# Giant Cell Arteritis and Polymyalgia Rheumatica

## Introduction

Giant cell arteritis and polymyalgia rheumatica are closely related inflammatory conditions that occur almost exclusively in adults over the age of 50, with peak incidence between 70 and 80 years. GCA is a large vessel vasculitis affecting the aorta and its branches, with a particular predilection for the cranial arteries, while PMR is an inflammatory condition causing proximal girdle pain and stiffness that may coexist with GCA in 40 to 60 percent of cases. The critical clinical importance of GCA lies in its status as a medical emergency when visual symptoms are present, as irreversible blindness occurs in 15 to 20 percent of untreated patients.

## Giant Cell Arteritis

### Epidemiology

The incidence of GCA ranges from 15 to 25 per 100,000 persons over the age of 50, with the highest rates observed in populations of Northern European and Scandinavian descent. The female-to-male ratio is approximately 2 to 3 to 1. The disease almost never occurs before age 50, with a mean age of onset around 72 years. Some studies have reported a seasonal variation with higher incidence during spring and summer months.

### Pathogenesis

The pathogenic process begins when dendritic cells residing in the arterial adventitia, specifically within the vasa vasorum, are activated by an as-yet-unidentified antigen, leading to the recruitment of T cells into the vessel wall. Both Th1 and Th17 immune responses predominate in GCA. The Th1 pathway, through interferon-gamma production, drives macrophage activation, giant cell formation, and intimal hyperplasia, which ultimately leads to luminal stenosis and ischemic complications. The Th17 pathway, through IL-17 production, drives systemic inflammation and is relatively responsive to glucocorticoid therapy. IL-6 is a central cytokine in GCA, driving the acute phase response, and serves as the molecular target of tocilizumab. Vascular remodeling with intimal hyperplasia progressively narrows the arterial lumen, producing the ischemic complications that define the disease. VEGF and PDGF drive neovascularization and intimal thickening as part of this maladaptive remodeling process.

### Clinical Manifestations

#### Cranial GCA

New-onset headache, typically temporal or diffuse, is the most common symptom of cranial GCA, present in approximately 70 percent of patients. Scalp tenderness, particularly over the temporal arteries, is a frequent accompanying finding. Jaw claudication, defined as pain with chewing that resolves with rest, carries the highest positive likelihood ratio of any clinical feature for GCA at approximately 4.2, making it an especially valuable diagnostic clue. Visual symptoms constitute a medical emergency and include anterior ischemic optic neuropathy, the most common cause of vision loss in GCA, which presents as painless monocular visual loss; amaurosis fugax, representing transient monocular visual loss that serves as a warning sign of impending permanent visual damage; central retinal artery occlusion; and diplopia from cranial nerve palsies involving cranial nerves III, IV, or VI. Without treatment, the contralateral eye is affected within 1 to 2 weeks in up to 50 percent of patients, underscoring the urgency of diagnosis and treatment. Temporal artery abnormalities on physical examination include thickening, tenderness, nodularity, reduced pulse, and beading. Tongue and scalp necrosis, while rare, are characteristic manifestations of severe ischemia.

#### Large-Vessel GCA

Large-vessel involvement of the aorta and its major branches occurs in 50 to 80 percent of GCA patients, though it is often subclinical. Upper extremity claudication from subclavian or axillary artery involvement is the most common symptomatic large-vessel manifestation. The risk of thoracic aortic aneurysm is increased 17-fold, and aneurysms may present years or even decades after the initial diagnosis. Aortic dissection is a rare but life-threatening complication. Lower extremity claudication from femoral artery involvement is less common. Large-vessel GCA may present without any cranial symptoms, a presentation sometimes termed "extracranial GCA," which can pose significant diagnostic challenges.

#### Constitutional Symptoms

Constitutional symptoms including fever, weight loss, night sweats, fatigue, and malaise may be the only presenting features of GCA. Fever may be the sole manifestation, making GCA a common and important cause of fever of unknown origin in patients over 65 years of age.

<image>A clinical anatomy illustration of giant cell arteritis showing a lateral view of the head and upper body with the arterial system highlighted. On the head, show the superficial temporal artery (with a magnified cross-section showing: normal artery vs GCA-affected artery with transmural granulomatous inflammation, giant cells in the media, fragmented internal elastic lamina, and intimal hyperplasia causing luminal narrowing). Show the ophthalmic artery branch leading to the eye with an inset of fundoscopy showing anterior ischemic optic neuropathy (swollen, pale optic disc with flame hemorrhages). On the body, show large-vessel involvement: thickened aorta with mural inflammation, subclavian/axillary artery stenosis, and thoracic aortic aneurysm. