Annals of Neurosciences, Vol 13, No 2 (2006)
Annals of Neurosciences, Volume 13, Issue 2 (April), 2006
GIANT CELL ARTERITIS – AN UPDATE
Corresponding author
Dr. Mrinal Kanti Roy
31/17/1G, KB Sarani, Dum Dum, Kolkata-700080,
Ph No. 033–25593713, Mob No. 9433433021
Abstract
Giant cell arteritis, a disease almost exclusively confined to elderly population, though not very common in our country, is gaining much importance in clinical practice due to awareness of this entity amongst the treating physicians and advancement in pathogenesis especially inrelation to molecular biology, histopathology and immunology. To a treating neurologist the condition may present with various types of newurological problems including a catastrophic event, like sudden blindness. The treatment strategy has been undergoing changes in recent yeats and obviously the experience, which will be gathered in course of time, if translated in right perspective will go a long way to benefit the sufferes.
Key words: Giant cell arteritis, Blindness, Polymyalgia rheumatica.
Introduction
At the present state of our knowledge, the classification of vasculitic syndrome, as a group of heterogeneous disorders, is truly difficult because of various clinico pathological manifestations and involvement of different types of vessels at different locations by the disease process. However, with the recent knowledge about immune mediated mechanisms in many diseases and availability of pathogenic models, we can now classify these disorders in relation to the size of the vessels involved and their histopathological findings. The central nervous system is unique in the sense that, it responds to various insults in many ways, sometimes leading to serious event within a short span of time. Out of various vasculitic syndromes, giant cell arteritis has got a special importance in the neurological practice because of the involvement of extra cranial vessels and rarely intracranial ones with far reaching effects. A number of important clinical manifestations like headache, sudden visual loss and myalgia etc can mimic other neurologic disorders, which are in fact the manifestations of giant cell arteritis. Keeping this in mind, we would like to discuss the recent development of giant cell arteritis with special reference to its pathogenesis, clinical implication and treatment in this review.
Giant cell arteritis is a chronic vasculitis of large and medium sized vessels. Although it may be wide spread, symptomatic vessel inflammation usually involves the cranial branches of arteries originating from aortic arch. The first clinical description of giant cell arteritis was presented by Hutchinson in 1890 (1). However it was not reported again until the 1930, when Horton and colleagues described the histological appearance of granulomatous arteritis of temporal vessels (2). In 1950, Paulley and Hughes first recognized the association between giant cell arteritis with polymyalgia rheumatica (3).
Epidemiology
Before autopsy study became available, giant cell arteritis was thought to be less frequent, like in Olmsted country, Minnesota, the average annual incidence was 17.8 cases per 1,00,000 persons 50 years of age or older (4), but autopsy studies suggest that giant cell arteritis may be more common than is clinically apparent. Data regarding exact incidence and prevalence of this disorder in our Country is scarce, due to less occurrence of this entity in comparison to other types of vasculitis. Women are affected twice as often as men. The incidence of giant cell arteritis increases after the age of 50 years and peaks between 70 and 80years. Population surveys show higher frequencies of giant cell arteritis at higher latitude (5, 6). Now-a-days the incidence of giant cell arteritis appears to have increased worldwide. In addition there is evidence of periodic clustering of cases of giant cell arteritis (4). Thoracic aortic aneurysm and dissection of aorta are important late complications and those are the main cause of mortality in this disease (7).
Diagnostic Criteria
Criteria for the classification of giant cell arteritis were formulated by American College of Rheumatology in 1990 (8). These criteria were designed for use in investigative studies to help distinguish giant cell arteritis from other type of vasculitis; they are not useful for making the diagnosis in individual patients.
| CRITERION | DEFINITION |
|---|---|
| Age at onset of disease > 50yrs. | Development of symptoms or finding beginning at the age of 50 yrs. or older. |
| New Headache | New onset or new type of localized pain in the head. |
| Temporal artery abnormality | Tenderness of temporal artery to palpation or decreased pulsation, unrelated to atherosclerosis of cervical arteries. |
| Elevated erythrocyte sedimentation rate | Erythrocyte sedimentation rate >50mm per hour according to Westergren method. |
| Abnormal finding on biopsy of temporal artery. | Artery biopsy specimen shows vasculitis characterized by a predominance of mononuclear cell infiltrates or granulomatous inflammation, usually with multinucleated giant cells. |
For the purpose of classification, a patient with vasculitis is said to have giant cell (Temporal) arteritis if at least three of these five criteria are met. These yield a sensitively of 93.5% and a specificity of 91.2%.
