Diagnosis and Management of Giant Cell Arteritis

Special Report


Stephen A. Paget, MD, FACP, FACR

Stephen A. Paget, MD, FACP, FACR

Physician-in-Chief Emeritus, Hospital for Special Surgery

New research has spurred some controversy in the diagnosis and management of giant cell arteritis (GCA), also known as temporal arteritis (TA), particularly whether ultrasound is valuable in diagnosis and whether steroid-sparing agents are worth using. These are important issues because of the considerable risks of blindness if GCA is not diagnosed and treated effectively and in a timely manner.

GCA frequently occurs in concert with polymyalgia rheumatica (PMR). Half of those with GCA also have the proximal, symmetrical achiness, stiffness and soreness of PMR, and 5 to 10% of those with pure PMR develop TA within a year after the onset of the first disease. In the U.S., the average annual incidence of PMR is 52.5 per 100,000 patients age 50 and older, and the prevalence is about 0.5 to 0.7%.; the incidence and prevalence of GCA is about one-third that of PMR. These disorders occur primarily in patients over age 50, with risk increasing with age and with twice as many women affected than men.

Diagnostic Features

Because of the diversity of symptoms, GCA patients may go to multiple physicians - including but not limited to internists, ophthalmologists, neurologists, otorhinolaryngologists, dentists, and rheumatologists - before a diagnosis is made. The diagnosis is often missed, which presents grave risk of irreversible blindness.

Aside from the characteristic musculoskeletal hallmark of PMR, the two disorders may share such constitutional symptoms and signs as fatigue, fever, and weight loss. Depending on the area of arterial involvement, other signs and symptoms of GCA may include:

  • headache and scalp pain, occurring in 50-75% of patients - often described as severe, constant, unresponsive to simple analgesics, and continuing throughout the night;
  • jaw and/or tongue pain, especially while chewing or talking , occurring in 50%;
  • pain in the ear, pinna, parotid gland pain;
  • development of a tortuous, prominent, nodular, or tender temporal artery, although it is not invariable;
  • decreased vision, with the possibility that the second eye will become involved within a week or two if the first eye remains untreated; observation may find diplopia, ptosis, amaurosis fugax, partial field defects, anterior ischemic optic neuropathy and, infrequently, exudates, hemorrhages and frank vasculitis; and
  • arm or leg claudication and, uncommonly, stroke, subclavian steal syndrome, intestinal infarction, and aortic aneurysm.

Diagnosis should be based on clinical findings. Implementation of corticosteroid therapy should not be delayed while awaiting supporting (but not necessarily diagnostic) evidence from laboratory tests and temporal artery biopsy.

Laboratory testing may reveal elevated erythrocyte sedimentation rate (ESR), elevated C reactive protein (CRP), elevated alkaline phosphatase in one third of patients and, in 50% of patients, normocytic, normochromic anemia and thrombocytosis.

Temporal artery biopsy is an important diagnostic test but may be unrevealing because of the skipped nature of the inflammatory lesions. Thus, as many as 30% of biopsies may be negative in the presence of active, vision-threatening vasculitis. In contrast, although biopsy should be performed on the symptomatic side of the head, incorporating multiple sections of 2-3 cm of vessel, preferably including areas with inflammation, tenderness, or nodularity, positive biopsy may be found in vessels that appear normal. Further, positive biopsies may be found for up to three weeks after the initiation of steroid therapy.

The difficulty of diagnosis and biopsy has led to a search for further diagnostic tools, most recently focusing on color duplex ultrasonography as a non-invasive tool. Schmidt, et al, found a hypoechoic halo, representing edema in the arterial wall, around the superficial temporal artery in 73% of patients with biopsy-proven GCA.[1] The halo had a sensitivity of 73% and was 100% specific for GCA. However, more recently, Salvarani, et al, found that a hypoechoic halo around the lumen of the temporal arteries had a sensitivity of only 40% and a specificity of 79% for biopsy-proven GCA.[2] Thus, while temporal artery biopsy remains the gold standard in diagnosis, ultrasound can be helpful in supporting a clinical diagnosis before biopsy results return and in the 30-40% of GCA patients in whom the biopsy is negative.

Management

As soon as the clinical diagnosis is made, patients should immediately be started on corticosteroids. Fortunately, GCA is highly responsive to corticosteroids. Indeed, the dramatic improvement within one to three days of initiating steroid therapy helps confirm the diagnosis. If significant benefit is not seen within five to seven days, an alternative diagnosis should be considered - or a companion GCA may be present in PMR patients, requiring a higher steroid dose because the inflammatory setpoint of the two disorders is different. GCA usually requires 60mg prednisone daily in divided doses - or even higher doses if organ or tissue damage is threatened or already present. If visual symptoms are revealed as a fixed loss or amaurosis fugax, high-dose intravenous Solu-Medrol should be given, with doses ranging from 50 mg every eight hours to one gram per day for three days; high-dose oral steroids in divided doses should follow.

