inter- leukin 6, and angiogenic response are substantially decreased in this subset of patients. 49,50 Angiogenic activity of interleukin 6 might be an important protective mechanism for ischaemia in giant-cell arteritis. Clinical manifestations Polymyalgia rheumatica Polymyalgia rheumatica is typically characterised by aching and stiness in the morning in the neck, shoulder, and pelvic girdles. Typically the stiness in the morning lasts 30 min or more. Shoulder pain is the presenting nding in 7095% of patients, whereas hips and neck are less frequently involved (5070%). The pain usually radiates distally towards the elbows and knees. It can begin in one shoulder or hip, but soon becomes bilateral. Occasionally the symptoms begin more peripherally. Pain is most severe with movement, and interferes with sleep at night. On examination, painful restriction of active and often passive movements of the shoulders and hips is present, without detectable proximal joint swelling. Systemic signs and symptoms such as low-grade fever, depression, fatigue, anorexia, and weight loss occur in up to 40% of patients. 1,51
High, spiking fevers are uncommon in polymyalgia rheumatica in the absence of giant-cell arteritis. 52,53 Distal musculoskeletal manifestations are seen in about half of patients. 5455 They include carpal tunnel syndrome; non-erosive, self-limited, asymmetric peri- pheral arthritis (predominantly aecting the knees and wrists); and diuse distal extremity swelling with pitting oedema mostly over the dorsum of the hands and wrists, but also over the ankles and tops of the feet. Giant-cell arteritis One or more systemic manifestations, including fever, malaise, anorexia, and weight loss, are present in most patients. 51,57 Fever is usually low grade, but it reaches 3940C in about 15% of patients and might be the presenting manifestation or the only feature of giant-cell arteritis. 52,53 A new-onset headache is the most frequent symptom, occurring in two thirds of patients. 51,58 Head pain is usually over the temporal or occipital areas, but it may localise to any part of the head. Pain is usually continuous throughout the day, often interferes with sleep, and responds incompletely to analgesics. Nearly half of patients suer from jaw claudication, due to ischaemia of the muscles of mastication. 57 Jaw claudication is a high predictor of giant-cell arteritis, but is not pathognomonic. 59
Occasionally, intermittent claudication can aect the arms, tongue, or the muscles involved in swallowing. On physical examination, the frontal or parietal branches of the supercial temporal arteries may be thickened, nodular, tender, or occasionally red. Pulses may be decreased or absent. Scalp tenderness arises in around half of patients; it is usually worsened by brushing or combing the hair. It is seen most often in patients with headaches. Permanent partial or complete loss of vision in one or both eyes occurs in less than 20% of patients, and is often an early manifestation. 48,60,61 Visual loss is related to anterior ischaemic optic neuropathy, which is caused most commonly by narrowing or occlusion of the posterior ciliary arteries. Less commonly, visual loss is caused by retinal artery occlusion. The early fundoscopic appearance noted in anterior ischaemic optic neuropathy consists of slight pallor and oedema of the optic disc, with scattered cotton-wool patches and small haemorrhages (gure 2). Later, optic atrophy occurs (gure 2). Patients who are aected typically report a feeling of a shade covering one eye, which can progress to total blindness. The eye is not painful. If untreated, the second eye is likely to become aected within 12 weeks. Once visual impairment is established, it is usually permanent. Amaurosis fugax is reported in 1015% of patients, and can precede permanent visual loss. Transient diplopia is present in around 6% of patients. Polymyalgia rheumatica is the most frequent musculoskeletal manifestation in giant-cell arteritis, occurring in around 40% of patients. Distal symptoms, such as peripheral arthritis and distal swelling with pitting oedema, can arise in 25% of patients. 62 Less frequent onset patterns of polymyalgia rheumatica and giant-cell arteritis The diagnosis of polymyalgia rheumatica and giant-cell arteritis is straightforward in patients with typical features. However, both disorders are characterised by a wide range of clinical manifestations, and can present with atypical features, resulting in a challenging diagnosis. Ref number Editor Author Created by Section Text retyped Image redrawn Special Characters Palette Urgent Special instructions $ +<> 07tl6309_2 Editor name: HC Author name Illustrator name Section name Tick Marks Axis break Error bar Shaker 65 roman Subscript 123456789 Superscript 1 2 3 4 5 6 7 8 9 Superiors (GLYPHS) Inferiors Key 1 Key 2 Key 3 Key 4 Key 5 Key 1 Key 2 Key 3 Key 4 Key 5 Key 4 Key 5 Key 4 Key 5 D E F G H I J K L Shaker 85 bold A B C A B Figure 2: Photographs of the optic disc in patients with giant-cell arteritis and visual loss due to anterior ischemic optic neuropathy, in the early acute phase (A) and after 3 months of prednisone therapy (B) (A) Optic disc oedema and a ame-shaped haemorrhage is shown. (B) Optic atrophy is shown. Seminar 238 www.thelancet.com Vol 372 July 19, 2008 Swelling and pitting oedema of the hands and feet similar to that seen in patients with remitting seronegative, symmetric synovitis with pitting oedema syndrome are present in 812% of patients with polymyalgia rheumatica. 5456 These ndings are frequently unilateral in patients with polymyalgia rheumatica, usually aect the dorsum of the hands and, less frequently, of the feet and promptly remit after small doses of corticosteroids. MRI shows that a substantial tenosynovitis is the underlying lesion. 63 When these distal ndings occur in elderly people, polymyalgia rheumatica might represent the cause, and clinicians should be alerted to investigate other signs and symptoms of this disease. Recent studies report a positive temporal artery biopsy in only 139% of patients with polymyalgia rheumatica without clinical features of giant-cell arteritis, compared with the 1520% that was reported in earlier studies. 1,28,64
