Amyloidosis is a group of systemic or localized diseases characterized by extracellular deposition of highly ordered fibers (amyloid fibrils) composed of low-molecular-weight protein subunits. When amyloid deposits in the temporal artery, it can present with clinical features mimicking giant cell arteritis (GCA).
Classification
Amyloidosis is broadly classified as follows based on the site of production:
Most temporal artery amyloidosis is caused by AL (light chain) amyloidosis. In AL amyloidosis, monoclonal light chain variable region immunoglobulin fragments are deposited, and it is associated with plasma cell disorders such as multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS).
History and Epidemiology
Amyloid deposition in temporal artery biopsies was first reported in 1975, and in 1986, the Mayo Clinic reported a case series (22 cases) of jaw claudication due to AL amyloidosis [1]. Over the following 30 years, case reports mimicking giant cell arteritis have accumulated [2,3].
AL amyloidosis is slightly more common in men, with a mean age at diagnosis of 65 years, and the mean age of patients with temporal artery involvement is reported as 72 years. Compared to giant cell arteritis (mean age of onset 75 years, female predominance), temporal artery amyloidosis tends to have a slightly younger onset and male predominance [3,4].
Ocular symptoms of ocular amyloidosis are diverse and include eyelid papules/nodules, conjunctival thickening, lattice corneal dystrophy, vitreous amyloid deposition (pseudouveitis-like), and retinal vascular sheathing.
In Japan, giant cell arteritis itself is a rare disease compared to Western countries (especially common in Scandinavians; incidence in the UK is about 1.2/10,000 people). When symptoms resembling giant cell arteritis are present, a systematic evaluation of differential diagnoses including this disease is required.
Giant cell arteritis is a T-cell-mediated granulomatous vasculitis that presents with full-thickness arteritis involving mononuclear cell infiltration and giant cell formation in the arterial wall. Temporal artery amyloidosis is caused by ischemia due to deposition of amyloid fibers in the vessel wall. Although the symptoms are very similar, giant cell arteritis is more common in women and at age 75, whereas temporal artery amyloidosis is more common in men and at age 72, and often has an underlying plasma cell disorder (MM, MGUS). Temporal artery biopsy is necessary for definitive differentiation.
The subjective symptoms of temporal artery amyloidosis largely overlap with those of giant cell arteritis and polymyalgia rheumatica (PMR).
The main points of comparison between giant cell arteritis and temporal artery amyloidosis are shown below.
| Feature | Giant cell arteritis | Temporal artery amyloidosis |
|---|---|---|
| Mean age at onset | 75 years | 72 years |
| Sex | Female > Male | Male > Female |
| Associated underlying diseases | Polymyalgia rheumatica (PMR) | Plasma cell disorders (MM, MGUS) |
| Laboratory findings | Elevated ESR and CRP | Elevated ESR and CRP + abnormal serum free light chains |
| Steroid response | Generally improves | Variable (improvement, no response, worsening) |
The main cause of temporal artery amyloidosis is systemic deposition of monoclonal light chains in AL amyloidosis. It usually deposits in small blood vessels but can also occur in medium to large arteries.
Underlying diseases
Risk factors
Familial primary amyloidosis can present with vitreous amyloidosis as an ocular complication, showing autosomal dominant inheritance and typically bilateral onset.
Carefully checking the patient’s personal and family history of plasma cell disorders and hematologic malignancies is the first step in differential diagnosis.
Amyloid Findings
Congo red staining: Shows apple-green birefringence and dichroism under polarized light. This is a specific finding for confirming amyloid.
Routine staining: Amorphous eosinophilic or orangeophilic material deposited in the vessel wall.
Management of Giant Cell Arteritis-Negative Cases
Re-evaluation recommended: In temporal artery biopsies negative for giant cell arteritis, it is recommended to add Congo red staining to consider amyloid involvement [2,5].
Re-evaluation by a pathologist: Re-evaluation of a negative temporal artery biopsy for giant cell arteritis by an experienced pathologist is considered important [6].
