Introduction. Overview

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1 Temporal arteritis James Goodwin MD ( Dr. Goodwin of the University of Illinois at Chicago has no relevant financial relationships to disclose. ) Originally released May 14, 1996; last updated September 21, 2016; expires September 21, 2019 Introduction This article includes discussion of temporal arteritis, arteritis of the aged, Bagratuni syndrome, cranial arteritis, giant cell arteritis, polymyalgia arteritica, Rumbold disease, senile rheumatic gout, and polymyalgia rheumatica. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview Temporal arteritis is an important cause of ischemic complications in elderly patients and timely diagnosis can prevent important morbidity, most notably blindness from either anterior ischemic optic neuropathy or central retinal artery occlusion. These patients, left untreated, are also at increased risk for ischemic stroke. Treatment with high-dose corticosteroids is effective in preventing these complications, and initial treatment with intravenous pulse corticosteroids leads to more sustained clinical remission and lower subsequent oral corticosteroid dosage requirement. Other adjunctive immunosuppressant drugs are also currently being used in this setting as steroidsparing agents. In this update, the author cites studies showing increased risk for a variety of ischemic cardiovascular complications among patients with temporal arteritis and patients who were taking statin drugs, which had a somewhat lesser incidence of these complications. He also reviews advances in biological treatment of giant cell arteritis with monoclonal antibodies with and without concomitant corticosteroid treatment. Key points Temporal arteritis is a systemic vascular disease in which inflammation, usually with giant cells, affects the internal elastic lamina, adventitia, and adjacent media of medium and large arteries with a predilection for those in the head and neck. It is a disease almost exclusively in the elderly (older than 60 years) and usually presents with headache along with manifestations of ischemia in tissues of the head including most commonly pain, ulceration, and necrosis involving the scalp and oral mucosa. Ischemia of the temporalis and masseter muscles produces a distinctive syndrome called jaw claudication with crescendo pain in the mandibular region while chewing solid food and gradual relief after cessation of muscular activity in the involved muscles. The most common serious complication is vision loss from ischemic optic neuropathy or central retinal artery occlusion. Ischemic stroke can occur secondary to emboli from involved extracranial carotid and vertebral arteries intracranial segments of the arteries are not involved, possibly because they lack an internal elastic lamina. Serious complications can be prevented by treatment with systemic corticosteroids in adequate doses over prolonged periods. Historical note and terminology The earliest case report of what was probably temporal arteritis is attributed to Ali Ibn Isa, a 10th century oculist (Woods 1936). Hutchinson described another early case in a man of 80 named Rumbold, who presented with painful, swollen, and reddened temporal arteries in the apparent absence of systemic symptoms. The inflammation subsided gradually and left the arteries as "pulseless impervious cords" (Hutchinson 1889). Some authors have since referred to temporal arteritis as Rumbold disease. Credit for the earliest complete description of the disease with pathologic documentation of characteristic inflammation and giant cells in the temporal artery must be accorded to Horton and colleagues from the Mayo Clinic. The following is their succinct clinical description derived from examining 2 patients:

2 Both patients were admitted to the Clinic in the spring of 1931 because of fever, weakness, anorexia, loss of weight, anemia, mild leukocytosis, and painful, tender areas over the scalp and along temporal vessels. These manifestations had been present for 4 weeks to 6 weeks. Temporal artery biopsy in these 2 cases yielded granulomatous arteritis and periarteritis (Horton et al 1932). Since this report, temporal artery biopsy has remained as the mainstay of pathologic diagnosis, though biopsy of other accessible cranial vessels has occasionally been advocated. As cases accumulated, it became apparent that temporal arteritis usually presents with headache and symptoms of systemic illness exclusively in elderly persons. Another painful syndrome, now called "polymyalgia rheumatica" after Barber (Barber 1957), shares with temporal arteritis the strong predilection for the elderly and the association with signs and symptoms of systemic illness. In the mid-1950s the concept that temporal arteritis and polymyalgia rheumatica are but 2 clinical manifestations of the same basic disease process was introduced (Paulley and Hughes 1960). Hamrin and Ostberg both provided landmark publications, the former reporting his series of 93 cases of polymyalgia rheumatica with analysis of the relationship with temporal arteritis and underlying vascular pathology, and the latter reporting an autopsy study that revealed the link between the clinical syndrome called "polymyalgia rheumatica and giant cell arteritis of the aorta and its main branches" (Hamrin 1972; Ostberg 1973). Clinical manifestations Presentation and course New headache or dramatic change in pattern of longstanding headache in an elderly patient is the most common presentation of temporal arteritis. The pain may have a local component along the temporal and other external carotid branches, but often the character of the headache is nonspecific (Hamilton et al 1971). Only a few individuals have localized pain, induration, and tenderness over the temporal arteries or erythematous nodules along the vessels, though it is worth looking for these physical signs. In some cases the temporal arteries are palpably indurated and may show a "ropy" appearance beneath the skin. The incidence of headache in temporal arteritis is about 80% in large series, so one cannot dismiss the diagnosis entirely in the absence of headache. Severity of the headache is variable, and headache was the symptom that led to referral of only 41 patients of 175 patients in the 1960 Mayo Clinic series. The typical headache, if one can be said to occur, is maximal over the temples and suboccipital region. Occipital arteries as well as branches of the external carotid artery are commonly involved, and pain in these vessels should be sought during the history and by palpation. Tenderness specifically along extracranial branches of the carotid system is particularly useful in diagnosis when present. Momentary stabbing or