Pathogenesis
Giant cell arteritis is probably a polygenic disease in which multiple environmental and genetic factors influence susceptibility and severity. The increased incidence at higher latitudes and in Scandinavian countries support the evidence of environmental and genetic causes (4–6).
Viral cause has been suspected in giant cell arteritis. An increased prevalence of antibodies against Para influenza virus type 1 was reported in giant cell arteritis (9).A close temporal relation between the observed incidence peaks of giant cell arteritis and epidemics of Mycoplasma pneumoniae, parvovirus B19 and chlamydia pneumoniae infection has been found (10) A significant association between histologic evidence of giant cell arteritis and the presence of parvovirus B19 DNA in temporal artery specimen has been reported (11). The most commonly studied genetic association is with the genes of the HLA complex. As in the case of rheumatoid arthritis, HLA-DRB1*04 and DRB1*01 alleles are associated with susceptibility to giant cell arteritis. These alleles may influence the severity of disease (12). A model for the pathogenesis of giant cell arteritis has been proposed by Weyand and Goronzy (13).
Progress in the understanding giant cell arthritis has been derived from three key observations. First it is now clear that giant cell arteritis is a T-cell dependent disease. The CD4+T-cells that orchestrate the injury of tissues are a sine-qua-non in the vasculitic process. Second, T-cell activation in the non lymphoid environment of the arterial wall requires the activation of specialized antigen presenting cells, the dendritic cells. Third, the blood vessel determines the site specificity of giant cell arteritis. Resident cells of arterial wall respond uniquely to the immune injury mediated by tissue infiltrating cells.
The end result is an occlusive vasculopathy caused by the rapid proliferation of the intima or formation of an aortic aneurysm caused by destruction of arterial wall.
T-Cell Dependent Vasculitic Inflammation
The CD4 +T-cell is the critical cellular player in the vasculitic lesion. The antigen of different types (viral, toxins, drugs, Auto antigens) first recognized by dendritic cells located in the adventitia in healthy medium sized arteries. Dendritic cells are normally immature and have a role in maintaining T-cell unresponsiveness and thus preventing the activation of T-cells. But in giant cell arteritis, adventitial dendritic cells after interacting with antigen become mature and activated. They produce inflammatory cytokines interleukin-6, interleukin-18 and express CD83, CD86, a co receptor required for successful interaction between T-cells and dendritic cells. These mature dendritic cells have lost the ability to tolerate T-cells; instead they have acquired the ability to initiate and maintain T-cell activation.
Tissue resident T-cells induce and maintain inflammatory infiltrates by releasing interferon g. Though interferon g producing T-cells are located in the adventitia, the cellular infiltrates in the media help to form granuloma a unique spatial relation of activated T-cells and macrophage. Formation of granuloma is strictly dependent on T-cells and deficiency of interferon γ prevents formation of granulomas.
Granulomatous reaction induced by T-cells causes extensive damage of arterial wall. One should remember that tissue necrosis, by release of lytic enzymes, which is characteristic of Wegner's granulomatosis or Churg Straus vasculitis, is not a feature of giant cell arteritis. Here lipid peroxidation mediated by reactive oxygen intermediates is an important pathway of arterial wall damage (13). The chief target of the oxidative attack is medial smooth muscle cell, probably because only macrophages in the media produce reactive oxygen intermediates. Oxygen derived free radicals and their metabolites injure tissue through several mechanisms; the most important is oxidation of membrane lipids, resulting in structural disintegration and cell death.
Following immune mediated injury of arterial wall, intimal cells become hyperplastic to heal and repair of inflammatory injury and by doing so, rapid concentric hyperplasia of the intima cause luminal stenosis and resulting ischaemia of supplied organ, which is the most feared complication of giant cell arteritis. Intimal hyperplasia is achieved by mobilization and migration of myofibroblast and deposition of extracellular matrix. Platelet derived growth factor produced by smooth muscle cells and macrophages in the media-intima junction play central role for myofibroblast activation and matrix production. Simultaneously vascular endothelial growth factor released from macrophages and multinucleated giant cell causes angiogenesis or neocapillary formation in the media and hyperplastic intima. Thus a coordinated action of the arterial wall and the invading immune cells, causing inflammation, started in the adventitia with extensive tissue damage and granuloma formation in the media and ultimate hyperproliferation of intima leads to the pathogenic hallmark of giant cell arteritis.