A high ESR and the presence of systemic manifestations are predictors of coexistent silent giant-cell arteritis in polymyalgia rheumatica. Patients with polymyalgia rheumatica with silent giant-cell arteritis do not develop ischaemic complications; therefore, temporal artery biopsy is not indicated in patients with polymyalgia rheumatica in the absence of cranial manifestations, unless a high inammatory response is present. Up to 15% of patients with giant-cell arteritis present with fever of unknown origin. 52 Fever can reach 3940C, and dominate the clinical picture. Shaking, rigors, and sweats mimic sepsis. Giant-cell arteritis is responsible for only 2% of all cases of fever of unknown origin, but of up to 16% in patients older than 65 years. 52 In such cases, a careful examination of the temporal arteries is indicated and, if other disorders are excluded, a temporal artery biopsy should be considered. Ocular involvement may represent the presenting manifestation of an otherwise clinically silent giant-cell arteritis. In one prospective study, 65 21% of patients with this disease and visual loss did not have other cranial or systemic manifestations at disease onset. Giant cell arteritis should be suspected when patients older than 50 years present with visual loss caused by anterior ischaemic optic neuropathy or (less commonly) occlusion of the central retinal artery, particularly when raised ESR values are present. Aortic arch syndrome occurs in about 1015% of patients, presenting with claudication of the arms; bruits over the carotid, subclavian, axillary and brachial arteries; and absent or decreased pulses in the neck or arms. 66,67 Large artery involvement in giant-cell arteritis can also aect the legs. 68 Thoracic aortic aneurysms and dissection of the aorta are important late complications of giant-cell arteritis. Aneurysms tend to arise several years after the diagnosis, and when other symptoms have subsided. 66,67 Thoracic aortic aneurysms are 17 times more frequent in patients with giant-cell arteritis than in non-aected people. A chest radiograph every year is adequate to screen for thoracic aortic aneurysm. Neurological manifestations occur in about 30% of patients. 69 In around 14% of all patients they consist of neuropathies, including mononeuropathies and peripheral polyneuropathies of the upper or lower extremities. 70 Less common (34%) are transient ischaemic attacks, and strokes caused by severe obstruction or occlusion of the internal carotid or vertebral arteries. 69,71 Inammation of intracranial or intradural arteries is very rare. 32 Respiratory tract symptoms including cough, sore throat, and hoarseness occur in about 10% of patients. 72 When these symptoms are prominent or an initial manifestation, the diagnosis of giant-cell arteritis can be delayed. Scalp necrosis, ulceration or infarction of the tongue, pericardial and pleural eusions, 73 myocardial infarctions, 74 female genital tract or breast involvement, 75,76
syndrome of inappropriate antidiuretic secretion, 77 and dysarthria 78 are rare presentations of giant-cell arteritis. Laboratory ndings and imaging Laboratory ndings in both polymyalgia rheumatica and giant-cell arteritis are non-specic but indicate the inammatory nature of these syndromes. An ESR of at least 40 mm/h has been included in all sets of criteria for the diagnosis of polymyalgia rheumatica. 13 However, a Ref number Editor Author Created by Section Text retyped Image redrawn Special Characters Palette Urgent Special instructions $ +<> 07tl6309_3 Editor name: HC Author name Illustrator name Section name Tick Marks Axis break Error bar Shaker 65 roman Subscript 123456789 Superscript 1 2 3 4 5 6 7 8 9 Superiors (GLYPHS) Inferiors Key 1 Key 2 Key 3 Key 4 Key 5 Key 1 Key 2 Key 3 Key 4 Key 5 Key 4 Key 5 Key 4 Key 5 D E F G H I J K L Shaker 85 bold A B C A B C Figure 3: Ultrasonography (A) and MRI (B) of the shoulder, and uorodeoxyglucose-positron emission tomography (C) of patients with isolated (absence of signs or symptoms of giant-cell arteritis) untreated polymyalgia rheumatica (A) Ultrasonography shows the presence of uid within the subacromial bursa (arrows) and surrounding the long biceps tendon groove (arrowheads). (B) An axial T2 weighted section shows subacromial and subdeltoid bursitis (pentagon), joint eusion (arrow), and tenosynovitis of the long head of the biceps (arrowhead). (C) Fluorodeoxyglucose-positron emission tomography shows inammatory uorodeoxyglucose uptake in the shoulders (arrows) and absence of vascular uptake. Seminar www.thelancet.com Vol 372 July 19, 2008 239 normal ESR has been reported in 720% of the patients with polymyalgia rheumatica. 79 The American College of Rheumatology classication criteria for giant-cell arteritis include an ESR of 50 mm/h or more. 4 However, an ESR less than 40 mm/h has been noted in 54% of patients, and less than 50 mm/h in 108%. 80 Therefore, a normal ESR does not exclude polymyalgia rheumatica or giant-cell arteritis, particularly when other clinical ndings suggest these diagnoses. C-reactive protein is not as aected by extraneous factors as the ESR, so is a more sensitive indicator of disease activity in both disorders. 79,81 The ESR is a time honoured laboratory parameter in both diseases, and we suspect its use will continue. Some data indicate that blood concentrations of interleukin 6 are the most sensitive indicators of disease activity and course; 82,83
however, the test is not readily available in most laboratories. Tests for rheumatoid factor and for anticyclic citrullinated peptide antibodies are usually negative. 84 A moderate anaemia of chronic disease (ie, normocytic anaemia) is present in most patients, and concentrations of liver enzymesparticularly alkaline phosphataseare mildly raised in roughly a third, particularly in those with giant-cell arteritis that is proven by biopsy. Scintigraphy, MRI, ultrasonography, and uorode- oxyglucose-positron emission tomography have been used in polymyalgia rheumatica to detect synovitis in proximal joints and periarticular structures and could help with diagnosis. 30,8689 Bilateral subacromial-subdeltoid bursitis and trochanteric bursitis are the most frequent lesions, and are present in almost all patients with polymyalgia rheumatica who have pain in shoulder and pelvic girdles, respectively (gure 3 and gure 4). Ultrasonography and MRI are equally eective in conrmation of the presence of these lesions, with sensitivities and specicities more than 90%. 88,89
Ultrasonographic evidence of bilateral shoulder bursitis can lend support to the diagnosis of polymyalgia rheumatica in patients with normal ESR. 90 Ultrasonography and high-resolution MRI are useful adjunctive methods in diagnosis of giant-cell arteritis 9193
since they can show inammatory changes in temporal arteries. A recent meta-analysis 92 has conrmed that a hypoechoic halo around the lumen of temporal arteries on ultrasonography has a high specicity for giant-cell arteritis; however, its sensitivity is substantially lower than is the specicity. 91,92 Bright enhancement (a sign of mural inammation) of the temporal artery on high-resolution contrast-enhanced MRI is also highly specic for giant-cell arteritis. 93 Conventional angiography, CT, CT angiography, MRI, MR angiography, and ultrasonography can document large-vessel involvement in giant-cell artertitis. 94,95