ice pick headache accompanying new-onset persistent headache in an elderly person may be a useful indicator of temporal arteritis as the cause (Rozen 2010). Diffuse tenderness of the scalp, face, or oral mucosa results from ischemia secondary to widespread arteritic involvement of extracranial vessels. Some patients describe "head pains" rather than headache, indicating the relatively superficial character of the discomfort (Paulley and Hughes 1960). Patients should be asked if they are experiencing new tenderness when they comb their hair, or if a hat or the temple pieces of their glasses are causing new pain in 1 or both temples. The pain in the vessel may be dependent on pulsatile blood flow and may cease with thrombosis of the vessel. Similarly, the pain may be relieved when an involved segment of temporal artery is removed for biopsy. When present, pain relief after biopsy is a strong element favoring the diagnosis, and patients should be asked about this a few days after the biopsy when the local pain from the surgery has subsided. Pain and ulceration of the oral mucosa tongue or scalp is an especially useful sign favoring temporal arteritis. Scalp necrosis and ulceration can be mistaken for herpes zoster. The histopathology in temporal arteritis consists of lymphocytic vasculitis, scarring with myxoid degeneration, and fat necrosis in the dermis (Ghaffar and Todd 2010). Ischemia of the tongue can be misdiagnosed as glossitis with beefy enlargement and loss of taste sensation. In a review, the mean interval between onset of temporal arteritis and scalp necrosis was 3 months in 19 patients who had not been started on corticosteroids. Jaw claudication is nearly pathognomonic for temporal arteritis, though it can be present on the basis of severe atherosclerosis of the external and internal carotid arteries in rare instances. Both the internal and external carotid systems must be affected together to produce jaw claudication, as each system provides collateral flow to the other when occlusive disease involves only 1. Jaw claudication must be distinguished from other causes of pain around the

3 lower face and dentition. The pain of claudication builds progressively with the muscular activity of chewing rather than occurring with the pressure of biting down, whereas dental pain occurs even with the first bite and pain occurs with any jaw movement with pathology in the temporomandibular joint. As with claudication elsewhere, the pain is relieved with rest and usually requires at least a few seconds to dissipate when the patient stops chewing. Careful history taking is the only way to elicit these fine points and correctly identify claudication or ischemia as the mechanism of pain. Many patients with temporal arteritis have low-grade fever, leukocytosis, or mild anemia either at presentation or during the course of the illness. Depression, listlessness, and general malaise are common complaints among the elderly, but increased intensity of 1 or more of these symptoms may signal the onset of temporal arteritis. Nonspecific complaints like these have been shown to precede the more specific symptoms, even for several months, in up to half the patients. Weight loss, weakness, and inanition may be profound in the occasional patient. Isolated psychiatric symptoms with psychotic features can be a presenting feature of temporal arteritis. Sudden onset of psychosis in the elderly may warrant a short course of corticosteroids. Prompt remission of symptoms with steroid treatment is another important factor in diagnosis. Low back pain can be the presenting symptom of abdominal aortic giant cell arteritis, and 18 FDG-PET is useful to identify the aortic involvement in this setting (Fernandez-Lopez et al 2007). Occasionally, ischemic complications can appear before any of the systemic signs or symptoms of illness, making diagnosis extremely difficult. Some authors have called this type of presentation "occult temporal arteritis" (Cullen 1963). Although the signs and symptoms of temporal arteritis are variable, once they have begun they are usually continuous or progressive until effective treatment is established, but Purvin and Kawasaki described 4 cases with spontaneous remission of symptoms and signs (Purvin and Kawasaki 2007). Because of its greater-than-chance association with temporal arteritis, it is important to be aware of the signs and symptoms of polymyalgia rheumatica. It is not uncommon for patients with polymyalgia to develop additional symptoms of temporal arteritis after they have had the original illness for some time, sometimes years. Polymyalgia, like temporal arteritis, almost exclusively affects persons over the age of 50 years. The clinical picture consists of pain and stiffness in the shoulder or pelvic girdles. Pain and limited motion of the axial skeleton including the cervical and thoracic spine are common. Pain and stiffness are often worse on arising in the morning, with some improvement of mobility as the day proceeds. Onset may be insidious or acute. Severity of symptoms can be asymmetric, but the disorder is invariably bilateral. There may be mild swelling of the shoulders and even distal joints in the extremities, but as a rule no articular deformity is manifest either clinically or by radiographic examination. Pain is almost always accompanied by systemic symptoms identical to those encountered in temporal arteritis. Headache, jaw claudication, and scalp pain or tenderness define the clinical transition from polymyalgia to temporal arteritis and determine the need for more aggressive corticosteroid or immunosuppressive management. Axillary artery bruit can be a presenting sign of transition to giant cell arteritis in patients with polymyalgia rheumatica (Czihal et al 2011). The authors point out that axillary artery bruit is very uncommon in atherosclerosis. On physical examination there are few findings in patients with polymyalgia. One prominent characteristic feature is that the passive range of motion in neck or pelvis far exceeds the active range. That is, the examiner can slowly move the patient's neck through a greater range than the patient can by using his or her own neck muscles. Patients with polymyalgia have an increased incidence of arterial bruits over the large arteries of the arms and legs as well as over the carotid and subclavian vessels. Polymyalgia rheumatica may have a range of atypical presentations including peripheral synovitis, mild weakness, and normal sedimentation rate. In fact, there is considerable overlap between polymyalgia rheumatica and seronegative rheumatoid. The duration of polymyalgia has ranged in various reports from 6 months to as long as 14 years, but most patients are ill with it for 1 to 3 years.

