Giant cell arteritis

Autoimmunity Reviews 2 (2003) 199–203

Giant cell arteritis Henry Penn, Bhaskar Dasgupta* Department of Rheumatology, Southend General Hospital, Prittlewell Chase, Westcliff-on-Sea, Essex SS00RY, UK Accepted 3 January 2003

Abstract Giant cell arteritis is the most common vasculitis in Caucasians. The aetiology of this disease remains uncertain. This article reviews some of the recent work in epidemiology and pathology in this field, with particular regard to the immunohistochemical findings in temporal artery biopsy specimens. The possible correlation between clinical features and biopsy specimen histology is discussed, and a model of pathogenesis is presented. 䊚 2003 Elsevier Science B.V. All rights reserved. Keywords: Giant cell arteritis; Rheumatic disease; Vasculitis

1. Introduction Giant cell arteritis (GCA) is an inflammatory rheumatic disease predominantly seen in the elderly, and is characterized by vasculitis of large and medium sized vessels. It is closely related to polymyalgia rheumatica, and frequently coexists with that disease. GCA has probably been present in Europe for several centuries. In the tenth century, Ali Ibn Isa, an Arab physician from Baghdad described temporal artery inflammation associated with headaches and visual disturbances w1x. Horton et al. first demonstrated the characteristic histology of GCA in the 1930s w2x. 2. Epidemiology GCA is the commonest vasculitis in Europe. The most impressive risk factor for the disease is *Corresponding author. Tel.: q44-1702-221048; fax: q441702-221990.

age, with cases under the age of 50 being rare. Female sex also predisposes to developing GCA; with a relative risk of 2.5- to 3-fold women. This ratio rises with age. Both GCA and PMR are common in Caucasians, but rare in Asians and Blacks. There is a positive correlation between incidence and increasing latitude. The incidence has been estimated in over 50s at 7y100 000 of in Italy, 17.8y100 000 (Olmsted County, USA) and 30y100 000 in Denmark. This may represent an underestimate however, as there is evidence that in postmortem specimens there are a number of undiagnosed (sub clinical) cases. GCA may be linked to environmental agents. Its acute onset, association with infections and vaccinations, occurrence in conjugal pairs and presence of antibodies to intermediate filaments suggest such an association. A prospective case control study found parainfluenza a serological association between Human Para influenza virus

1568-9972/03/$ - see front matter 䊚 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1568-9972Ž03.00012-0

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and GCA and PMR w3x. This association was most marked in the biopsy proven cases of GCA. Other infective agents that have also been proposed as possible etiological agents (measles, respiratory syncytial virus, HSV 1 and 2) were not found to be associated in this study. Epidemiological studies show a correlation between rates of GCA and the incidence of parvovirus B19 infection. Mycoplasma pneumoniae infections show a similar correlation. Chlamydia pneumoniae has been found in biopsy specimens using immunohistochemistry and PCR in one study. Non-infective environmental agents have also been linked to development of GCA. Smoking and arterial disease may be associated, as may be sun exposure in those with skin sensitivity. Nulliparity and prolonged sun exposure (actinic hypothesis) in genetically predisposed people with skin sensitivity have been described as risk factors. The relationship with increasing age has led to the suggestion that ageing of the immune system leads to failure of tolerance mechanisms, allowing triggering or perpetuation of a maladaptive inflammatory response 3. Immunogenetics Familial aggregation and racial differences suggest a role of heredity in susceptibility to GCA. Early studies showed links between both PMR and GCA and HLA DR-4. DR4 negative patients with PMRyGCA have increased frequency of DR3, DR8, DR13. There is no difference between HLA DR4 positive and DR4 negative patients in their clinical presentations. Weyand and Goronzy have identified a conserved amino acid sequence within the second hypervariable region of the DRB1 in GCA that maps to the antigen binding cleft of HLA-DR w4x. Dababneh et al. in 1998 reported association of HLA-DRB1*0401 with GCA regardless of PMR status w5x. The association of HLA- DRB1*0101 and *0102 though present, was less strong. Patients with isolated PMR showed significant association with DRB1*13 and*14. A weak association between presence of the RA DRB1 shared epitope and GCA (but not with isolated PMR) was seen in this study. The same group in another study has