Arteriography with several views can outline bilateral, smooth, tapering stenoses, or occlusions of the subclavian, axillary, and proximal brachial arteries. Arteries in the legs are less frequently involved. 68,94
Ultrasonography shows stenoses or occlusions of large vessels, or both, and also inammatory oedema of the vessel wall (halo sign) (gure 5). 95 Vessel-wall oedema on MRI can also indicate disease activity. The extent of the examination is more restricted with MRI and ultrasonography than with arteriography. Ref number Editor Author Created by Section Text retyped Image redrawn Special Characters Palette Urgent Special instructions $ +<> 07tl6309_4 Editor name: HC Author name Illustrator name Section name Tick Marks Axis break Error bar Shaker 65 roman Subscript 123456789 Superscript 1 2 3 4 5 6 7 8 9 Superiors (GLYPHS) Inferiors Key 1 Key 2 Key 3 Key 4 Key 5 Key 1 Key 2 Key 3 Key 4 Key 5 Key 4 Key 5 Key 4 Key 5 D E F G H I J K L Shaker 85 bold A B C B C A Figure 4: Ultrasonography (A) and MRI (B) of the hip and uorodeoxyglucose-positron emission tomography (C) of patients with isolated (absence of signs or symptoms of giant-cell arteritis) untreated polymyalgia rheumatica (A) Ultrasonography shows the presence of uid within the trochanteric bursa (surrounding white line and arrows). (B) An axial T2 weighted section shows trochanteric bursitis (arrows) and joint eusion (arrowhead). (C) Fluorodeoxyglucose-positron emission tomography shows inammatory uorodeoxyglucose uptake in the hips (arrows) and absence of vascular uptake. Ref number Editor Author Created by Section Text retyped Image redrawn Special Characters Palette Urgent Special instructions $ +<> 07tl6309_5 Editor name: HC Author name Illustrator name Section name Tick Marks Axis break Error bar Shaker 65 roman Subscript 123456789 Superscript 1 2 3 4 5 6 7 8 9 Superiors (GLYPHS) Inferiors Key 1 Key 2 Key 3 Key 4 Key 5 Key 1 Key 2 Key 3 Key 4 Key 5 Key 4 Key 5 Key 4 Key 5 D E F G H I J K L Shaker 85 bold A B C A B Figure 5: Fluorodeoxyglucose-positron emission tomography (A) and colour-doppler ultrasonography of the axillary artery (B) of a patient with large-vessel giant-cell arteritis presenting with fever of unknown origin (A) Fluorodeoxyglucose-positron emission tomography shows increased tracer uptake in the axillary (arrowheads) arteries and in the aorta (arrow). (B) Colour-Doppler ultrasonography of the left axillary artery of the same patient shows vessel wall oedema (halo sign [dark area around the lumen of the vessel which is indicated by the dotted line]). Both increased tracer uptake on positron emission tomography scan and the presence of a halo on ultrasonography are consistent with active vessel wall inammation. Seminar 240 www.thelancet.com Vol 372 July 19, 2008 Fluorodeoxyglucose-positron emission tomography seems to be a promising method in the detection of occult involvement of the aorta and large vessels in patients with giant-cell arteritis, especially those presenting with fever of unknown origin (gure 5). 83% of patients with giant-cell arteritis have evidence of large-vessel inammation at diagnosis that is conrmed by positron emission tomography, although most patients do not develop arterial stenosis, occlusion, or aneurysms. 96 Dierential diagnosis Several disorders can mimic polymyalgia rheumatica. 97
Peripheral arthritis, particularly aecting both hands, can pose a challenge in the distinction of polymyalgia rheumatica from elderly-onset rheumatoid arthritis. Pronounced symmetrical peripheral synovitis, positive rheumatoid factor and anticyclic citrullinated peptide antibodies, and the development of joint erosions and extra-articular manifestations dierentiate rheumatoid arthritis from polymyalgia rheumatica. Follow-up is sometimes needed to establish the correct diagnosis. 84 Swelling and oedema of the hands and feet in polymyalgia rheumatica is similar to that occurring in patients with remitting seronegative, symmetric synovitis with pitting oedema syndrome. 54,63,98 The similarities and concurrence of the two disorders suggest that they might constitute part of the same disease. 55 Late onset spondyloarthritis is characterised by oligoarthritis; distal pitting oedema, mainly of the lower limbs; restricted involvement of the axial skeleton; constitutional symptoms (ie, fever, anorexia, weight loss), and raised ESR. 99 Proximal symptoms similar to polymyalgia rheumatica have also been described. 100 The presence of other manifestations of spondyloarthritis, such as peripheral enthesitis, dactylitis, anterior uveitis, the association with HLA-B27, and radiological evidence of sacroiliitis help dierentiate late onset spondyloarthritis from polymyalgia rheumatica. Polyarticular calcium pyrophosphate deposition disease might also present with polymyalgic symptoms. 101 The identication of calcium pyrophosphate dihydrate crystal in the synovial uid or the typical radiographical ndings accord with the diagnosis of calcium pyrophosphate deposition disease. Patients with bromyalgia are usually younger than are those with other disorders, do not have typical joint stiness in the morning, and have normal acute-phase reactants. Proximal muscular weakness rather than pain, increased muscle enzyme concentrations, and myopathic electromyographic changes distinguish polymyositis from polymyalgia rheumatica. 102
Musculoskeletal aching in some malignancies and infections can mimic polymyalgia rheumatica. 97,103,104 The presence of more diuse pain, absent or minimal joint stiness in the morning, little if any proximal joint restriction, and absence of adequate response to prednisone, should suggest further investigations. However, no association exists between polymyalgia rheumatica and malignancies. Other vasculitides can also aect the temporal artery such as Wegeners granulomatosis and polyarteritis nodosa. The involvement of respiratory tract or kidney (or both), the histopathology, and the presence of antineutrophil cytoplasmic antibodies dierentiate these vasculitides from giant-cell arteritis. Takayasus arteritis aects the aorta and its major branches, but starts at an earlier age. Primary vasculitis of the CNS aects only intracranial arteries. Treatment and course Giant-cell arteritis Glucocorticoids are the treatment of choice. Adequate doses quickly suppress clinical manifestations of this disorder and prevent most further ischaemic complications. If visual loss has occurred before start of treatment, it is not usually reversed. 