Clinical background

Giant cell arteritis (GCA) is a serious and relatively common systemic vasculitis that occurs in adults older than 50 years. The key symptoms and signs of GCA include both systemic and neuro-ophthalmic manifestations ( Table 40.1 ). Systemic manifestations may involve a long prodromal period of multiple symptoms including weight loss, fatigue, fever, and malaise. Generalized muscle pain, claudication of the jaw or tongue, or localized scalp or temporal pain, swelling, and tenderness are also commonly observed in this disease. Ischemic manifestations from vascular compromise include blindness, stroke, aortitis with aneurysm, myocardial ischemia, and bowel infarction. Neuro-ophthalmic manifestations include arteritic anterior ischemic optic neuropathy, posterior optic neuropathy, choroidal ischemia, diplopia, retinal arterial occlusions, and ocular ischemic syndromes, occuring in up to 70% of patients. It is estimated that 15–20% of patients with GCA suffer permanent and potentially bilateral visual loss from ischemic infarction of the optic nerve.

Although the original descriptions of GCA are attributed to Hutchinison in 1890, initial references to this disease were first noted in ancient Egypt. The hallmark granulomatous inflammation with giant cells was described in 1932 by Horton. Use of the terms temporal or cranial arteritis is commonly found in the literature but may preclude the understanding that GCA is a systemic, not localized, disease.

Epidemiology of GCA depends on geography; it is a rare disease in Japan, and the incidence in Europe increases in association with higher latitudes. Recent literature suggests that prior reports of a lower prevalence among Hispanic and Black individuals was underestimated, perhaps because of ascertainment bias. In western countries the frequency is commonly defined at about 20 per 100 000 individuals older than age 50. However, for reasons that remain obscure, this increases over time, reaching a peak at between 70 and 80 years of age and women are twice as likely to be affected as compared to men. The cyclical increase in incidence of GCA every 7 years in the large epidemiologic Minnesota study, as well as other associations between onset of GCA and epidemics of specific bacterial or viral infections, suggests an environmental or infectious impact on disease prevalence. Genetically there is an association between GCA and HLA-DRB1*04. Other associations have been reported between genetic polymorphisms in multiple genes and susceptibility to GCA or its complications. These genes include matrix metalloproteinase 9 (MMP 9), platelet glycoprotein receptor IIIA, interferon-γ (IFN-γ), and the interleukin (IL)-10 and IL-6 promoters.

Diagnostic evaluation of patients with suspected GCA is challenging as there are no specific laboratory examinations. On physical examination, a palpable, tender, enlarged temporal artery may be identified and the abnormal portion should be biopsied for histopathologic analysis ( Figure 40.1 ). Histology, when positive, can be diagnostic but the characteristic giant cells identified at the junction of the intima and media are only observed in about half of the cases; the remaining positive biopsy specimens demonstrate a nonspecific mixed inflammatory response and may show disruption of the internal elastic lamina ( Figure 40.2 ). One potential challenge is that the lesions are not continuous and may only involve a portion of the artery, therefore a long segment of artery (greater than 15 mm) must be carefully evaluated in its entirety, and sometimes multiple biopsies increase the diagnostic yield.

External appearance of involved artery. The photo demonstrates the characteristic irregularly enlarged and ropey appearance of a giant cell arteritis-involved artery. This would typically be tender to the touch and the pulse may be decreased or absent.

Histologic section of involved artery. In this example the lumen of the artery is nearly occluded and there is evidence for inflammatory infiltrate and giant cells.

Some patients with suspected GCA do not have a positive biopsy and then the diagnosis is based on the clinical history, physical examination, and nonspecific laboratory diagnostic indicators of inflammation. Laboratory findings include elevations in the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and platelet counts. Although these are not specific for GCA, the sensitivity of an elevated ESR and CRP in a patient suspected of having GCA is greater than 99%, and the positive likelihood value of thrombocytosis alone is high in patients with other signs and symptoms referable to GCA. However, it is also important to note that a normal ESR does not exclude GCA as a diagnosis and may occur in more than 15% of affected individuals. Recent improvements in imaging techniques have been applied to the diagnosis of GCA with varying results. Color duplex ultrasonography, high-resolution magnetic resonance imaging, and positron emission tomography imaging have all been reported as helpful in the diagnosis, yet the accuracy remains controversial and thus these are not routinely performed for GCA diagnosis.

The differential diagnosis of GCA is dependent on the presenting symptoms and signs. If one considers only the ophthalmologic presentations, then there are three main categories of subjective complaints: (1) transient visual disturbance; (2) double vision; and (3) loss of all or part of the vision in one or both eyes. The differential diagnosis for transient visual obscurations lasting several minutes includes emboli; or that lasting seconds includes swelling of the optic disc. New-onset double vision in the elderly is a common occurrence in association with medical ischemic etiologies of cranial mononeuropathies, such as hypertension or diabetes. However GCA is a potential diagnosis even in the presence of these common systemic diseases and must be carefully considered in each individual patient. Permanent vision loss from GCA is most frequently associated with an arteritic form of anterior ischemic optic neuropathy (AAION) characterized by swelling of the optic disc; however, it may also be secondary to posterior ischemia of the retrobulbar optic nerve or from central retinal or cilioretinal artery occlusions ( Figure 40.3 ). AAION must be differentiated from nonarteritic anterior ischemic optic neuropthy (NAION) through clinical evaluation and suspicion, an accompanying cilioretinal artery occlusion which is diagnostic of a vasculitic etiology, or through fluorescein angiography which, in the case of AAION, may demonstrate a marked delay in disc or choroidal perfusion. Formal visual field testing and analysis should be performed on any patient with suspected GCA but the defects observed may vary widely depending on the involvement of the optic nerve. Progressive loss of visual field is ominous and may be observed as evidence for worsening clinical status ( Figure 40.4 ).