reported association of GCA with higher frequency of relapses with HLA-DR4*0401. Other genetic polymorphisms have also been studied. Such associations have been described with polymorphisms of the tumour necrosis factor gene, interleukin-I gene cluster and intercellular adhesion molecule-1. Anti cardiolipin antibodies have been demonstrated in some patients with GCA, and in one study 50% of cases had a significantly raised titre at diagnosis. In this study, there was a reduction in the titre with treatment, and a rise was seen in most patients whose disease ‘flared’ w6x. 4. Pathogenesis The pathological hallmark of GCA is granulomatous inflammation of medium and large vessels. The granulomata are made up of necrotic tissue, multinucleated giant cells, macrophages, lymphocytes, and fibroblasts. There is also non-granulomatous infiltration of lymphocytes. The media is most frequently affected between the internal and external lamina, but all three layers may be inflamed. The inflammatory process is most commonly found in the arteries arising from the aorta, particularly the superficial temporal, ophthalmic, posterior ciliary and vertebral arteries. There is patchy distribution of inflammation (skip lesions). The feared complication of GCA is visual loss due to ischaemia. This is primarily due to an occlusive vasculopathy rather than thrombosis— the proliferation of the intima results in loss of the lumen. Hence it is the growth of the intima, which is the most important complicating event, rather than the arteritis. This is presumably the reason why aneurysm formation is uncommon in this disease, and is limited to the aorta. The intimal proliferation is dependent on several factors. The degree to which thickening can occur is limited by the blood supply. Usually the intima and media are avascular, hence neovascularisation is an important pathological process, without which lumen obliteration is less likely w7x. Vascular endothelial growth factor (VEGF) expression is associated with this process w8x. Inflammation leads to the proliferation of myofibroblasts in the arterial wall. These cells are thought to undergo

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mitosis in response to platelet-derived growth factor (PDGF) w9x. Temporal artery biopsy specimens are heterogeneous. There is a spectrum of inflammatory infiltrate found in positive biopsies, from those with full-blown granulomatous panarteritis, to those with less infiltration and no intimal proliferation. The presence of giant cells is strongly correlated with intimal proliferation, and hence vascular occlusion. There is some evidence that the pathological findings in these biopsies is associated with the rate of ischaemic complications, and preliminary studies have been done looking at the pattern of cytokine expression in association with the clinical phenotype at presentation and follow up w10,11x. The suggestion from these studies is that there is a difference between the cytokine profile in occlusive and non-occlusive disease. Those with significant intimal hyperplasia express higher levels of interferon-g (secreted by T cells), IL-1, and the myofibroblast stimulating PDGF. They also have a higher chance of having multi-nucleated giant cells, which secrete VEGF, allowing intimal growth. The initial arterial injury causing this disease remains unclear. The pathology suggests that it probably originates in the media, since this is where necrosis and granuloma formation is most commonly seen. The sequel to the injury includes neutrophil infiltration, which secretes toxic reactive oxygen species and matrix metalloproteinases. Following the initial injury, the adaptive immune system becomes involved. Granulomata are T cell dependent structures, and there are CD4q cells surrounding the layer of macrophages. Studying the T cells has revealed that there is a clonal expansion of a subset of these cells, and cells with the same antigen specificity can be found in spatially distinct lesions. This suggests an important role for T cells in the development andyor propagation of the disease. The antigen involved has not been elucidated. The pattern of cytokines secreted in occlusive disease is strongly suggestive of a Th1 response, and it may be that as with other diseases, Th1 responses correlates with tissue injury, whereas a Th2 response is protective. Along with the local vasculitis, there is usually a prominent systemic inflammatory response.