Muscle biopsy is indicated when polymyalgia rheumatica is mimicked.
Giant cell arteritis is diagnosed when 3 or more of the 5 diagnostic criteria are met.
In giant cell arteritis, 25–50% develop anterior ischemic optic neuropathy (AAION), and 15–40% have bilateral involvement. About 20% of patients with giant cell arteritis have occult giant cell arteritis (vision loss without systemic symptoms).
Even if the biopsy result is negative for giant cell arteritis, if symptoms persist, the possibility of amyloidosis should be considered. Congo red staining and re-evaluation by an experienced pathologist are recommended. At the same time, screening for plasma cell disorders (serum protein electrophoresis, free light chains, immunofixation) is important.
Temporal artery amyloidosis and giant cell arteritis have similar symptoms but differ greatly in treatment, so accurate differential diagnosis is a prerequisite for determining treatment strategy.
Treatment of AL amyloidosis is determined based on symptoms, site, severity of organ damage, and clone characteristics. Prompt referral to oncology or hematology is essential.
Steroids may also be used to treat AL amyloidosis, similar to giant cell arteritis, but the dosing regimen may differ. Steroid response in amyloidosis patients varies and can include improvement, no response, or worsening. It is important to note that long-term steroid therapy can cause side effects and may delay diagnosis.
In giant cell arteritis, immediate high-dose glucocorticoid administration is the standard treatment. Prompt treatment is necessary because of the risk of blindness if the condition worsens, and it often becomes bilateral (15–40%), so early steroid therapy is required.
When severe vitreous opacity due to vitreous amyloidosis causes vision loss, vitrectomy is indicated, but amyloid may redeposit in the residual vitreous. When ocular disease appears, systemic symptoms are often already advanced, and attention to systemic prognosis is necessary.
Steroid response is variable; improvement, no response, or worsening are all possible. Unlike giant cell arteritis, steroids are not a curative treatment, and chemotherapy/immunotherapy for AL amyloidosis is the mainstay of treatment. If symptoms do not improve after starting steroids for suspected giant cell arteritis, reconsider differential diagnoses including amyloidosis, and consider referral to hematology/oncology.
AL amyloid deposition usually occurs in small blood vessels but can also be seen in medium to large vessels. Amyloid deposition in the temporal artery wall causes arterial stenosis, leading to ischemia. This is the mechanism by which optic nerve damage resembling arteritic anterior ischemic optic neuropathy (AAION) occurs.
Amyloid deposition in the arterioles supplying the masseter muscle causes vascular narrowing, leading to relative ischemia during chewing and resulting in jaw claudication.
Giant cell arteritis is primarily a T-cell-mediated granulomatous systemic vasculitis with a particular affinity for the short posterior ciliary arteries. Vision loss occurs through thrombotic occlusion leading to optic disc ischemia. Histologically, it progresses from nonspecific inflammation of the arterial wall to granulomatous inflammation, causing arterial stenosis and occlusion. Granulomatous panarteritis with mononuclear cell infiltration and giant cell formation is the histological definition.
In temporal artery amyloidosis, such inflammatory cell infiltration is not observed; instead, amorphous amyloid fiber deposits invade the vessel wall, causing similar ischemic symptoms. This is a fundamental difference [4].
Tocilizumab (IL-6 receptor antagonist) for giant cell arteritis has shown clinical efficacy with glucocorticoid-sparing effects in randomized controlled trials (RCTs). However, it is important to note that this is a treatment for giant cell arteritis and is not directly indicated for temporal artery amyloidosis.
The introduction of a fast-track diagnostic pathway for giant cell arteritis has been shown to reduce diagnostic delays and improve clinical outcomes. Such a rapid diagnostic system may also lead to early detection of temporal artery amyloidosis, a mimic of giant cell arteritis.
The GAPS study reported a sensitivity of 92% and specificity of 85% for PET-CT in diagnosing giant cell arteritis. It is useful for early differentiation between giant cell arteritis and its mimics, and is attracting attention as an advanced imaging method that may also contribute to the detection of temporal artery amyloidosis.
