BASICS

DESCRIPTION

• Giant cell arteritis (GCA) is also known as temporal arteritis or granulomatous arteritis.

• It is a systemic inflammatory vasculitis that affects medium-sized to large arteries.

• Arterial wall inflammation leads to luminal occlusion and tissue ischemia, which cause the clinical manifestations of this vasculitis.

• Vision loss is a frequent complication of GCA, and once it occurs it tends to be both permanent and profound.

• Bilateral involvement is not uncommon.

• Causes of visual loss include arteritic anterior ischemic optic neuropathy (AAION), central retinal artery occlusion, posterior ischemic optic neuropathy, ocular ischemic syndrome, cilioretinal artery occlusion, and branch retinal artery occlusion.

EPIDEMIOLOGY

Incidence

• GCA predominantly affects Caucasians over 50 years of age, with women affected at least twice as often as men.

• Overall incidence is 15 to 25 per 100,000/year in individuals over the age of 50 years; however, incidence increases with age: from 2.3 per 100,000/year among patients in their 6th decade of life, to 44.7 per 100,000/year among patients in their ninth decade and older.

• GCA is more frequent among people of Scandinavian and Northern European descent, irrespective of their place of residence.

• There is some evidence to suggest an inherited component.

Genetics

• Some studies have found an association with HLA-DR4 haplotype and 60% of patients express the B1^∗0401 or B1^∗0404/8 variant of the HLA-DR4 haplotype.

• The intercellular adhesion molecule 1 (ICAM-1) genes may also predispose to GCA. ICAM-1 is strongly expressed in the inflammatory infiltrate of the temporal artery in GCA and G/R 241 polymorphisms in the ICAM-1 gene are associated with GCA susceptibility.

GENERAL PREVENTION

Prevention of visual loss depends on early diagnosis with adequate and timely intervention.

PATHOPHYSIOLOGY

• Both the adaptive and innate immune systems have been implicated.

• The acute-phase response mediated by the innate immune system is responsible for the systemic inflammatory component of GCA.

• Interleukin-6 being is critical by stimulating the production of acute-phase proteins.

• Circulating monocytes are a major source of interleukin-6; however, the mechanism and site of monocyte activation in GCA are unknown.

• Inappropriate activation of the adaptive immune system by dendritic cells is thought to cause the vascular lesions seen in GCA.

• Both T-cells and macrophages are attracted to the vessel wall via the vasa vasorum.

• In the adventitial layer, selective clonal expansion of CD4+ T cells leads to the release of cytokines such as interferon gamma (IFN-γ), which recruit macrophages into the vessel wall to form a prominent granulomatous reaction.

• Intimal hyperplasia, tissue ischemia and luminal occlusion also occur.

ETIOLOGY

The exact etiology of GCA is unknown, a variety of infectious agents have been suggested as potential immune triggers for the disease, including herpes virus, parainfluenza virus, cytomegalovirus, parvovirus B19, chlamydia, and mycoplasma.

COMMONLY ASSOCIATED CONDITIONS

• Giant-cell arteritis and polymyalgia rheumatica frequently occur together in the same patient.

• Polymyalgia rheumatica is a systemic inflammatory disease that manifests as myalgias of the neck, shoulder, and pelvic girdle.

DIAGNOSIS

HISTORY

• Patients should be specifically interrogated for the following symptoms:

• Constitutional: Poor appetite, weight loss, fatigue, night sweats, general malaise, fever or unknown origin.

• Symptoms associated with polymyalgia rheumatic: stiff and painful shoulder, girdle muscles.

• Symptoms associated with arteritis of carotid arteries and their branches: Headaches that are new and severe. Scalp tenderness, or direct temporal artery tenderness. Jaw claudication (highly specific for GCA). Less frequent are tongue claudication, facial pain.

• Visual symptoms: Transient visual loss, diplopia, sudden visual loss, graying of vision, eye pain.

• Ocular involvement without the presence of other GCA symptoms, or occult GCA, occurs between 5 and 38%.

PHYSICAL EXAM

• AAION: Chalky white optic disc edema (unlike nonarteritic anterior ischemic optic neuropathy [NAION], which shows a hyperemic swollen optic nerve), at times associated retinal edema. This produces abnormalities in optic nerve function: relative afferent papillary defect, dyschromatopsia, decrease visual acuity, visual field defect.

– Central retinal artery—Note the lack of an embolic plaque in artery. Also, there is no sparing of the cilioretinal artery.

– Diplopia due to 4th, 6th, or 3rd cranial nerve ischemia.

– Changes in temporal arteries: Loss of pulse, tender to palpation.

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• There is no single clinical symptom, sign or laboratory test specific for GCA.

• Westergren erythrocyte sedimentation rate (WESR): Approximately 80% of patients with GCA will have elevated ESR. But ESR is a nonspecific indicator of inflammation and can also be increased in malignancy, infection, connective tissue disorders, trauma, anemia, and hypercholesterolemia.

• “Normal” ESR is present in up to 17% of diagnosed cases, and thus cannot be used to exclude GCA.

• WESR increases with age. Upper limit is and has been defined as the age divided by two for men, and the age plus 10 divided by 2 for women.