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There are up-regulated monocytes in the peripheral circulation, which secrete cytokines, including IL6. This results in the raised acute phase response, including elevated erythrocyte sedimentation rate and C reactive protein. There has been a study suggesting that patients with severe systemic symptoms, and high levels of peripheral IL-6 and C reactive protein, have a lower rate of ischaemic episodes but this observation is not confirmed by other studies. These patients do, however, seem to require longer courses of steroids. 5. Clinical features Headache is the main symptom in more than 60% of patients. It is usually a sudden onset, severe, localized pain in the temporal region. Occasionally it occurs in the occipital region and sometimes it is non-localized. The temporal artery may be tender, thickened, or non-pulsatile. The scalp may be tender. Intermittent claudication of the muscles of mastication and tongue is correlated with a raised risk of visual loss. Low-grade fever may be seen and patients may present as pyrexia of unknown origin. Visual symptoms are important early manifestations and include transient and permanent visual loss, diplopia and ptosis. Early fundoscopy may show slight pallor and oedema of optic disc, scattered cotton–wool exudates and small haemorrhages due to ischaemic neuritis. Optic atrophy may develop later. Permanent visual loss may be seen in 0–20%. Risk of permanent visual loss is reported in patients with transient visual loss, jaw claudication or both. Other neurological manifestations may occur. Large arteries may be involved in 10–15% of the cases, presenting with upper extremity claudication, absent pulses in the neck and arms, Raynaud’s and bruits over the carotid, subclavian axillary and brachial arteries. Thoracic artery aneurysm and dissection of the aorta may complicate GCA in up to 7% of cases. Angina pectoris, congestive heart failure and myocardial infarction secondary to coronary arteritis have also been reported. The American College of Rheumatology has produced a classification for the diagnosis of GCA (Table 1) w12x. Temporal artery biopsy remains

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Table 1 Classification criteria for GCA (traditional format) Criterion

Definition

(1) Age at disease onset 050 years (2) New headache (3) Temporal artery abnormality

Development of symptoms or findings beginning at age 50 or older New onset of or new type of localized pain in the head Temporal artery tenderness to palpation or decreased pulsation unrelated to arteriosclerosis of cervical arteries Erythrocyte sedimentation rate 050 mmyhour by the Westergren method Biopsy specimen with the artery showing vasculitis characterized by prominence of mononuclear cell infiltration or granulocyte inflammation, usually with multinucleated giant cells

(4) Elevated erythrocyte sedimentation rate (5) Abnormal artery biopsy

For purposes of classification, a patient with vasculitis shall be said to have giant cell (temporal arteritis if at least 3 of these 5 criteria are present).

the gold standard for diagnosis, and perhaps in the future will provide prognostic information.

been shown to reduce interferon-gamma secretion by a cyclo-oxygenase independent mechanism w15x.

6. Treatment Take-home messages Corticosteroids are the treatment of choice for PMR and GCA. Oral steroids are the common practice but intravenous methylprednisolone can be used for neuro-ophthalmic manifestations. Prednisolone is initiated at doses of 40–80 mg daily. It can be reduced to 40 mg by the end of 1 month, by 5 mg every 1–2 weeks thereafter until the dose of 20 mg is reached. Further reduction could be by 2.5 mg every 2–4 week while monitoring clinical symptoms and ESR or CRP. There is clear evidence that the cumulative steroid dosage is directly related to incidence of steroid side effects. This makes the case for using minimum effective steroid doses. It is our practice to co-prescribe calcium and vitamin D with low dose steroids, and bisphosphonates with higher doses ()15 mg daily). Methotrexate has been tried as a steroid-sparing agent in two trials with varying results. Hoffman et al. reported in a study of 98 patients over 12 months no difference in relapses, GCA related morbidity, steroid dosage, treatment toxicity between methotrexate and placebo w13x. However, Jover et al., in 42 patients over 24 months showed a significant decrease in steroid dosage and relapses with methotrexate compared to placebo w14x. Acetylsalicylate has been proposed as a candidate drug in view of its effects in vitro, where it has

● GCA is the most common vasculitis in Caucasians. ● Neuro-ophthalmic complications of GCA are common. ● Temporal biopsy remains the gold standard investigation. ● There is a subset of patients who do not suffer with ischaemic complications, and biopsies from these patients show less granulomatous inflammation and intimal proliferation. ● Immunohistochemistry shows that the granuloma formation leading to ischaemia is driven by interferon-gamma. ● Further studies are needed to confirm the value of biopsy in prognostication and guiding treatment. ● There is a need for careful disease assessment to maintain an acceptable balance between benefits and risks of long-term steroid therapy.

References w1x Hamilton CR, Shelley WM, Tumulty PA. Giant cell arteritis and polymyalgia rheumatica. Medicine 1971;50:1 –27.