Pathologic Findings
The diagnosis of giant cell arteritis is established by biopsy, usually of temporal artery. If the temporal artery is clearly abnormal on physical examination, only a small segment needs to be removed for histopathological review. When extra cranial arteries are normal on palpation and giant cell arteritis is suspected, it is important to obtain a biopsy of longer segment of temporal artery (3–5cms), and consider performing a contra lateral biopsy if the result of first one is normal. When possible, temporal artery biopsy should be performed before treatment is initiated; however examination of temporal artery biopsy specimen may reveal evidence of arteritis after more than two weeks of corticosteroid therapy.
The pathologic findings of temporal artery biopsy are those of a panarteritis with mononuclear infiltrates penetrating all layers of the arterial wall. Typically activated T-cells and macrophages are arranged in granulomas. Multinucleated giant cells, when present are usually close to the fragmented internal elastic lamina. Often the intimal layer is hyperplastic leading to concentric occlusion of the macro lumen.
Clinical Manifestations
Onset of giant cell arteries is usually gradual, but it can be abrupt. Systemic symptoms like fever is present in about half of the patients. Fever is usually low-grade, but can reach 39–40°C in about 15% of patients and may be the presenting clinical manifestation (14).
Headache is probably most frequent symptom and occurs in two third of patients (15). The pain is frequently marked and usually located over the temporal and occipital areas, but may be less well defined. Scalp tenderness is usually confined to the temporal region and seen most often in those with headache.
Nearly half of the patients suffer from jaw claudication. Occasionally intermittent claudication may occur in the muscles of tongue or those involved in swallowing.
On physical examination, the frontal and parietal branches of the superficial temporal artery may be thickened, nodular, tender or occasionally erythematous. Pulses may be decreased or absent. The occipital arteries and less often post auricular or facial arteries may be enlarged or tender.
Neurological manifestation-Permanent partial or complete loss of vision in one or both eyes occur in up to 20% of patients and is often an early manifestation of the disease (16, 17). Affected patients may typically report partially obscured vision (a shade covering one eye), which may progress to total blindness. If untreated, the other eye is likely to become affected within one or two weeks. Once established visual impairment is usually permanent. Amaurosis fugax is an important visual symptom that precedes permanent visual loss in 44% of patients (17). Diplopia or visual hallucinations occur less frequently. Visual loss is caused by ischaemia of the optic nerve or tract as a result of arteritis or branches of the ophthalmic or posterior ciliary artery and less commonly retinal arteriole. The early fundoscopic findings consist of ischaemic optic neuritis with a slight pallor and edema of the optic disc and scattered cotton-wool patches and small hemorrhages. Other common neurologic manifestations (18) include neuropathies (14%) like mononeuropathies, mononeuritis multiplex and peripheral neuropathy of arms and legs (19). Less common findings are transient ischemic attacks or stroke in the territory of the carotid or vertibro basilar artery.
Respiratory tract findings, including cough with or without sputum, sore throat and hoarseness occur in about 10% of patients. Musculoskeletal manifestations are common. Polymyalgia rheumatica is the most frequent, occurs in around 40% of patients with giant cell arteritis, but distal symptoms such as peripheral arthritis and swelling, pitting edema of the hands and feet may occur in 25% of patients (20).
In approximately 10–15% of patients the branches of aortic arch particularly subclavian and axillary arteries become narrowed resulting claudication of arms. Bruits may be heard on auscultation over the carotid, subclavian, axillary and brachial arteries. Pulses in the neck and arms may be decreased or absent.
Thoracic aortic aneurysm is 17 times more common in-patient with giant cell arteritis than without this disease(7). This is usually a late complication and may rupture and result in death. A yearly chest radiograph is adequate to screen for thoracic aortic aneurysm.