The steroid dose is maintained for two to three weeks, during which laboratory values normalize. Subsequent steroid taper of 5-10 mg every 7-10 days should be guided by the clinical response. It is never wise to "chase the ESR" because patients may be subjected inappropriately to a dangerously high cumulative dose of steroids. (An alternative cause, such as infection, should be considered in the presence of a persistently elevated ESR, e.g. over 50 mm/hour, in the absence of GCA or PMR symptoms.) Subsequent flares rarely require such high doses and may only require increases of 5-10 mg prednisone.

Steroid-treated GCA is a self-limiting illness lasting for one to two years in most patients. However, a subgroup of patients with both PMR and GCA can have active inflammatory disease for 7-10 years. Thoracic aneurysms with giant cells in the tissue can develop as long as 15 years after the initial diagnosis, successful treatment, and discontinuation of steroids. One study showed that survival was decreased in patients with GCA who had permanent visual loss and who required more than 10 mg of prednisone per day at six months.

This finding - plus the constant desire of physicians to find new ways to spare steroids, and because the high doses of steroids used for GCA are more apt to cause associated morbidity in this older age group, rheumatologists are looking for the potential of other agents to help reduce the dose and control the inflammation.

The general principle has been to use the lowest possible dose to control the disorder in the beginning and then taper off and get out as quickly as possible. Several studies have evaluated the potential of using methotrexate to facilitate the taper and discontinuation as steroids. Randomized, controlled studies have reached opposite conclusions on whether methotrexate is effective in sparing steroids and controlling the inflammation.

The most recent study, by Hoffman, et al, was a multi-center study with a tremendous flaw: it used alternate-day steroids, which are known not to control GCA.[3] The study by Spiera, et al, could be faulted because of underpowering and, in some patients, steroid tapers that were too rapid.[4] However, the most methodologically sound study - by Jover, et al, in Spain - was the only one with positive results and merits our attention.[5] Among their 42 patients, methotrexate was maintained for 24 months; relapses were seen in 45% of those on MTX , compared to 84.2% of those on placebo.

Currently, the compromise is to get out as fast as is safely possible once the disease is under control, i.e. within six months to a year. If people either have too much toxicity from the steroid or a maximal steroid dose does not adequately control the disorder, weekly doses of methotrexate (7.5-20mg/wk) or azathioprine (2 mg/kg/day) are often employed. Thus the front-loading with the steroids can control the disease and prevent blindness, but adding or switching to an alternative drug can help reduce the severe side effects of long-term high steroids.

The Future

Clearly, other new medications will be tried. The pathobiology of GCA tells us that it is an inflammatory disease in which cytokine profiles in biopsy specimens contain the T lymphocyte products interferon-gamma (INF-gamma) and interleukin 2 (IL-2) and the macrophage products IL-1beta, IL-6, and transforming growth factor beta. These findings all lead us to believe that MTX, azathioprine , one of the TNF inhibitors, or other more specific blocking agents as they come along, may be useful. Indeed, a study looking at etanercept (Enbrel) and infliximab (Remicade) for this disorder is underway.

Until we develop a much more focused therapy, such as a biologic agent chosen specifically for this disease, as opposed to a shotgun like steroids, my recommendation is that when you can't get out after a year of steroids, or you know the disease is very active and will require a lot more steroid for far too long - which can only be discerned from the personality of the disorder as you follow it - it may be time to add another agent that can help you taper off the steroid.

[1] Schmidt WA, Kraft HE, Vorpahl K, Volker L, Gromnica-Ihle EJ. Color duplex ultrasonography in the diagnosis of temporal arteritis. N Engl J Med. 1997 Nov 6;337(19):1336-42.

[2] Salvarani C, Silingardi M, Ghirarduzzi A, Lo Scocco G, Macchioni P, Bajocchi G, Vinceti M, Cantini F, Iori I, Boiardi L. Is duplex ultrasonography useful for the diagnosis of giant-cell arteritis? Ann Intern Med. 2002 Aug 20;137(4):232-8.

[3] Jover JA, Hernandex-Garcia C, Morado IC, Vargas E, Banares A, Fernandex-Gutierrez B. Combined treatment of giant-cell arteritiz with methotrexate and prednisone: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001 Jan 16;134(2):106-14.

[4] Spiera R, Mitnick HJ, Kupersmith M, Richmond M, Spiera H, Peterson MG, Paget SA. A prospective, double-blind, randomized, placebo controlled trial of methotrexate in the treatment of giant cell arteritis (GCA). Clin Exp Rheumatol. 2001 Sep-Oct;19(5):495-501.

[5] Hoffman GS, Cid MC, Hellmann DB, Guillevin L, Stone JH, Schousboe J, Cohen P, Calabrese LH, Dickler H, Merkel PA, Fortin P, Flynn JA, Locker GA, Easley KA, Schned E, Hunder GG, Sneller MC, Tuggle C, Swanson H, Hernandez-Rodriguez J, Lopez-Soto A, Bork D, Hoffman DB, Kalunian K, Klashman D, Wilke WS, Scheetz RJ, Mandell BF, Fessler BJ, Kosmorsky G, Prayson R, Luqmani RA, Nuki G, McRorie E, Sherrer Y, Baca S, Walsh B, Ferland D, Soubrier M, Choi HK, Gross W, Segal AM, Ludivico C, Puechal X. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum. 2002 May;46(5):1309-18.

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