H. Penn, B. Dasgupta / Autoimmunity Reviews 2 (2003) 199–203 w2x Horton BT, Magath TB, Brown GE. An undescribed form of arteritis of temporal vessels. Proceedings of the Staff Meetings of the Mayo Clinic, 1932. p. 7700– 7701. w3x Duhaut P, Bosshard S, Dumontet C. Giant cell arteritis and polymyalgia rheumatica: role of viral infections. Clin Exp Rheumatol 2000;18:S22 –S23. w4x Weyand CM, Goronzy JJ. Arterial wall injury in giant cell arteritis. Arthritis Rheum 1999;42:844 –53. w5x Dababneh A, Gonzalez-Gay MA, Garcia-Porrua C, Hajeer A, Thomson W, Ollier W. Giant cell arteritis and polymyalgia rheumatica can be differentiated by distinct patterns of HLA class II association. J Rheumatol 1998;25:2140 –5. w6x Liozin E, Roblot P, Paire D, et al. Anticardiolipin antibody levels predict flares and relapses in patients with giant cell arteritis A longitudinal study of 58 biopsy proven cases. Rheumatology 2000;39(10):1089 – 94. w7x Kaiser M, Younge B, et al. Formation of new vasa vasorum in vasculitis. Production of angiogenic cytokines by multinucleated giant cells. Am J Pathol 1999;155:765 –74. w8x Weyand CM, Goronzy JJ. The pathogenesis of giant cell arteritis. Bull Rheum Dis 2002;51(8):111.

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w9x Kaiser M, Weyand CM, et al. Platelet derived growth factor, intimal hyperplasia, and ischaemic complications in giant cell arteritis. Arthritis Rheum 1998;41:623 –33. w10x Weyand CM, Hicok KC, Hunder GG, Goronzy JJ. Tissue cytokine patterns in patients with polymyalgia rheumatica and giant cell arteritis. Ann Intern Med 1994;121:484 –91. w11x Weyand CM, et al. Disease patterns and tissue cytokine profiles in giant cell arteritis. Arthritis Rheum 1997;40:19 –26. w12x Hunder GG, Bloch DA, Michael BA, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33:1122. w13x Hoffman GS, Cid MC, Hellmann DB, et al. A multicenter, randomised, double blind, placebo controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 2002;46(5):1309 –18. w14x Jover JA, Hetrnandez-Garcia C, Morado IC, et al. Combined treatment of giant cell arteritis with methotrexate and prednisolone: a randomised, double blind, placebo-controlled trial. Annals Int Med 2001;134(2):106 –14. w15x Weyand CM, Kaiser M, Yang H, et al. Therapeutic effects of acetylsalicylic acid in giant cell arteritis. Arthritis Rheum 2002;46:457 –66.

The World of Autoimmunity; Literature Synopsis Anti-angiotensin II receptor autoantibodies in preeclampsia Wallukat et al. (Can J Physiol Pharmacol 2003;81:79) provide evidence that women meeting the criteria for preeclampsia have all autoantibodies directed against the angiotensin II AT1 receptor. These antibodies recognize an epitope on the 2nd extracellular loop of the receptor, and can accelerate the beating rate of neonatal rat cardiomyocytes. The agonistic effect of these autoantibodies can be blocked with either a peptide corresponding to the AT1 receptor’s second extracellular loop, or with the AT1 receptor blocker losartan. The agonistic antibodies behave pharmacologically similar to angiotensin II as long-term stimulation with either of them down-regulated the At1 receptor-mediated response to a second stimulation. In addition, both recognized a specific conformation of AT1 receptor. These findings which support a possible role of angiotensin II AT1 antibodies in the pathogenesis of preeclampsia could also support an attempt to treat these patients with AT1 receptor blocker. B23 autoantibodies in scleroderma Autoantibodies against B23, a nuclear phosphoprotein, were found in about 11% of randomly selected sera obtained from scleroderma patients (Ulanet et al., Arthritis Care Res 2003;49:85). The presence of these antibodies was associated with pulmonary hypertension, antifibrillarin antibodies, anti-RNP, and decreased lung capacity. Among this cohort of 92 patients, it seems that anti-B23 is one of the nucleolar autoantigens targeted by the minority of patients, but might be associated with certain clinical phenotype.