A 79-year-old female presented with new-onset pain in the neck and both shoulders, with a previous history of giant cell arteritis, treated with 7.5 mg of prednisone daily. The patient began to have occipital pressure pain and diplopia 11 months ago, when the erythrocyte sedimentation rate was 78 mm/h and a temporal artery biopsy showed granulomatous arteritis; after 6 days of treatment with 60 mg of prednisone daily, the patient’s diplopia disappeared; with the gradual reduction of glucocorticoids, the patient did not experience any worsening of headache or visual symptoms. What should be the management of this patient?
Clinical Question
Giant cell arteritis is an inflammatory vascular lesion that commonly affects large and medium-sized arteries with well-developed walls with outer trophoblastic vessels. Vascular beds usually involved include: peripheral branches of the carotid artery (e.g., temporal and occipital arteries), ophthalmic artery, vertebral artery, distal subclavian artery, axillary artery, and thoracic aorta. Vasculitis leads to lumen occlusion, resulting in ischemic complications such as ischemic optic neuropathy, with 10-15% of patients with ischemic optic neuropathy losing their vision. In addition, aortitis can be complicated by arterial entrapment and aneurysms.
Rheumatic polymyalgia causes pain and stiffness in specific muscle groups, primarily those located in the neck, shoulders, upper arms, and pelvis; symptoms are most pronounced in the morning, and the etiology of the myalgia is unknown. Imaging shows the presence of inflammation of the bursa and pars interarticularis, in addition to high levels of cytokine expression in the intertissue fluid of the painful muscles. The levels of acute phase reactants in the blood samples were significantly elevated, suggesting that the muscle pain was associated with a strong systemic inflammatory response of the body.
Clinical points
Currently, the immune-mediated diseases giant cell arteritis and rheumatic polymyalgia are considered to be chronic diseases that occur in patients aged 50 years and older.
If possible, the diagnosis of giant cell arteritis should be established by histological lesions.
Glucocorticoids are the standard therapy for giant cell arteritis and rheumatic polymyalgia, with larger doses of hormones used for giant cell arteritis.
Patients with giant cell arteritis and rheumatic polymyalgia often experience a rebound in the course of glucocorticoid tapering, and the dose of hormone therapy often needs to be increased by 10-20% to be effective.
Arteritis ischemic optic neuropathy, which can lead to blindness, should be treated as an emergency and requires prompt diagnosis and initiation of high-dose glucocorticoid therapy.
In 1/4 patients with giant cell arteritis, the lesion involves the aorta and major branches of the aorta. Large vessel lesions can be diagnosed definitively by computed tomography (CT) or magnetic resonance imaging (MRI).
Giant cell arteritis or rheumatic polymyalgia do not usually reduce life years, but glucocorticoid therapy is often associated with side effects. The patient’s general condition should be closely monitored, with special attention to the presence of osteoporosis and to the prevention of Pneumocystis carinii pneumonia.
Pathophysiological features
Molecular studies of large vessel vasculitis show that vascular wall dendritic cells trigger a pathological cascade response and recruit T cells and macrophages to form a granulomatous infiltrate. Two major immune response pathways have been identified: the IL12-Th1-INFγ axis and the IL6-Th17-IL17/IL21 axis, the latter of which can be effectively inhibited by glucocorticoids.
Effector cytokines released into the arterial wall activate inflammatory cells that target endothelial cells, vascular smooth muscle cells and fibroblasts, leading to obstructive intimal hyperplasia of the vascular lumen. In turn, protein hydrolases (e.g., metalloproteinases) and pro-angiogenic factors (e.g., vascular endothelial growth factor and platelet growth factor) work together to promote remodeling of the vessel wall, leading to the corresponding imaging features manifesting and associated clinical manifestations.
Evaluation and management
Giant cell arteritis should be diagnosed with a combination of history, clinical evaluation, laboratory tests, and imaging, with the diagnosis confirmed by histological examination. Unless complicated by giant cell arteritis, rheumatic polymyalgia is relatively difficult to diagnose due to the lack of characteristic clinical and laboratory examination features.
Laboratory tests
Significantly elevated erythrocyte sedimentation rate (ESR) and C-reactive protein levels (CRP) are common in giant cell arteritis and rheumatic polymyalgia, with ESR and CRP appearing similar to thrombocytosis and anemia. Detection of inflammatory markers is useful for disease diagnosis and long-term monitoring, but elevated levels of these markers should not be used as the sole marker for administering immunosuppressive therapy.
Currently, no highly specific biological markers have been identified for giant cell arteritis and rheumatic polymyalgia. Levels of interleukin 6 (IL6, the main inducer of CRP products) are characteristically elevated in untreated patients and are rapidly suppressed after treatment.
In addition, IL6 levels tend to be higher than normal in patients with chronic disease. However, for guidance of clinical decision making, there is no evidence that IL6 levels are superior to CRP, and testing for IL6 is not recommended in routine screening.
When clinically indicated, autoantibodies (e.g., anti-neutrophil cytoplasmic antibodies [ANCA] or anti-cyclic citrullinated peptide antibodies) may be tested to rule out other rheumatic diseases, and serum electrophoresis may be used to identify monoclonal gammopathies. Fever of undetermined origin is recommended to be identified by blood culture.
Imaging
Macrovascular inflammation occurs in patients with giant cell arteritis. In patients with biopsy-confirmed giant cell arteritis, magnetic resonance angiography (MRA) or computed tomography angiography (CTA) of the aorta and its major branches is useful to evaluate the arteries involved in the lesion (including stenosis, entrapment, and aneurysm) and to monitor progression (Figure 1).