4 Prognosis and complications Although the patient is often most interested in pain relief, the possibility of an ischemic complication is, for the physician, the most compelling component of temporal arteritis. Because it is impossible to know when an ischemic event might occur, it is necessary to make the diagnosis and initiate corticosteroid treatment quickly. The most common ischemic complications of temporal arteritis involve the eye and vision. In an earlier review of large series, I found that visual loss occurs in a third to half of patients (Goodwin 1980). Sudden total binocular blindness has been reported, and in many cases the second eye becomes involved only hours to days after the first ischemic event. The threat of rapid progression to binocular blindness constitutes the emergency in treatment of temporal arteritis. Some clinicians believe that simultaneous occurrence of ischemic optic neuropathy and central retinal artery occlusion in the same eye or in opposite eyes is pathognomonic for temporal arteritis. Multiple attacks of amaurosis fugax alternating between eyes are also a strong indicator of temporal arteritis and do not often occur in atherosclerotic carotid artery disease. Most ischemic visual events occur after several weeks of symptoms, but usually less than 6 months from onset of symptoms. Font and colleagues found that among 146 patients with biopsy proven temporal arteritis, 23 (15.75%) had visual loss (Font et al 1997). All of the patients who lost vision had had classic symptoms of temporal arteritis for an average of 1.3 months or of polymyalgia rheumatica for an average of 10.8 months prior to vision loss. Also, it is important to note that 65.2% of these patients had had premonitory visual symptoms for an average of 8.5 days prior to permanent vision loss. These statistics provide support for the urgency of correct diagnosis and prompt initiation of treatment in temporal arteritis and in polymyalgia rheumatica. In a study of 90 biopsy-positive cases of temporal arteritis, univariate analysis showed that the most common risk factors for progressive visual loss were older age, elevated C-reactive protein, and disc swelling (Loddenkemper et al 2007). The most frequent cause of blindness in temporal arteritis is anterior ischemic optic neuropathy, but central retinal artery occlusion accounts for a significant number of blind eyes, sometimes in conjunction with anterior ischemic optic neuropathy. In 1958 Wagener and Hollenhorst studied 100 affected eyes in 58 patients at the Mayo Clinic and found anterior ischemic optic neuropathy in 64% of the eyes and ischemic changes in the distribution of the central retinal artery in 7% (Wagener and Hollenhorst 1958). In that series a total of 54 of 122 (44%) had visual impairment from temporal arteritis. Thirty years later, Caselli and colleagues found permanent visual loss in only 14 of 166 (8.4%) of biopsy-positive patients in the Mayo Clinic cohort, of whom 12 lost vision in 1 eye and 2 in both (Caselli et al 1988). The incidence of visual complications was assessed in a population-based study of temporal arteritis in Denmark (Fledelius and Nissen 1992). Ten of 264 (3.8%) patients with temporal arteritis from a county sample and a hospitalbased series had significant visual impairment. The authors acknowledged that the rate of visual impairment is lower than in published series from other parts of the world. They also speculate that the diagnosis is made earlier in Denmark and that early steroid treatment may be preventing permanent complications in more patients than elsewhere. An important long-term prospective study of 170 patients between 1973 and 1995 was reported by Hayreh. Fifty percent of the patients presented with visual symptoms, of which 97.7 had vision loss, 30% amaurosis fugax, and 6% diplopia. Of those with vision loss, the etiology was anterior ischemic optic neuropathy in 81%, central retinal artery occlusion in 14%, cilioretinal artery occlusion in 22% (12 of 55 patients with fluorescein angiogram), posterior ischemic optic neuropathy (disc not swollen) in 7%, and ocular ischemia in 1 patient (Hayreh et al 1998). Retabulation of 114 eyes in 84 consecutive patients from the same clinic between 1974 and 1999 indicated anterior ischemic optic neuropathy in 91%, central retinal artery occlusion in 10.5%, cilioretinal artery occlusion in 10%, and posterior ischemic optic neuropathy (no disc edema acutely) in 4% either alone or in different combinations (total >100) (Hayreh et al 2002). Galor and Lee provide a well-documented case of slowly progressive blindness in 1 eye secondary to choroidal ischemia in a 93 year old man with biopsy positive giant cell temporal arteritis who happened to be on Coumadin for atrial fibrillation. After a month, vision in that eye had dropped to finger counting but returned to 20/50 a day after treatment with IV solumedrol (methylprednisolone) was begun. The authors suggest the rate of visual progressive loss may have been slowed because of the Coumadin and cite other references suggesting a beneficial effect of anticoagulation for visual loss in temporal arteritis (Galor and Lee 2006). The incidence of visual complications in any cohort of patients with temporal arteritis is subject to tremendous