Laboratory Findings
A markedly elevated erythrocyte sedimentation rate is a hallmark of giant cell arteritis. The criteria of the American College of Rheumatology include an erythrocyte sedimentation rate of at least 50mm per hour to classify giant cell arteritis. However 22.5% of patients may have a normal erythrocyte sedimentation rate before treatment (20). The C-reactive protein level has been found to be more sensitive indicator of disease activity than erythrocyte sedimentation rate both at diagnosis and during relapse (21).
Levels of interleukin-6 appear to be a sensitive indicator of active disease. Most patients have mild to moderate anemia of chronic disease, and approximately one third of patients have mildly abnormal liver functions. Tests of rheumatoid factors and antinuclear antibodies are usually negative.
Imaging
A role of color duplex ultrasonography in the diagnosis of giant cell arteritis has been proposed by Schmidt.et.al (22), who found that a dark halo around the lumen of temporal artery, which was specific for diagnosis of giant cell arteritis.
If a diagnosis of extra cranial giant cell arteritis is suspected, arteriography, computed tomography (CT) and magnetic resource angiography are the required diagnostic tests. On arteriography, the typical finding is bilateral stenosis or occlusion of subsclavian, axillary and proximal brachial arteries. Femoral arteries and their branches are less commonly affected. Best imaging technique to detect aortic aneurysms or dissection is CT or MRI. The finding of thickened aortic wall on CT or MRI is a direct indication of active disease.
Treatment
Corticosteroid: Corticosteroids are the drug of choice for giant cell arteritis. Prednisolone should be started at least 40–60mg per day as a single or divided dose. Initial pulsed intravenous doses of methyl prednisolone (1000mg everyday for 3 days) may be given to patients with recent or impending visual loss. Response to steroid is usually rapid with resolution of many symptoms. A lack of improvement within few days should alert physician to question the diagnosis. The initial doses of corticosteroid is usually given for two to four weeks, then it can be gradually reduced each week or every two weeks by a maximum of 10% of the total daily dose. If the doses of corticosteroid are reduced or withdrawn too quickly, a relapse or recurrence of symptoms usually occurs. However, about 30–50% of patients have spontaneous exacerbation of disease, especially during first two years, which is independent of corticosteroid regimen (23).
Regular assessment of clinical symptoms, the erythrocyte sedimentation rate or the C-reactive protein value is the most useful way of monitoring the patient. An isolated finding of an increase erythrocyte sedimentation rate during the therapy is not a valid reason to increase the dose. A treatment course of one to two years is often required. However some patients have a more chronic, relapsing course and may require low dose of corticosteroid for several years (23,24). No consistently reliable predictors of the duration of corticosteroid therapy have been found. One study suggested that measurement of interleukin-6 levels after four weeks of therapy was helpful in identifying more severe disease (23). Corticosteroid related adverse events are quite common. Calcium and vitamin D supplementation should be given with corticosteroid therapy in all patients of giant cell arteritis.
In studies of cytotoxic agents, methotrexate has been used as a corticosteroid-sparing agent. This drug may be given to patients who need high dose of corticosteroid to control active disease and who have serious side effects but the results are conflicting (25).
Aspirin: Although thromboembolic occlusion is not a mechanism in giant cell arteritis, therapeutic benefit has been reported with the use of low-dose aspirin (26). Prevention of platelet aggregation is potentially effective, even in patients with partial luminal occlusion. In addition, a potent anti-inflammatory action of aspirin has been described in the mouse chimera model of giant cell arteritis. Aspirin interferes with the transcriptional activation of the interferon-γ gene, a mechanism of action that may be particularly useful in inhibiting T-cell function in the granulomatous infiltrates.
Future Trends
Some studies have shown that serum levels of interleukin-6 are persistently increased in patients with giant cell arteritis after months of corticosteroid treatment, despite the rapid control of symptoms. Future studies will clarify whether this marker of inflammation can be used to monitor disease activity and to gauge the rate of reduction in the corticosteroid dose.
Large multicentric, randomized, double blind, placebo-controlled studies are required to define the role of methotrexate or other immuno suppressants as corticosteroid sparing drugs. A recent pilot study found that infliximab was efficacious in patient with corticosteroid resistant giant cell arteritis (27).
Finally a better understanding of the molecular mechanism involved in the pathogenesis of giant cell arteritis should provide targets for therapy as well as help to determine whether there is any relation of the disease with infectious cause or triggering mechanism.
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