13,105,106 Glucocorticoid therapy should be initiated as soon as the diagnosis of giant-cell arteritis is established. We recommend an initial dose of 4060 mg per day of prednisone (or equivalent) as a single or divided dose. 13 If the patient does not respond promptly, the dose should be increased. Initial high-dose intravenous methylprednisolone (1000 mg every day for 3 days) can be tried in patients with recent visual loss, although no documentation suggests that it helps more than oral prednisone. A small randomised controlled trial showed that intravenous pulse methylprednisolone (15 mg/kg per day for 3 days) given at onset of treatment allowed more rapid tapering of the glucocorticoid dose over the ensuing weeks, and resulted in a higher frequency of discontinuation of oral glucocorticoid therapy, than did oral prednisone, 107 but a larger trial which used pulse glucocorticoid therapy at a lower dose did not show an additional benet over oral glucocorticoids. 108 Treatment with alternate-day glucocorticoid administration has been proposed to reduce the risk of adverse reactions related to glucocorticoids, but is associated with a higher rate of treatment failure than daily administration (70% vs 20%), 109 and is not recommended. The initial dose of glucocorticoids is usually given for 24 weeks until all reversible signs and symptoms have resolved and acute phase reactants are back to normal. Then, the dose can be gradually reduced each week or every 2 weeks by a maximum of 10% of the total daily dose. The necessary duration of glucocorticoid therapy is variable, but in most cases it can be discontinued within 12 years. Some patients have a chronic relapsing course and might need low doses of glucocorticoids for several years. 51,110,111 Even with gradual reduction of doses of glucocorticoids, clinical ares have been reported to occur in more than 50% of patients, particularly during the rst 1216 months, when the prednisone dose is reduced to about 510 mg per day. 111113 Seminar www.thelancet.com Vol 372 July 19, 2008 241 The decision to reduce glucocorticoids should be based on the regular assessment of clinical symptoms and signs, and the ESR or concentration of C-reactive protein. An isolated increased ESR is not usually a valid reason to raise the dose. Some evidence suggests that interleukin 6 might be more sensitive than ESR and CRP for detection of a disease-related, acute phase response and therefore be a better predictor of disease are. 114 Adverse events related to glucocorticoids are common, and are related to the age of patients and the cumulative dose of glucocorticoids. In a population-based study, 111
86% of patients with giant-cell arteritis had adverse events including bone fractures, avascular necrosis of the hip, diabetes mellitus, infections, gastrointestinal bleeding, cataract, and hypertensions. 111 Calcium (10001500 mg per day) and vitamin D (800 IU per day) should be given to all patients who take glucocorticoids. Bisphosphonates are suggested for patients with abnormal bone-mineral density (T score less than 1 SD). Bone-mineral density at lumbar spine and hip should be done when patients are starting glucocorticoids or soon afterwards. If normal, bone-mineral density should be repeated after 12 months of glucocorticoid treatment. 115,116
Three recent randomised controlled trials 112,113,117 have assessed the ecacy of methotrexate in recent-onset giant-cell arteritis; however, these studies arrived at dierent conclusions. A meta-analysis 118 of data from the above trials reported that adjunctive methotrexate treatment in doses of 7515 mg per week reduced the risk of a rst relapse by 35%, and of a second relapse by 51%. Additionally, adjunctive treatment with methotrexate reduced the cumulative exposure to glucocorticoids. However, the advantage of the treatment eect of methotrexate compared with placebo fully appeared only after 2436 weeks, and there was no dierence between groups in the occurrence of adverse events. We feel that methotrexate might be useful in treatment of patients at high risk of side-eects related to glucocorticoids for comorbid conditions such as diabetes mellitus, severe osteoporosis, and severe hypertension, but not on a routine basis. Higher doses of methotrexate (2025 mg per week) have not been adequately studied. Studies of azathioprine 119 and antitumour necrosis factor (TNF) 120 have not shown a consequential eect. However, a role for iniximab in patients with glucocorticoid-refractory disease cannot be excluded. 121,122 Although ischaemic damage in giant-cell arteritis is not usually attributed to thromboembolic occlusion, two retrospective studies 123,124 have shown that aspirin use was associated with a reduction of cranic ischaemic complications of giant-cell arteritis. Experimental studies lend support to these ndings. 125 Although a prospective study is needed to dene the role of aspirin in giant-cell arteritis, we recommend low-dose aspirin, in the absence of specic contraindications, as an adjunctive drug in this disease at diagnosis, together with a proton-pump inhibitor because of the combined treatment with glucocorticoids. Polymyalgia rheumatica An initial dose of 1020 mg per day of prednisone or equivalent is adequate, in most cases, in the absence of associated giant-cell arteritis. 126 Usually the response to glucocorticoids is rapid, with complete or nearly complete resolution of the musculoskeletal aching and stiness within a few days. A few patients with isolated polymyalgia rheumatica need a progressive dose increase to 30 mg per day. The absence of improvement after 30 mg per day of prednisone for 1 week should alert the physicians to question the diagnosis. After 23 weeks, the daily dose can be reduced by 25 mg every 2 weeks to 10 mg per day. Subsequently, daily doses are reduced by 1025 mg every month until the treatment is suspended. Two recent studies 83,127 reported a relapse frequency of 50% in patients with polymyalgia rheumatica. Increased initial doses of glucocorticoids and faster tapering were substantial predictors of relapse, so eorts should be made to keep the initial glucocorticoid dose as low as possible, and to discontinue slowly. The presence and degree of symptoms and an ESR or C-reactive protein concentration can be used to monitor the dose of glucocorticoids. 79 A treatment course of 12 years is often required. However, some patients might need low doses of glucocorticoids for several years. 51,128 Some studies have suggested that persistently raised concentrations of C-reactive protein and interleukin 6 are helpful in identication of patients with relapsing disease. 82,83 About 65% of patients with polymyalgia rheumatica have at least one serious event related to giant-cell arteritis; in particular the risk of vertebral fractures is ve times greater in women with polymyalgia rheumatica. Older age at diagnosis, a cumulative dose of prednisone of at least 2 g, and female sex independently increased the risk of adverse events. 