5 potential bias from many factors. For instance, a review of 47 patients with biopsy positive temporal arteritis done at an ophthalmologic hospital in Switzerland found vision loss in 33 patients (70%). Obviously, the denominator in their fraction, the patients referred to an eye hospital are likely to include an inflated percent with eye complications. Of the 33 patients with vision loss, 22 (66%) had anterior ischemic optic neuropathy and 7 (21%) had central retinal artery occlusion, consistent with earlier series. Anterior ischemic optic neuropathy presents with sudden visual loss, commonly with "altitudinal" or upper and lowerhalf loss of visual field and pale swelling of the optic nerve head. A rare posterior ischemic optic neuropathy presents with the same visual deficit but with no optic disc edema. The physiologic cup is a normal depression in the central surface of the optic disc that is typically enlarged in glaucoma (cupping of the disc). Various reports have described cupping as a late manifestation of anterior ischemic optic neuropathy. In a review of fundus photographs, the size of the physiologic cup was compared between 2 groups of patients with anterior ischemic optic neuropathy: 92 patients with arteritic anterior ischemic optic neuropathy and 102 patients with nonarteritic anterior ischemic optic neuropathy. Cupping was present in 92% of eyes with arteritic disease and in only 2% of eyes with nonarteritic disease (Danesh-Meyer et al 2001). Central retinal artery occlusion is characterized by sudden loss of visual function, either with total blindness or with predilection for the upper or lower altitudinal half visual field, as in ischemic optic neuropathy. During the first few minutes blood flow may cease in the arteries, leaving only the appearance of white threadlike "ghost" vessels until flow is reestablished, usually within just a few minutes. The fundus may then appear normal despite ongoing blindness or dense visual field loss. Within 12 to 24 hours the infarcted inner retinal layers develop edema that appears white and opaque, obscuring retinal vessel segments and underlying structures. The edema is often most apparent at the fovea, which appears unnaturally red against the surrounding abnormally white retina. This is because the retina is thin at the fovea and the whiteness is much less intense there. This appearance has been called the relative cherry red spot. Within 2 to 3 weeks the retinal edema fades, leaving the fundus looking relatively normal again. Within a few months Wallerian degeneration of axons in the retinal nerve fiber layer reaches the optic nerve head, causing pallor and loss of capillaries that accompany atrophy of the neural tissue. Temporal arteritis may cause ischemia of the entire globe, either unilateral or bilateral; this may be refractory, even to intensive treatment with pulse intravenous methylprednisolone followed by high-dose oral prednisone treatment (Hwang et al 1999). Caselli and colleagues analyzed the neurologic complications in 166 consecutive cases of biopsy-proven temporal arteritis at the Mayo Clinic and found that overall 31% of the patients followed for a median of 17 months (ranging from 15 to 19 months) had some form of neurologic impairment, either transient or permanent (Caselli et al 1988). They found a total of 5 (3%) patients who had brain infarction, 3 in the carotid artery distribution and 2 vertebrobasilar. The authors comment that this hardly exceeds the expected rate of cerebral infarction from atherosclerosis in the age group of the cohort, and that the relation to arteritis remains unproved. Large-artery disease, defined as the presence of bruit or diminished pulse amplitude, was found in 54 patients. The carotid arteries were affected in 31, upper limb arteries in 29, and lower limb arteries in 15. This relative frequency follows closely the distribution of arterial involvement demonstrated in an autopsy study of patients with polymyalgia rheumatica reported by Ostberg (Ostberg 1973) and in the accompanying clinical analysis by Hamrin (Hamrin 1972). A retrospective analysis of stroke among 98 patients with giant cell arteritis at a single hospital found that stroke had occurred at initial presentation in 6 patients, 3 of which involved the vertebrobasilar territory, and there were no additional strokes during follow-up of these patients (Zenone and Puget 2013). Pupillary dilatation is sometimes encountered in temporal arteritis, usually from ischemia involving the third cranial nerve. Prasad and colleagues describe isolated pupillary mydriasis in an 85-year-old man who had biopsy-positive temporal arteritis with the development of denervation supersensitivity with meiosis in response to 0.125% pilocarpine. The patient also had segmental pupillary sphincter involvement, and the overall picture was most consistent with tonic pupil. The authors favor ischemia of the ciliary ganglion or the postganglionic parasympathetic fibers as the etiology (Prasad et al 2009). The Mayo Clinic group studied the patterns of tissue-specific inflammatory response in a group of 23 patients with typical inflammatory lesions in temporal artery specimens (Weyand et al 1997). They found that those with ischemic complications expressed higher concentrations of IFN gamma mrna (P=0.008) and IL-1 beta mrna (P=0.02).