• C-reactive protein (CRP) is an acute-phase protein. An elevated CRP has a specificity of up to 97.5% in patients with GCA, and may be elevated in the presence of a normal ESR. CRP is considered to be more sensitive than an elevated ESR.

• ESR and CRP together have higher sensitivity than either individually.

• Other tests: Elevated platelet count, normochromic normocytic anemia, fibrinogen, interleukin-6 (IL-6) and a2- and β-globulins have been found in GCA.

Imaging

• Fluorescein angiography may show prolonged choroidal and central retinal arterial filling times, and choroidal nonperfusion or filling defects suggestive of AAION.

• Ultrasonography of affected arteries is a may demonstrated changes in the arterial or be used to track the arterial course prior to biopsy.

Diagnostic Procedures/Other

• Temporal artery biopsy (TAB) is the gold standard for the diagnosis of GCA and should be performed on all patients in whom the diagnosis of GCA is suspected.

• Histological confirmation is recommended since long-term corticosteroid treatment is not without complications.

• TAB should never delay the instigation of treatment.

• TAB should be performed within one week of initiating systemic corticosteroids; however, histological evidence remains up to 6 weeks following treatment.

• Minimum length of 20 mm should be obtained to avoid skip lesions.

• If the TAB result is negative and the suspicion of GCA is high, a contralateral TAB should be performed.

Pathological Findings

• GCA is characterized by granulomatous inflammation affecting all layers of medium-sized and large arteries that have an internal elastic lamina.

• The inflammatory infiltrate is composed of activated CD4+ T cells, macrophages, and giant cells.

• Giant cells are not necessary for a diagnosis of GCA.

• Luminal stenosis or occlusion may be visualized due to intimal hyperplasia and subsequent mural thickening secondary to myofibroblast migration and proliferation.

• “Skip lesions” or segments of uninvolved regions adjacent to areas of inflammation are common.

DIFFERENTIAL DIAGNOSIS

NAION.

TREATMENT

The goal of treatment is to prevent ongoing ischemic damage. If the visual loss is the major symptom, the aim is to halt the progression of visual loss in the affected eye and prevent involvement of the contralateral eye.

MEDICATION

First Line

• Systemic corticosteroids are the mainstay of treatment. Intravenous methylprednisolone 1 g/d, usually for a minimum of 3 days, is recommended if there is visual loss.

• High-dose oral prednisone 1 mg/kg for GCA without visual symptoms.

Improvement of systemic symptoms usually occurs within 24–72 hours after initiation of therapy, but normalization of ESR may take several weeks.

Second Line

Methotrexate has been shown to have some benefit as a steroid-sparing agent.

ADDITIONAL TREATMENT

General Measures

Elderly patients being treated with high-dose prednisone should be admitted to hospital.

Issues for Referral

• A referral to a general physician should be made for prevention and management of potential complications of long-term high-dose corticosteroid treatment.

• These include diabetes, loss of bone density, GI disturbance, mood alteration, difficulty sleeping.

Additional Therapies

• Bone maintenance treatments: Calcium, vitamin D, bisphosphonates. This needs to be managed in consultation with general physician.

• GI disturbance: Patients are often treated with proton pump inhibitors (omeprazole) to prevent GI disturbance.

• Sleep difficulties: Patients may need additional medication to assist with sleeping.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Systemic Steroid Dosage

• Most patients will remain on oral prednisone 1 mg/kg for a minimum of 4 weeks after which steroids should be tapered on the basis of symptoms and serial monitoring of inflammatory markers.

• The rate of steroid taper is about 10 mg per month initially (or 10% of the total daily dose every 1–2 weeks), then decreased to 5 mg per month, and even as low as 1 mg per month, once a dose of 10 or 15 mg per day is reached.

• Most patients will require treatment for a minimum of 1 to 2 years.

• Patients will need continued treatment with bone sparing agents, proton pump inhibitors and management of diabetes, and other possible complications of corticosteroid use.

Patient Monitoring

In most GCA patients with ESR/CRP elevation, it can be used accurately to monitor disease activity along with patients’ symptoms.

PATIENT EDUCATION

• Patients should be educated about the side effects of corticosteroid use.

• Relapses are associated with a recurrence of symptoms or a rise in ESR/CRP. They are most common in the first 18 months, with a median time of around 7 months. Patients should be educated to contact their doctor if they have any recurrence of their GCA symptoms.

PROGNOSIS

• The prognosis for visual recovery is poor.

• Progressive visual loss may occur despite the early institution of high-dose corticosteroid treatment.

• Visual deterioration occurs in about 27% of eyes despite high-dose intravenous methylprednisolone.

• The greatest risk of visual deterioration is in the first 6 days.

• Treatment with intravenous corticosteroids is effective in reducing the likelihood of fellow eye involvement. Without treatment the risk of fellow eye involvement is 54 to 95%

COMPLICATIONS

• Causes of mortality associated with GCA include cardiovascular, neurological, and gastrointestinal events. Vasculitis of the coronary arteries may result in myocardial infarction or congestive heart failure. Ischemic brain damage is the second most common cause of GCA-related death after cardiac disease.

• Necrotizing segments of bowel are uncommon, but can also be fatal.

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