129 The measures proposed to prevent or treat osteoporosis induced by glucocorticoids should also be adhered to in polymyalgia rheumatica. 115,116 Methotrexate has been proposed as a corticoid-sparing drug in polymyalgia rheumatica with conicting results. However, a recent randomised controlled trial 130 has suggested that methotrexate can be eective in polymyalgia rheumatica when the drug is started at disease onset and given for at least 1 year at a dose of at least 10 mg per week. This schedule can reduce the incidence of ares and the amount of prednisone needed to maintain remission. Two pilot studies 131,132 reported that TNF-blocking agents had a glucocorticoid-sparing eect in the treatment of patients who are resistant to glucocorticoid therapy. However, iniximab was ineective in a recent randomised controlled trial of newly diagnosed polymyalgia rheumatica. 133 Seminar 242 www.thelancet.com Vol 372 July 19, 2008 Future perspectives The development of standardised classication and diagnostic criteria would help in a comparison of studies from dierent centres and assist clinicians. Additional investigation is needed about the use of pulse glucocorticoids at the onset of treatment for giant-cell arteritis to conrm whether this regimen reduces toxic eects of glucocorticoids. Identication of risk factors for extended and relapsing disease might allow a more eective use of glucocorticoids and could help in the decision about the use of methotrexate. Randomised controlled trials are needed to assess new therapeutic agents. Strong evidence suggests that interleukin 6 has a major role in sustaining disease activity in giant-cell arteritis and polymyalgia rheumatica. 82,83,114 Therefore, interleukin-6 inhibition with tocilizumab (humanised anti-interlukin-6 receptor monoclonal antibody) might be a logical target for future randmoised controlled trials. 134 Other possible therapeutical agents include new formulations of glucocorticosteroids and abatacept, a recombinant fusion protein that modulates CD28- mediated T-cell costimulation. 135
A better understanding of the molecular mechanisms involved in the pathogenesis of polymyalgia rheumatica and giant-cell arteritis should facilitate the development of drugs that are able to inhibit selectively single molecules or pathways that contribute to inammation. Conict of interest statement We declare that we have no conict of interest. Acknowledgments We thank Italo Portioli for his continuous support in the study of polymyalgia rheumatica and giant-cell arteritis; GianLuigi Bajocchi, Luigi Boiardi, Luca Cimino, PierLuigi Macchioni, Riccardo Meliconi, Ignazio Olivieri, Nicol Pipitone, and Lia Pulsatelli for their collaboration in patient care and in clinical studies on polymyalgia rheumatica and giant-cell arteritis; Libero Barozzi and Giulio Zuccoli for providing MRI documentation; Mauro Silingardi, Alberto Nicolini, and Angelo Ghirarduzzi for providing US documentation; Annibale Versari for his collaboration in positron emission tomography studies and for provision of positron emission tomography images; and Alberto Cavazza for providing histological documentation. This Seminar is dedicated to the memory of Paolo Manganelli, a kind, soft spoken gentleman and friend who was an outstanding clinician, teacher, and researcher. References 1 Chuang T-Y, Hunder GG, Ilstrup DM, Kurland LT. Polymyalgia rheumatica: a 10-year epidemiologic and clinical study. Ann Intern Med 1982; 97: 67280. 2 Healey LA. Long-term follow-up of polymyalgia rheumatica: evidencefor synovitis. Semin Arthritis Rheum 1984; 13: 32228. 3 Bird HA, Esselinckx W, Dixon ASJ, Mowat AG, Wood PHN. An evaluation of criteria for polymyalgia rheumatica. Ann Rheum Dis 1979; 38: 43439. 4 Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatology 1990 criteria for the classication of giant cell (temporal) arteritis. Arthritis Rheum 1990; 33: 112228. 5 Rao K, Allen NB, Pincus T. Limitations of the 1990 American College of Rheumatology classication criteria in the diagnosis of vasculitis. Ann Intern Med 1998; 129: 34552. 6 Taylor-Gjevre R, Vo M, Shukla D, Resch L. Temporal artery biopsy for giant cell arteritis. J Rheumatol 2005; 32: 127982. 7 Chakrabarty A, Franks AJ. Temporal artery biopsy: is there any value in examining biopsies at multiple levels? J Clin Pathol 2000; 53: 13136. 8 Boyev LR, Miller NR, Green WR. Ecacy of unilateral versus bilateral temporal artery biopsies for the diagnosis of giant cell arteritis. Am J Ophthalmol 1999; 128: 21115. 9 Hall JK, Volpe NJ, Galetta SL, Liu GT, Syed NA, Balcer LJ. The role of unilateral temporal artery biopsy. Ophthalmology 2003; 110: 54348. 10 Achkar AA, Lie JT, Hunder GG, OFallon WM, Gabriel SE. How does previous corticosteroid treatment aect the biopsy ndings in giant cell (temporal) arteritis? Ann Intern Med 1994; 120: 98792. 11 Younge BR, Cook BE, Bartley GB, Hodge DO, Hunder GG. Initiation of glucocorticoid therapy: before or after temporal artery biopsy? Mayo Clin Proc 2004; 79: 48391. 12 Smetana GW, Shmerling RH. Does this patient have temporal arteritis? JAMA 2002; 287: 92101. 13 Salvarani C, Cantini F, Boiardi L, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med 2002; 347: 26171. 14 Salvarani C, Crowson CS, OFallon WM, Hunder GG, Gabriel SE. Reappraisal of the epidemiology of giant cell arteritis in Olmsted County, Minnesota, over a fty-year period. Arthritis Rheum 2004; 51: 26468. 15 Nordborg E, Nordborg C. Giant cell arteritis: epidemiological clues to its pathogenesis and an update on its treatment. Rheumatology 2003; 42: 41321. 16 Gran JT, Myklebust G. The incidence of polymyalgia rheumatica and temporal arteritis in the county of Aust Agder, south Norway: a prospective study 19871994. J Rheumatol 1997; 24: 173943. 17 Salvarani C, Macchioni PL, Zizzi F, et al. Epidemiologic and immunogenetic aspects of polymyalgia rheumatica and giant cell arteritis in Northern Italy. Arthritis Rheum 1991; 34: 35156. 18 Gonzalez-Gay MA, Miranda-Filloy JA, Lopez-Diaz MJ, et al. Giant cell arteritis in Northwestern Spain. A 25-year epidemiologic study. Medicine 2007; 86: 6168. 19 Chaudhry IA, Shamsi FA, Elzaridi E, Arat YO, Bosley TM, Riley FC. Epidemiology of giant cell arteritis in an Arab population: a 22-year study. Br J Ophthalmol 2007; 91: 71518. 20 Kobayashi S, Yano T, Matsumoto Y, et al. Clinical and epidemiologic analysis of giant cell (temporal) arteritis from a nationwide survey in 1998 in Japan: the rst government-supported nationwide survey. Arthritis Rheum 2003; 49: 59498. 21 stberg G. On arteritis with special reference to polymyalgia arteritica. Acta Pathol Microbiol Scand (A) 1973; 237 (suppl): 159. 22 Salvarani C, Gabriel SE, OFallon WM, Hunder GG. The incidence of giant cell arteritis in Olmsted County, Minnesota: apparent uctuations in a cyclic pattern. Ann Intern Med 1995; 123: 19294. 