6 Formation of giant cells was associated with local synthesis of IFN gamma (P=0.003). Tissue from patients with concomitant polymyalgia rheumatica had higher levels of IL-2 mrna transcripts (P=0.001). In a preliminary way, this work shows that the characteristics of the inflammatory lesion may, in the future, allow patients to be chosen for more intense treatment based on patterns of inflammatory response that indicate a higher likelihood of developing ischemic complications. Along these same lines, a study of a group of 36 patients with temporal arteritis from Barcelona found relatively higher expression of interleukin-1beta, tumor necrosis factor alpha and interleukin-6 mrna in temporal arteries from patients who went on to have longer time to first remission on steroids, higher steroid dose requirements, and longer required duration of steroid treatment (Hernandez-Rodriguez et al 2004). Various measures of neovascularization or ischemia induced angiogenesis in patients with temporal arteritis have shown that higher levels of this response to ischemia correlated significantly with having fewer ischemic complications. This suggests that the capacity to mount vigorous new vessel formation may be an effective compensatory mechanism in temporal arteritis (Cid et al 2002). Death from ischemia in temporal arteritis is rare but has been reported on occasion, usually from vertebral artery occlusion and brainstem infarction or from coronary occlusion and myocardial infarction (Sheehan et al 1993; Freddo et al 1999). A particularly dramatic death was reported secondary to aortoduodenal fistula that developed in a patient with temporal arteritis (Lagrand et al 1996). Though death from temporal arteritis is dramatic and usually precipitates a case report, an epidemiologic study indicated that life expectancy of patients with temporal arteritis is not significantly less than that of age-matched controls (Matteson et al 1996). An analysis of the Mayo Clinic series of patients with temporal arteritis followed over the past 50 years found 46 incident cases of large-artery complications among 168 patients in the cohort. These complications included 30 cases of aortic aneurysm and 21 cases of large artery stenosis (Nuenninghoff et al 2003a). In general, the survival in this group of temporal arteritis patients with large vessel complications was not different from the total group of temporal arteritis patients. The exception was the development of aortic dissection, which markedly increased mortality (Nuenninghoff et al 2003b). The presence of traditional risk factors for atherosclerosis at the time of temporal arteritis diagnosis was found to significantly increase the risk of developing an ischemic complication, especially hypertension (Gonzalez-Gay et al 2004b). Among 103 giant cell arteritis patients followed for 48.9 ± 14.8 months, the incidence rate ratios of patients versus controls were 12-fold greater for peripheral vascular disease and 5-fold greater for coronary artery disease, and it was found that being on a statin drug reduced the incidence of cardiovascular hospitalizations among these temporal arteritis patients (Pugnet et al 2016). A meta-analysis of 7 studies showed that among temporal arteritis patients compared with controls the relative risk for venous thromboembolism was 2.26, 95% confidence interval (1.38 to 3.71) (Ungprasert et al 2016). The incidence of aortic aneurysm is dramatically increased in patients with temporal arteritis as compared with an age-matched general population. Gonzalez-Gay and colleagues found that 20 (9.5%) of 210 biopsy-proven temporal arteritis patients in northwestern Spain had aortic aneurysms (16 thoracic and 6 abdominal). The population incidence of aortic aneurysm and dissection in their region was 18.9 per 1000 person years at risk, which was similar to that in Olmsted County as published by the Mayo Clinic group. Hypertension and polymyalgia rheumatica with a marked inflammatory response at the time of diagnosis were the most predictive characteristics for later development of aortic disease (Gonzalez-Gay et al 2004a). Another study from Spain involved a cohort of 54 patients with biopsy-proven giant cell arteritis who were screened for aortic structural damage, and significant damage was found in 12 patients (22.5%) after a median follow-up of 5.4 years after initial diagnosis (Garcia-Martinez et al 2008). Prospective follow-up of the 36 remaining patients from this original group of 54 giant cell arteritis patients was carried out with repeat aortic screening every 4 years for a median of 10.3 years (Garcia-Martinez et al 2014). Thirty-six patients were screened a second time, and 14 were available for a third screening at 8 years. Twelve (33.3%) of the 36 patients had developed aortic structural damage, all but 1 in the thoracic aorta at final screening. Ascending and descending aortic diameters significantly increased over time. One patient died from aortic dissection. The authors concluded that aortic structural damage is maximal within the first 5 years of diagnosis but continues over time, and dilatation continues, but without persistence of detectable disease activity. Surgical repair of these arteritic aortic aneurysms is extremely hazardous but can be carried out successfully (Atluri and Woo 2007).

7 Marie and co-workers reviewed records at the Internal Medicine Department of the University of Rouen and found 66 patients with nonatherosclerotic aortic complications, including aortitis, aortic ectasia, and aortic aneurysm; of these, 48 had associated temporal arteritis (Marie et al 2009). Seventy-seven percent of these arteritic cases were without symptoms referable to the aorta (no dysphagia, dyspnea, thoracic or abdominal pain, or back pain). Aortic helical computed tomography demonstrated either isolated aortitis manifest by circumferential thickening of the aortic wall in 41 cases, aortitis with aortic ectasia in 3 cases, and aortic thoracic aneurysm with thoracic and abdominal aortitis in another 3 cases. One case had both aortic abdominal aneurysm and aortitis. Aortitis was most commonly identified at the time of temporal artery diagnosis (41 cases) but was identified after initial diagnosis in 7 patients. After 6 months of treatment, 34 cases had repeat aortic helical computed tomography. This demonstrated complete disappearance of aortitis in nearly 9%, improved aortitis in 47%, unchanged findings in 41%, and deterioration of aortic thoracic aneurysm in 1 patient. Because of the high prevalence of potentially catastrophic aortic involvement, the authors recommend screening with aortic helical computed tomography on an annual basis. An analysis of the prevalence, timing, and characteristics of relapses in patients with temporal arteritis in a cohort of 106 patients followed longitudinally for 7.8 ± 3.3 years (Alba et al 2014). Sixty-eight patients (64%) had at least 1 relapse, and 38 patients (36%) had 2 or more. First relapse was characterized as polymyalgia rheumatic in 51%, cranial symptoms in 31%, and systemic symptoms in 18%. Relapses occurred predominantly in the first 2 years of treatment. The time required to achieve maintenance prednisone dosages was significantly longer, and the cumulative prednisone dose required during the first treatment year was significantly higher in patients with relapses than those without. Clinical vignette CL is a 78-year-old woman who presented with a 2-month history of malaise, poor appetite with weight loss, and generalized weakness. For 2 weeks she had also had frequent vertex headaches that were