MRA and CTA can also be used to detect large vessel involvement in patients with suspected giant cell arteritis without biopsy confirmation, as well as in patients with clinical manifestations of peripheral ischemic disease.
Due to the effective use of MRA and CTA, conventional angiography has been used less frequently in the planning of angioplasty procedures.
Because 18F-FDG PETCCT does not reliably discriminate between vasculitis and non-vascular inflammatory injury and has low resolution in treated vasculitis, it is not recommended for routine performance of this test.
Color Doppler ultrasound can be used for visualization of superficial arteries, such as the temporal arteries, but has limitations for visualization of deep arterial vessel walls. In addition, high-field intensity MRI has emerged as a highly sensitive method for detecting temporal artery inflammation, but neither color ultrasound nor MRI has been able to replace temporal artery biopsy, which is also highly sensitive to small inflammatory changes.
Figure
Figure 1: CTA and MRA images of the aortic arch in two patients with giant cell arteritis. Figure A shows a CTA image of a 71-year-old female patient with biopsy-confirmed giant cell arteritis after aortic root reconstruction and “elephant trunk grafting” of the aortic arch, which stops at the proximal descending aorta. The arrow shows the maximally dilated aneurysm in the proximal descending aorta. The images are composed of data reformatted from consecutive axial maps in the sagittal and coronal planes. Figure B shows a contrast-enhanced MRA image of the aortic arch and its branches in a 72-year-old female patient with biopsy-confirmed giant cell arteritis. Arrows show bilateral stenotic lesions in the subclavian and axillary arteries, and arrows indicate occlusion of the long segment of the proximal brachial artery. Images courtesy of Dr. D. Fleischmann (Panel A) and Dr. F. Chan (Panel B), Department of Radiology, Stanford University.
In rheumatic polymyalgia, ultrasonography or MRI can confirm the diagnosis of subacromial, subdeltoid, rotator, and cervical bursitis, as well as biceps tenosynovitis. The presence of peripheral synovitis should be differentiated from other conditions, such as rheumatoid arthritis or inflammatory osteoarthritis. Ultrasound findings are not necessary for the diagnosis of rheumatic polymyalgia in the current classification criteria.
Pathological analysis
Histologic staging is the gold standard for diagnosis. However, the presence of negative results on biopsy does not exclude the diagnosis of giant cell arteritis.
Treatment
Immunosuppressive therapy
Both giant cell arteritis and rheumatic polymyalgia are sensitive to glucocorticoid therapy, and although there are no specific indications for glucocorticoids in these two diseases, the disease is well controlled in most cases with glucocorticoid monotherapy (Figure 2).
Treatment
Treatment
Figure 2: Treatment of giant cell arteritis and rheumatic polymyalgia.
Treatment of giant cell arteritis depends on the stage of the disease and is listed for newly diagnosed patients (induction therapy), patients in the chronic phase (maintenance therapy) and patients with rebound disease (management of rebound). Glucocorticoids are the basis of treatment, with other immunosuppressive agents having only a weak effect or no glucocorticoid replacement. b : Glucocorticoids are administered at low doses in the management of rheumatic polymyalgia. crp stands for C-reactive protein and esr for erythrocyte sedimentation rate.
Questions to be explored
There are no clear diagnostic criteria for giant cell arteritis and rheumatic polymyalgia. Rheumatic polymyalgia is particularly difficult to diagnose because there are often no disease-specific symptoms or indications. For the treatment of both diseases, randomized trials are also needed to determine the best option. And the significance of imaging for disease diagnosis and monitoring is not yet clear.
Currently, giant cell arteritis and rheumatic polymyalgia are considered to be chronic diseases. Patients often have abnormally high levels of inflammatory markers, even 2 years after receiving treatment. The management of patients in the subacute phase remains unclear, as does the impact of long-term aggressive immunosuppressive therapy on disease outcome.
Related guidelines
The American College of Rheumatology (ACR) and the Church Hill Conference on Vasculitis discussed criteria to differentiate giant cell arteritis from other vasculitis (Table 1). The diagnostic specificity of these criteria as applied to the general population has not been clarified.
The BSR has developed guidelines for the management of giant cell arteritis and rheumatic polymyalgia, and the EULAR has published guidelines for the treatment of large vessel vasculitis. The recommended therapies in this article are generally consistent with these existing guidelines.
Table
Table 1: ACR refers to American College of Rheumatology, ESR refers to erythrocyte sedimentation rate, and EULAR refers to European League Against Rheumatism. According to the ACR-EULAR interim classification criteria, the diagnosis of rheumatic polymyalgia requires meeting the mandatory criteria, in addition to an additional criteria score of four or more when the ultrasound findings criteria are not met, and an additional criteria score of more than five when the ultrasound findings criteria are met.
Summary and Recommendations
The patient in the profile has a biopsy-confirmed diagnosis of giant cell arteritis and is sensitive to high-dose glucocorticoid therapy with good results with hormone tapering. The patient now presents with symptoms of rheumatic polymyalgia and there is no evidence to support the presence of an ischemic recurrence. In the present case, the prednisone dose should be temporarily increased to 10 mg/day to suppress the myalgia.
Once clinical symptoms have resolved, a tapered reduction of the hormone is again attempted while clinical response and inflammatory marker levels are tested. Recurrence of other diseases increases the risk of large vessel involvement and should be evaluated with MRA or CTA. Patients should be followed closely to monitor possible side effects of glucocorticoid therapy.