Optic disc appearance in anterior ischemic optic neuropathy (AION). (A) The optic disc is pale, swollen, and accompanied by a small vascular occlusion to the right of the disc. This is a typical appearance of an arteritic form of AION. (B) The optic disc exhibits a segmental swelling of the inferior half with peripapillary hemorrhages, typical, although not diagnostic, of the nonarteritic form of AION.

Progressive visual field changes in untreated giant cell arteritis. The figure shows the gray scale of the visual field for the right and left eyes of a patient with giant cell arteritis. On the day of presentation (day 1) the patient complained of decreased vision in both eyes and there is an altitudinal-style loss of the inferior half of the visual field in each eye. The underlying diagnosis of GCA was not made and within 2 weeks the patient lost the remaining vision in the right eye (day 13). Prompt high-dose steroid treatment was initiated and the remaining vision was spared.

Glucocorticoids remain the primary treatment for GCA; however, the high doses and long duration that are required for effective control of disease are also associated with significant morbidity ( Box 40.1 ). In particular, the risk of bone fractures is significant and prophylactic therapy to decrease osteoporosis should be used concomitantly with the steroid treatment. Differing opinions about the optimum initial steroid dose or route of administration remain, although there is some evidence in support for high-dose intravenous induction therapy in producing sustained remissions and decreasing the total steroid requirement. Steroid-sparing agents have been attempted and clinical trials report varying conclusions regarding the utility of methotrexate, although a recent meta-analysis of the published trials supports an adjunctive role for methotrexate in GCA therapy in conjunction with steroids. Recent interest in use of biologic agents in the treatment of immune-mediated disease prompted trials of agents that target tumor necrosis factor-α (TNF-α). There have been discordant results from the clinical trials with TNF-α blockade and there have been two case reports of individuals who developed GCA while on one of the TNF-α blockers, supporting controversies in the utility of this therapy for control of GCA. A monoclonal antibody that targets the B-cell-associated CD20 was used in two patients to deplete B lymphocytes; respiratory complications were observed in one individual. In addition to steroid therapy, the use of aspirin has been suggested as adjunctive therapy. Retrospective studies demonstrate that low-dose aspirin may reduce risks of ischemic complications of GCA. Prospective controlled clinical trials will be required to assess the utility of aspirin in GCA.

Therapy is generally effective in reducing systemic symptoms of GCA such as fatigue, fever, headache, and jaw claudication and this therapeutic response is typically dramatic, occurring within hours to days of starting steroids. However, it is unusual for visual functions to recover following the onset of therapy; thus permanent vision loss remains a major complication of disease. In addition, progressive loss of vision may occur despite onset of steroid therapy, but will generally present within the first week. If untreated or treated with insufficient immunosuppressive therapy, then the risk for loss of vision in the fellow eye within 2 weeks following AAION in the first eye is significant. Long-term complications of GCA include thoracic aortic aneurysms and ischemia.

Pathology

The pathological hallmark of GCA is a granulomatous inflammatory infiltrate involving all layers of the vessel wall, in particular in the intima or media with concomitant damage or destruction of the inner elastic lamina ( Box 40.2 ). The presence of giant cells is not required in order to make the diagnosis. Skip lesions, areas without apparent evidence for inflammation, can occur in 8.5–28.3% of involved specimens. Typically the inflammatory infiltrate consists of a mixture of lymphocytes, predominantly CD4+ T cells, mononuclear cells, and occasional neutrophils and eosinophils. Some pathologic findings are preserved in biopsies of individuals who have already been on prolonged steroid therapy and may be best detected using special immunohistochemical or histologic stains. Following steroid therapy, findings common to involved arteries include loss of the internal elastic lamina and infiltration of lymphocytes, mononuclear cells, and epithelioid histiocytes in a band at the junction of the outer layer of muscle and adventitia.

Etiology

The etiology of GCA is unknown but the pathophysiology of disease is mediated by an immune mechanism. What agents could initiate or modify the disease process? Several pathogens have been implicated as potential initiating agents either because of a temporal association between onset of GCA and known epidemics or because of the presence of genetic fingerprints of microbial agents in association with lesions. Epidemiologic studies of large populations demonstrate a temporal correlation between the onset of GCA and various acute systemic microbial diseases, including Mycoplasma pneumoniae, parvovirus B19, and Chlamydia pneumoniae, suggesting a direct or indirect effect of infection on the clinical manifestation of GCA. A number of candidate microorganisms have been entertained as specific inducing agents in GCA lesions. Genetic analysis of affected arteries yielded conflicting evidence for parvovirus DNA, herpesvirus zoster DNA, C. pneumoniae DNA, and yet unidentified sequences of microbial origin. The significance of the relationship of these or other microorganisms to GCA pathogenesis requires additional future investigation.