often severe and kept her from sleeping. In fact, she also had trouble combing her hair in the morning because it caused pain in the scalp. She consulted her dentist because chewing caused pain in the mandibular area, but he could find no dental cause for this. On further questioning she specified that the pain in her jaw would start a few seconds after she began to chew solid food and grow in severity over another 10 to 20 seconds to the point that she would have to stop chewing, after which the pain would subside over another 5 to 15 seconds. She was also having pain in the hips and stiffness of the legs that made walking difficult. On the day of her office visit she had experienced a brief episode of visual loss in her left eye that she described as a "shade being pulled down" over the upper half of the visual field. For about 20 seconds she lost all vision in the left eye, and then sight returned first in the lower half of the field and then the upper half, with full return of vision within 1 to 2 minutes. No pain was associated with this episode. Examination revealed a frail-looking elderly woman in some distress. There was evidence of recent weight loss, and she had trouble rising from the waiting room chair to enter the office. Her gait appeared painful and stiff, and she held her head rigidly in the straight-ahead position as she walked. When asked to bend her neck forward or back or to turn her head to either side she winced with pain. The examiner was able to move her head and neck in all directions passively, but it required slow steady movement to avoid causing pain. Blood pressure was 180/95 taken from her right arm and 140/80 from the left arm. There was a loud left subclavian bruit. An ulcer was noted in the buccal mucosa next to the left lower teeth. There were no localizing findings on neurologic examination. Active and passive flexion of either leg caused pain in the hips and upper thighs. Visual acuity was 20/30 either eye, and there was no subjective red desaturation either eye on viewing a red bottle cap with either eye singly. Visual fields were full to confrontation testing (finger counting in each quadrant). Complete blood count revealed moderate normochromic, normocytic anemia, and the Westergren erythrocyte sedimentation rate was 89 in the first hour. Carotid Duplex blood flow examination showed insignificant stenosis on either side, but ocular plethysmography showed reduced pulse amplitude in both eyes. Left temporal artery biopsy was performed, and methylprednisolone 1 gram was infused intravenously immediately afterward. She was instructed to return for an additional infusion of intravenous methylprednisolone 1 gram for the next 2 days, after which she was

8 placed on oral prednisone at a dose of 80 mg each morning. Microscopic examination of the temporal artery tissue revealed areas of intimal proliferation, fragmentation of the internal elastic lamina, and adjacent to disrupted segments of the elastic lamina, the media was infiltrated with lymphocytes, plasma cells, epithelioid cells, and multinucleated giant cells. Within 48 hours of treatment onset she was free of pain, and within 2 weeks her body weight and strength had returned to premorbid status. After 3 weeks the prednisone dosage was gradually tapered in decrements of 5 mg/day each month. Biological basis Etiology and pathogenesis The etiology is unknown. Temporal arteritis is a granulomatous vasculitis with preferential involvement of the aorta and its large primary branches, including the carotid and vertebral arteries that supply the brain and eyes (Ostberg 1973). In a populationbased study, it was found that patients with temporal arteritis were 17.3 times more likely to develop thoracic aortic aneurysm and 2.4 times more likely to develop abdominal aortic aneurysm than age- and sex-matched controls (Evans et al 1995). Lie found that of 72 cases of aortic and extracranial giant cell arteritis, 25% did not have the clinical manifestations of temporal arteritis. The ascending aorta and arch were most frequently involved (39%), followed by subclavian and axillary (26%) as well as femoropopliteal arteries (18%), paralleling the distribution found by Ostberg in his much earlier and smaller study (Ostberg 1973; Lie 1995). Further investigation of the variable distribution of giant cell arteritis in a cohort of patients in the Mayo Clinic series supports the concept that there is a fundamental biological difference between patients with cranial giant cell arteritis and those with similar histologic presentation primarily in the aortic arch and great vessels (Brack et al 1999). These authors compared 74 patients with subclavian and axillary giant cell arteritis, with 74 patients having cranial giant cell arteritis. The incidence of arteritis in the temporal artery biopsy was lower in the subclavian and axial group (negative biopsy in 42%) compared with the cranial arteritis group (100% positive biopsy). Subclavian and axial arteritis was biologically different from cranial arteritis cases in having higher concentrations of interleukin-2 gene transcripts in the artery tissue and over-representation of the HLA-DR beta 1*0404 allele. The cause and pathogenesis are unknown, but considerable attention has been focused on the immunologic characteristics of the cellular infiltrate, which is dominated by mononuclear cells and multinucleated giant cells (Lie 1990). Immunohistochemical studies have shown most of the lymphocytes in the infiltrate are of the CD4+ "helper" variety. Activation of T cells requires that the inciting antigen be presented to the lymphocyte by a specific autologous human leukocyte antigen molecule. The responsible antigen is unknown, but it has been thought likely to derive from some component of the internal elastic lamina of the involved arteries, as the granulomatous infiltrate is most intense adjacent to this part of the artery wall, and the lamina is usually fragmented and otherwise damaged where the inflammation is intense (Kimmelstiel et al 1952). Also, the relative frequency of inflammation in different portions of the arteries correlates positively with the amount of elastic tissue in the media and adventitia. Thus, although the carotid and vertebral arteries are often involved, the inflammation ceases at the point where these arteries penetrate the dura to become intracranial vessels, which is also the anatomic point at which the internal elastic lamina disappears from the vessel wall (Wilkinson and Russell 1972). Nordborg and Nordborg provided evidence that the inflammatory cells and other inflammatory markers, such as interleukin-2, are concentrated at the border between the arterial adventitia and the media using monoclonal antibody against inflammatory markers. They suggest that the cellular infiltrate enters the media from the adventitial vasa vasora and migrate to the internal elastic lamina and intima (Nordborg and Nordborg 1998). Weyand and colleagues studied allelic human leukocyte antigen polymorphisms important in determining immunoresponsiveness to exogenous antigens in the cellular infiltrate from temporal arteries of 42 patients with biopsy-proven temporal arteritis (Weyand et al 1992). The authors summarize their results as follows: "The giant cell arteritis patients shared a sequence motif spanning amino acid positions 28 to 31 of the HLA-DR beta 1 chain. In the structural model for HLA-DR molecules, this sequence motif can be mapped to the antigen-binding site of the HLA complex, suggesting a crucial role of antigen selection and presentation in giant cell arteritis."