23 Bas-Lando M, Breuer GS, Berkun Y, Mates M, Sonnenblick M, Nesher G. The incidence of giant cell arteritis in Jerusalem over a 25-year period: annual a seasonal uctuations. Clin Exp Rheumatol 2007; 25 (suppl 44): S1517. 24 Nuenningho DM, Hunder GG, Christianson TJH, McClelland RL, Matteson EL. Mortality of large-artery complication (aortic aneurysm, aortic dissection, and/or large-artery stenosis) in patients with giant cell arteritis. A population-based study over 50 years. Arthritis Rheum 2003; 48: 353237. 25 Salvarani C, Gabriel SE, OFallon WM, Hunder GG. Epidemiology of polymyalgia rheumatica in Olmsted County, Minnesota, 19701991. Arthritis Rheum 1995; 38: 36973. 26 Franzn P, Sutinen S, Von Knorring J. Giant cell arteritis and polymyalgia rheumatica in a region of Finland: an epidemiologic, clinical and pathologic study, 1984-1988. J Rheumatol 1992; 19: 27380. 27 Smeeth L, Cook C, Hall AJ. Incidence of diagnosed polymyalgia rheumatica and temporal arteritis in the United Kingdom, 1990-2001. Ann Rheum Dis 2006; 65: 109398. 28 Cantini F, Niccoli L, Storri L, et al. Are polymyalgia reumatica and giant cell arteritis the same disease? Semin Arthrititis Rheum 2004; 33: 294301. 29 Gonzalez-Gay MA. Giant cell arteritis and polymyalgia rheumatica: two dierent but often overlapping conditions. Semin Arthritis Rheum 2004; 33: 28993. 30 Blockmans D, De Ceuninck L, Vanderschueren S, Knockaert D, Mortelmans L, Bobbaers H. Repetitive 18-uorodeoxyglucose positron emission tomography in isolated polymyalgia rheumatica: a prospective study in 35 patients. Rheumatology (Oxford) 2007; 46: 67277. Seminar www.thelancet.com Vol 372 July 19, 2008 243 31 Wilkinson IMS, Russell RWR. Arteries of the head and neck in giant cell arteritis. A pathological study to show the pattern of arterial involvement. Arch Neurol 1972; 27: 37891. 32 Salvarani C, Giannini C, Miller DV, Hunder G. Giant cell arteritis: involvement of intracranial arteries. Arthritis Rheum 2006; 55: 98589. 33 Lie JT. Illustrated histopathologic classication criteria for selected vasculitis syndromes. Arthritis Rheum 1990; 33: 107487. 34 Klein RG, Campbell RJ, Hunder GG, Carney JA. Skip lesions in temporal arteritis. Mayo Clin Proc 1976; 51: 50410. 35 Esteban M-J, Font C, Hernandez-Rodriguez J, et al. Small-vessel vasculitis surrounding a spared temporal artery: clinical and pathologic ndings in a series of twenty-eight patients. Arthritis Rheum 2001; 44: 138795. 36 Meliconi R, Pulsatelli L, Uguccioni M, et al. Leukocyte inltration in synovial tissue from the shoulder of patients with polymyalgia rheumatica. Quantitative analysis and inuence of corticosteroid treatment. Arthritis Rheum 1996; 39: 1199207. 37 Elling P, Olsson AT, Elling H. Synchronous variations of the incidence of temporal arteritis and polymyalgia rheumatica in dierent regions of Denmark; association with epidemics of Mycoplasma pneumoniae infection. J Rheumatol 1996; 23: 11219. 38 Duhaut P, Bosshard S, Ducroix J-P. Is giant cell arteritis and infectious disease? Biological and epidemiological evidence. Presse Med 2004; 33: 140308. 39 Machado EBV, Gabriel SE, Beard CM, Michet CJ, OFallon WM, Ballard DJ. A population-based case-control study of temporal arteritis: evidence for an association between temporal arteritis and degenerative vascular disease? Int J Epidemiol 1989; 18: 83641. 40 Duhaut P, Pinede L, Demolombe-Rague S, et al. Giant cell arteritis and cardiovascular risk factors. A multicenter, prospective case-control study. Arthritis Rheum 1998; 41: 196065. 41 Gonzalez-Gay MA, Pineiro A, Gomez-Gigirey A, et al. Inuence of traditional risk factors of atherosclerosis in the development of severe ischemic complications in giant cell arteritis. Medicine 2004; 83: 34247. 42 Salvarani C, Boiardi L, Mantovani V, et al. HLA-DRB1 alleles associated with polymyalgia rheumatica in northern Italy: correlation with disease severity. Ann Rheum Dis 1999; 58: 30308. 43 Gonzalez-Gay MA, Amoli MM, Garcia-Porrua C, Ollier WER. Genetic markers of disease. Susceptibility and severity in giant cell arteritis and polymyalgia rheumatica. Semin Arthritis Rheum 2003; 33: 3848. 44 Weyand CM, Goronzy JJ. Medium- and large-vessel vasculitis. N Engl J Med 2003; 349: 16069. 45 Weyand CM, Wei M-A, Pryshchep O, Groschel S, Bernardino R, Goronzy JJ. Vascular dendritic cells in giant cell arteritis. Ann NY Acad Sci 2005; 1062: 195208 46 Lozano E, Segarra M, Garcia-Martinez A, Hernanadez-Rodriguez J, Cid MC. Imatinib mesylate inhibits in vitro and ex vivo biologic responses related to vascular occlusion in giant cell arteritis. Ann Rheum Dis; published online June 21, 2007. DOI:10.1136/ard.2007.070805. 47 Weyand CM, Hicok KC, Hunder GG, Goronzy JJ. Tissue cytokine patterns in patients with polymyalgia rheumatica and giant cell arteritis. Ann Intern Med 1994; 121: 48491. 48 Salvarani C, Cimino L, Macchioni PL, et al. Risk factors for visual loss in an Italian population-based cohort of patients with giant cell arteritis. Arthritis Rheum 2005; 53: 29397. 49 Hernandez-Rodriguez J, Segarra M, Vilardell C, et al. Elevated production of interleukin-6 is associated with a lower incidence of disease-related ischemic events in patients with giant cell arteritis: angiogenic activity of interleukin-6 as a potential protective mechanism. Circulation 2003; 107: 242834. 50 Cid MC, Hernandez-Rodriguez J, Esteban MJ, et al. Tissue and serum angiogenic activity is associated with low prevalence of ischemic complications in patients with giant cell arteritis. Circulation 2002; 106: 166471. 51 Salvarani C, Macchioni PL, Tartoni PL, et al. et al. Polymyalgia rheumatica and giant cell arteritis: a 5-year epidemiologic and clinical study in Reggio Emilia, Italy. Clin Exp Rheumatol 1987; 5: 20515. 52 Calamia KT, Hunder GG. Giant cell arteritis (temporal arteritis) presenting as fever of undetermined origin. Arthritis Rheum 1981; 24: 141418. 53 Gonzalez-Gay MA, Garcia-Porrua C, Amor-Dorado JC, Llorca J. Fever in biopsy proven giant cell arteritis: clinical implications in a dened population. Arthritis Rheum 2004; 51: 65255. 54 Salvarani C, Gabriel S, Hunder GG. Distal extremity swelling with pitting edema in polymyalgia rheumatica: report of nineteen cases. Arthritis Rheum 1996; 39: 7380. 55 Salvarani C, Cantini F, Olivieri I, Hunder GG. Polymyalgia rheumatica: a disorder of extraarticular synovial structures? J Rheumatol 1999; 26: 51721. 56 Salvarani C, Cantini F, Macchioni L, et al. Distal musculoskeletal manifestations in polymyalgia rheumatica. A prospective follow-up study. Arthritis Rheum 1998; 41: 122126. 57 Calamia KT, Hunder GG. Clinical manifestations of giant cell (temporal) arteritis. Clin Rheum Dis 1980; 6: 389403. 