9 It is interesting to note that although 60% of the temporal arteritis patients carried 1 of the closely related allelic variants at HLA-DR beta 1-*0401 and *0401/8, all of the patients who experienced ischemic optic neuropathy and visual loss carried the *0404 or *0401/8 allele, suggesting that these may be markers for increased disease severity. The same authors later found that the distribution of HLA-DR beta 1 alleles among patients with polymyalgia rheumatica resembles that of patients with temporal arteritis and that the profile of patients with rheumatoid arthritis is different at that locus. This finding means that the HLA-DR beta 1 allele profile does not distinguish which of the patients with polymyalgia are destined to develop concomitant temporal arteritis (Weyand et al 1994). Conversely, in a population of patients with polymyalgia rheumatica in a Mediterranean country, Salvarani and colleagues found no significant differences in the frequencies of HLA-DRB1 types and in the expression of HLA-DRB shared motif between polymyalgia rheumatica patients and controls (Salvarani et al 1999). Also, a series of 86 patients with polymyalgia rheumatica in Northwest Spain were found to be associated with HLA-DRB1*13/14 with only marginal increase in the frequency of HLA-DRB1*0401 and *0404 compared with controls. Sixty-two cases of biopsy-proven temporal arteritis from the same series demonstrated an association with HLA-DRB1*04 alleles, particularly *0401 and *0404 (Dababneh et al 1998). Thus, there may be population specific differences in HLA types in patients with both temporal arteritis and polymyalgia rheumatica. The specific predilection of temporal arteritis for the elderly prompted Martinez-Taboada and others to study agerelated changes in the T cell receptor repertoire in peripheral blood CD8+ T cells. They found a distinct Jbeta2.7+ CD8+ clonotype only among patients and suggested that age-related emergence of such clonotypes predisposes elderly patients to develop both polymyalgia and temporal arteritis (Martinez-Taboada et al 1996). In a striking departure from previous ideas, Petursdottir and colleagues suggested that, based on study of aortic tissue from 3 autopsy cases and 4 surgical specimens from patients with temporal arteritis, the primary event in giant cell arteritis is loss of smooth muscle cells. They used alpha-smooth muscle actin immunoreactivity to identify smooth muscle cells in the media of these specimens. There was subtotal loss of smooth muscle in regions most remote from inflammation, but these areas gave way to zones with total loss of muscle cells next to calcified, acellular areas that were surrounded by variable granulomatous inflammation (Petursdottir et al 1996). There has been speculation about the role a virus might play in the pathogenesis of giant cell arteritis, but there has been little proof until more recently. In a multicenter study Duhaut and colleagues investigated 305 new cases of temporal arteritis, of which 159 were biopsy proven and 76 cases of polymyalgia rheumatica, using serologic tests for IgG and IgM, directed against a number of viruses. There was a strong predominance of antibodies against parainfluenza type 1 virus in patients versus controls, the difference being larger in the biopsy positive cases (43% of patients vs. 20.9% of controls; odds ratio with controls 2.89; p ). There was no significant difference between patients and controls in the incidence of antibodies against the other viruses screened. The authors concluded that parainfluenza virus type 1 is associated with the onset of giant cell arteritis in a subset of patients (Duhaut et al 1999a). On the other hand, Gabriel, studying temporal artery biopsy tissue from 30 patients with temporal arteritis, found parvovirus B19 DNA more likely to be present in the temporal arteries of patients with temporal arteritis (29 out of 30) than in the temporal arteries of control subjects (Gabriel et al 1999). Angiotensin I receptors were found to be increased in the vascular smooth muscle within the media of temporal arteries from patients with temporal arteritis as compared with control arteries (Dimitrijevic et al 2009). The authors suggest that treatment of temporal arteritis with angiotensin receptor blockers might be an alternative or adjunct to corticosteroids in this condition. Studies indicate that 2 distinct pathogenetic mechanisms can be distinguished in temporal arteritis (Weyand and Goronzy 2003; Deng et al 2010). One, mediated by Th17 T-cells that produce interleukin 17, serves systemic inflammation with manifestations such as fever, malaise, anorexia, and headache and is corticosteroid responsive. The other, mediated by Th1 T-cells that produce interferon-gamma, mediates vascular wall inflammation and is corticosteroid resistant. It is suggested that new therapeutic approaches to the steroid-resistant inflammatory process in the large vessels, possibly involving manipulation of specific inflammatory cytokines and other inflammatory mediators, is needed. A new thread in the etiology-pathogenesis concept of temporal arteritis is the role of varicella zoster virus. This was the subject of an extensive study by Gilden and coworkers (Gilden et al 2015a). They found varicella zoster virus antigen in 61 of 82 (74%) of temporal arteritis pathologically-positive temporal artery specimens and in only 1 of 13

10 (8%) normal arteries. Earlier work had showed varicella zoster virus antigen and DNA in localized patches of the arteries that were called skip areas in pathologically-negative temporal artery specimens and reexamination of the virus-positive segments demonstrated typical pathologic findings of temporal arteritis (Nagel et al 2013), and this larger study also found the virus in isolated patches or skip areas. Gilden and colleagues provided a compelling clinical perspective to this work by describing a woman in her 70s with clinical features of both temporal arteritis and Takayasu aortitis with normal erythrocyte sedimentation rate, marginally elevated C-reactive protein, and initially negative temporal artery biopsy (Gilden et al 2015b). Her symptoms progressed despite treatment with high-dose (60 mg/day initially) prednisone. After steady clinical decline for 16 months, the original temporal artery specimen was found to be positive for varicella zoster virus and she was treated with intravenous acyclovir for 2 weeks followed by oral acyclovir and underwent a dramatic and lasting remission of all symptoms and signs of disease. Epidemiology" Analysis of epidemiologic studies in temporal arteritis is hindered by the variability of diagnostic criteria and differences in population bases in the various studies. In general the incidence is relatively high in northern regions including the United States, Scandinavia, and European countries, whereas a much lower incidence is reported in southern European countries. Genetic factors are probably important in view of the predilection of temporal arteritis to occur in Caucasians and the association with the HLA-DR4 genotype, at least in some studies. Baldursson and colleagues reported a total population-based study of the epidemiology of temporal arteritis in Iceland between 1984 and 1990 (Baldursson et al 1994). During the study interval the authors identified 133 confirmed cases of new temporal arteritis in Iceland; 94 were women and 39 men, giving a female-to-male ratio of 2.4. The age- and sex-adjusted incidence of temporal arteritis was calculated to be 27 in 100,000 per year overall, 36 in 100,000 per year for women, and 18 in 100,000 per year for men. As expected, the age incidence increased into the eighth decade of life. The mean age at diagnosis was 71.9 years (range 50 to 97), with no significant difference between men and women. Only 19 patients (14.3%) had visual symptoms, of which only 1 developed permanent blindness of 1 eye, but there was information on visual symptoms in only 63.9% of the cases. Also, this was not a longitudinal study of the cohort at risk for visual loss, so this information probably cannot be taken as representative of the disease. Machado and others at the Mayo Clinic published data indicating a rising incidence of temporal arteritis during the interval from 1950 to 1985 (Machado et al 1988). The overall incidence in Minnesota during that interval was lower than the Icelandic figures cited above, 17 in 100,000 per year, with age-adjusted rates 3 times higher for women (23.4 in 100,000 per year) than for men (7.4 in 100,000 per year). This is despite the similar ethnic mix in Iceland and Olmsted County, Minnesota, suggesting a role for environmental and other factors. The trend toward rising incidence over the interval was true only for women (35.4 in 100,000 per year in 1980 to 1985); the incidence for men dropped significantly (6.5 in 100,000 per year in 1980 to 1985), having reached a peak in the mid-1970s (15.4 in 100,000 per year in 1970 to 1974). The authors believe that this rise in incidence may be partly explained by changes in disease awareness among physicians and by other extraneous factors, but that a biological change is likely occurring as well. They point out the interesting fact that the preponderance of women increases in the older age groups, unlike other rheumatic and inflammatory diseases, where the predilection for women decreases with advancing age. Petersdottir and colleagues also found that the annual incidence increased significantly with time (P<0.001) for both men and women in a study of biopsy proven temporal arteritis between 1976 and 1995 in Goteborg, Sweden (Petursdottir et al 1999). In that study the average incidence was 22.2/ inhabitants over 50 years of age (women 29.8, men 12.5). Significant annual fluctuation was also found, with peak incidence in late winter and autumn. These seasonal fluctuations and the rising incidence suggested to the authors that an extrinsic triggering factor, such as infection may be involved. Gonzalez-Gay and colleagues found a rising annual incidence of biopsy-positive temporal arteritis in northwestern Spain between 1981 and 2005 but did not find peaks or valleys in the annual incidence or any seasonal variation in incidence (Gonzalez-Gay et al 2007). On the other hand, in Israel, Bas-Lando and colleagues found fluctuation in the annual incidence from 1980 to 2004 with 3 distinct peaks 8 to 10 years apart evidence of a possible infectious etiology, the authors suggest (Bas-Lando et al 2007). The highest incidence figures come from South Norway where 322 patients with either temporal arteritis or polymyalgia rheumatica were identified between 1987 and Two hundred fifty-six patients had polymyalgia