58 Gonzalez-Gay MA, Barros S, Lopez-Diaz MJ, Garcia-Porrua C, Sanchez-Andrade A, Llorca J. Giant cell arteriris: disease patterns of clinical presentation in a series of 240 patients. Medicine (Baltimore) 2005; 84: 26976. 59 Salvarani C, Gabriel SE, Gertz MA, Bjornsson J, Li C-Y, Hunder GG. Primary systemic amyloidosis presenting as giant cell arteritis and polymyalgia rheumatica. Arthritis Rheum 1994; 37: 162126. 60 Aiello PD, Trautmann JC, McPhee TJ, Kunselman AR, Hunder GG. Visual prognosis in giant cell arteritis. Ophthalmology 1993; 100: 55056. 61 Gonzalez-Gay MA, GarciaPorrua C, Llorca J, et al. Visual manifestations of giant cell arteritis: trends and clinical spectrum in 161 patients. Medicine (Baltimore) 2000; 79: 28392. 62 Salvarani C, Hunder GG. Musculoskeletal manifestations in a population-based cohort of patients with giant cell arteritis. Arthritis Rheum 1999; 42: 125966. 63 Cantini F, Salvarani C, Olivieri I, et al. Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome: a prospective follow-up and magnetic resonance imaging study. Ann Rheum Dis 1999; 58: 23036. 64 Gonzalez-Gay MA, Garcia-Porrua C, Amor-Dorado JC, Lorca J. Giant cell arteritis without clinically evident vascular involvement in a dened population. Arthritis Rheum 2004; 51: 27477. 65 Hayreh SS, Podhajsky PA, Zimmerman B. Occult giant cell arteritis: ocular manifestations. Am J Ophthalmol 1998; 125: 52126. 66 Bongartz T and Matteson EL. Large-vessel involvement in giant cell arteritis. Curr Opin Rheumatol 2006; 18: 1017. 67 Gonzalez-Gay MA, Garcia-Porrua C, Pineiro A, Pego-Reigosa R, Llorca J, Hunder GG. Aortic aneurysm and dissection in patients with biopsy-proven giant cell arteritis from northwestern Spain: a population-based study. Medicine (Baltimore) 2004; 83: 33541. 68 Le Hello C, Lvesque H, Jeanton M, et al. Lower limb giant cell arteritis and temporal arteritis : followup of 8 cases. J Rheumatol 2001; 28: 140712. 69 Caselli R, Hunder GG, Whisnant JP. Neurologic disease in biopsy-proven giant cell (temporal) arteritis. Neurology 1988; 38: 35259. 70 Caselli R, Daube JR, Hunder GG, Whisnant JP. Peripheral neuropathic syndromes in giant cell (temporal) arteritis. Neurology 1988; 38: 68589. 71 Gonzalez-Gay MA, Blanco R, Rodriguez-Valverde V, et al. Permanent visual loss and cerebrovascular accidents in giant cell arteritis: predictors and response to treatment. Arthritis Rheum 1998; 41: 1497504. 72 Larson TS, Hall S, Hepper NG, Hunder GG. Respiratory tract symptoms as a clue to giant cell arteritis. Ann Intern Med 1984; 101: 59497. 73 Valstar MH, Terpstra WF, de Jong RS. Pericardial and pleural eusion in giant cell arteritis. Am J Med 2003; 114: 70809. 74 Lie JT, Failoni DD, Davis DC Jr. Temporal arteritis with giant cell aortitis, coronary arteritis, and myocardial infarction. Arch Pathol Lab Med 1986; 110: 85760. 75 Bajocchi G, Zamorani G, Cavazza A, et al. Giant-cell arteritis of the female genital tract associated with occult arteritis and FDG-PET evidence of large vessel vasculitis. Clin Exp Rheumatol 2007; 25 (suppl 44): S3639. 76 Kariv R, Sidi Y, Gur H. Systemic vasculitis presenting as a tumorlike lesion. Four case reports and an analysis of 79 reported cases. Medicine (Baltimore) 2000; 79: 34959. Seminar 244 www.thelancet.com Vol 372 July 19, 2008 77 Luzar MJ, Whisler RL, Hunder GG. Syndrome of inappropriate secretion of antidiruetic hormone in association with temporal arteritis. J Rheumatol 1982; 9: 95760. 78 Lee CC, Su WW, Hunder GG. Dysarthria associated with giant cell arteritis. J Rheumatol 1999; 26: 93132. 79 Cantini F, Salvarani C, Olivieri I, et al. Erythrocyte sedimentation rate and C-reactive protein in the evaluation of disease activity and severity in polymyalgia rheumatica: a prospective follow-up study. Semin Arthritis Rheum 2000; 30: 1724. 80 Salvarani C, Hunder GG. Giant cell arteritis with low erythrocyte sedimentation rate: frequency of occurrence in a population-based study. Arthritis Rheum 2001; 45: 14045. 81 Hayreh SS, Podhajsky PA, Raman R, Zimmerman B. Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol 1997; 123: 28596. 82 Weyand CM, Fulbright JW, Evans JM, Hunder GG, Goronzy JJ. Corticosteroid requirements in polymyalgia rheumatica. Arch Intern Med 1999; 159: 57784. 83 Salvarani C, Cantini F, Niccoli L, et al. Acute phase response reactants and the risk of developing relapse/recurrence in polymyalgia rheumatica: a prospective follow up study. Arthritis Rheum 2005; 53: 3338. 84 Lopez-Hoyos M, Ruiz de Alegria C, Blanco R, et al. Clinical utility of anti-CCP antibodies in the dierential diagnosis of elderly-onset rheumatoid arthritis and polymyalgia rheumatica. Rheumatology 2004; 43: 65557. 85 Gonzalez-Gay MA, Lopez-Diaz MJ, Barros S, et al. Giant cell arteritis: laboratory tests at the time of diagnosis in a series of 240 patients. Medicine (Baltimore) 2005; 84: 27790. 86 ODuy JD, Wahner HW, Hunder GG. Joint imaging in polymyalgia rheumatica. Mayo Clin Proc 1976; 51: 51924. 87 Salvarani C, Cantini F, Olivieri I, et al. Proximal bursitis in active polymyalgia rheumatica. Ann Intern Med 1997; 27: 2731. 88 Cantini F, Salvarani C, Olivieri I, et al. Shoulder ultrasonography in the diagnosis of polymyalgia rheumatica: a case-control study. J Rheumatol 2001; 28: 104955. 89 Cantini F, Niccoli L, Nannini C, et al. Inammatory changes of hip synovial structures in polymyalgia reumatica. Clin Exp Rheumatol 2005; 23: 46268. 90 Cantini F, Salvarani C, Olivieri I, et al. Inamed shoulder structures in polymyalgia rheumatica with normal erythrocyte sedimentation rate. Arthritis Rheum 2001; 44: 115559. 91 Salvarani C, Silingardi M, Ghirarduzzi A, et al. Is duplex ultrasonography useful for the diagnosis of giant cell arteritis? Ann Intern Med 2002; 137: 23238. 92 Karassa FB, Matsagas MI, Schmidt WA, Ioannidis JPA. Meta-analysis: test performance of ultrasonography for giant cell arteritis. Ann Intern Med 2005; 142: 35969. 93 Bley TA, Weiben O, Uhl M, et al. Assessment of the cranial involvement pattern of giant cell arteritis with 3T magnetic resonance imaging. Arthritis Rheum 2005; 52: 247077. 94 Stanson AW. Imaging ndings in extracranial (giant cell) temporal arteritis. Clin Exp Rheumatol 2001; 18 (suppl 20): S4348. 95 Schmidt WA, Natusch A, Mller DE, Vorpahl K, Gromnica-Ihle E. Involvement of peripheral arteries in giant cell arteritis: a color Doppler sonography study. Clin Exp Rheumatol 2002; 20: 30918. 96 Blockmans D, de Ceuninck L, Vanderschueren S, Knockaert D, Mortelmans L, Bobbaers H. Repetitive 18F-uorodeoxyglucose positron emission tomography in giant cell arteritis: a prospective study of 35 patients. Arthritis Rheum 2006; 55: 13137. 97 Gonzalez-Gay MA, Garcia-Porrua C, Salvarani C, Olivieri I, Hunder GG. The spectrum of conditions mimicking polymyalgia rheumatica in Northwestern Spain. J Rheumatol 2000; 27: 217984. 98 McCarty DJ, ODuy JD, Pearson L, Hunter JB. Remitting seronegative symmetrical synovitis with pitting edema. RS3PE syndrome. JAMA 1985; 254: 276367. 99 Olivieri I, Salvarani C, Cantini F. Remitting distal extremity swelling with pitting edema: a distinct syndrome or a clinical feature of dierent inammatory rheumatic diseases? J Rheumatol 1997; 24: 24952. 100 Olivieri I, Garcia-Porrua C, Padula A, Cantini F, Salvarani C, Gonzalez-Gay MA. Late onset spondyloarthritis presenting with polymyalgia rheumatica features: description of 7 cases. Rheumatology Int 2007; 27: 92733. 101 Pego-Reigosa JM, Rodriguez-Rodriguez M, Hurtado-Hernandez Z, et al. Calcium pyrophosphate deposition disease mimicking polymyalgia rheumatica: a prospective followup study of predictive factors for this condition in patients presenting with polymyalgia symptoms. Arthritis Rheum 2005; 53: 93138. 102 Hopkinson ND, Shawe DJ, Gumpel JM. Polymyositis, not polymyalgia rheumatica. Ann Rheum Dis 1991; 50: 32122. 103 Niccoli L, Salvarani C, Baroncelli G, Padula A, Olivieri I, Cantini F. Renal cell carcinoma mimicking polymyalgia rheumatica. Clues for a correct diagnosis. Scand J Rheumatol 2002; 31: 10306. 104 Churcill MA, Geraci HJE, Hunder GG. Musculoskeletal manifestations of bacterial endocarditis. Ann Intern Med 1977; 87: 75459. 105 Pipitone N, Salvarani C. Are steroids alone sucient for the treatment of giant cell arteritis? Best Pract Res Clin Rheumatol 2005; 19: 27792. 106 Hayreh SS, Zimmerman B, Kardon RH: Visual improvement with corticosteroid therapy in giant cell arteritis. Report of a large study and review of literature. Acta Ophthalmol Scand 2002; 80: 35567. 107 Mazlumzadeh M, Hunder GG, Easley KA, et al. Treatment of giant cell arteritis using induction therapy with high-dose glucocorticoids: a double-blind, placebo-controlled, randomized prospective clinical trial. Arthritis Rheum 2006; 54: 331018. 108 Chevalet P, Barrier JH, Pottier P, et al. A randomized, multicenter, controlled trial using intravenous pulses of mrthylprednisolone in the initial treatment of simple forms of giant cell arteritis: a one year followup study of 164 patients. J Rheumatol 2000; 27: 148491. 109 Hunder GG, Sheps SG, Allen GL, Joyce JW. Daily and alternate-day corticosteroid regimens in treatment of giant cell arteritis: comparison in a prospective study. Ann Intern Med 1975; 82: 61318. 110 Andersson R, Malmvall B-E, Bengtsson B-A. Long-term corticosteroid treatment in giant cell arteritis. Acta Med Scand 1986; 220: 46569. 111 Proven A, Gabriel SE, Orces C, OFallon WM, Hunder GG. Glucocorticoid therapy in giant cell arterits: duration and adverse outcomes. Arthritis Rheum 2003; 49: 70308. 112 Jover JA, Hernandez-Garcia C, Morado IC, Vargas E, Banares A, Fernandez-Gutierrez B. Combined treatment of giant-cell arteritis with methotrexate and prednisone: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001; 134: 10614. 113 Homan GS, Cid MC, Hellmann DB, et al. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 2002; 46: 130918. 114 Weyand CM, Fulbright JW, Hunder GG, Evans JM, Goronzy JJ. Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum 2000; 43: 104148. 115 Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum 2001; 44: 1496503. 116 Sambrook PN. How to prevent steroid induced osteoporosis. Ann Rheum Dis 2005; 64: 17678 117 Spiera RF, Mitnick HJ, Kupersmith M, et al. A prospective, double-blind, randomized, placebo controlled trial of methotrexate in the treatment of giant cell arteritis (GCA). Clin Exp Rheumatol 2001; 19: 495501. 118 Mahr AD, Jover JA, Spiera RF, Hernandez-Garcia C, Fernandez-Gutierrez B, LaValley MP, Merkel PA. Adjunctive methotrexate for treatment of giant cell arteritis. An individual patient data meta-analysis. Arthritis Rheum 2007; 56: 278997. 119 De Silva M, Hazleman BL. Azathioprine in giant cell arteritis/polymyalgia rheumatica: a double-blind study. Ann Rheum Dis 1986; 45: 13638. 120 Homan GS, Cid MC, Rendt-Zagar KE, et al. Iniximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med 2007; 146: 62130. Seminar www.thelancet.com Vol 372 July 19, 2008 245 121 Hernandez-Rodriguez J, Segarra M, Vilardell C, et al. Tissue production of pro-inammatory cytokines (IL-1beta, TNFalpha and IL-6) correlates with the intensity of the systemic inammatory response and with corticosteroid requirements in giant-cell arteritis. Rheumatology (Oxford) 2004; 43: 294301. 122 Cantini F, Niccoli L, Salvarani C, Padula A, Olivieri I. Treatment of longstanding active giant cell arteritis with iniximab: report of four cases. Arthritis Rheum 2001; 44: 293335. 123 Nesher G, Berkun Y, Mates M, Baras M, Rubinow A, Sonnenblick M. Low-dose aspirin and prevention of cranial ischemic complications in giant cell arteritis. Arthritis Rheum 2004; 50: 133237. 124 Lee MS, Smith SD, Galor A, Homan GS. Antiplatelet and anticoagulant therapy in patients with giant cell arteritis. Arthritis Rheum 2006; 54: 330609. 125 Weyand CM, Kaiser M, Yang H, Younge B, Goronzy JJ. Therapeutic eects of acetysalcylic acid in giant cell arteritis. Arthritis Rheum 2002; 46: 45766. 126 Salvarani C, Cantini F, Boiardi L, Hunder GG. Polymyalgia rheumatica. Best Pract Res Clin Rheumatol 2004; 18: 70522. 127 Kremers HM, Reinalda MS, Crowson CS, Zinsmeister AR, Hunder GG, Gabriel SE. Relapse in a population based cohort of patients with polymyalgia rheumatica. J Rheumatol 2005; 32: 6573. 128 Ayoub WT, Franklin CM, Torretti D. Polymyalgia rheumatica: duration of therapy and long-term outcome. Am J Med 1985; 79: 30915. 129 Gabriel SE, Sunku J, Salvarani C, OFallon WM, Hunder GG. Adverse outcomes of anti-inammatory therapy among patients with polymyalgia rheumatica. Arthritis Rheum 1997; 40: 187378. 130 Caporali R, Cimmino MA, Ferraccioli G, et al. Prednisone plus methotrexate for polymyalgia rheumatica: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2004; 141: 493500. 131 Salvarani C, Cantini F, Niccoli L, et al. Treatment of refractory polymyalgia rheumatica with iniximab: a pilot study. J Rheumatol 2003; 30: 76063. 132 Catanoso MG, Macchioni PL, Boiardi L, Pipitone N, Salvarani C. Treatment of refractory polymyalgia rheumatica with etanercept: an open pilot study. Arthritis Rheum 2007; 57: 151419. 133 Salvarani C, Macchioni PL, Manzini C, et al. Iniximab plus prednisone or placebo plus prednisone for the initial treatment of polymyalgia rheumatica. A randomized trial. Ann Intern Med 2007; 146: 63139. 134 Strand V, Yazici Y. Interleukin-6 inhibition. Tolerability prole and clinical implications. Bull NYU Hosp JT Dis 2007; 65 (suppl 1): S2124. 135 Davis PM, Nadler SG, Stetsko DK, Suchard SJ. Abatacept modulates human dendritic cell-stimulated T-cell proliferation and eector function independent of IDO induction. Clin Immunol 2008; 126: 3847.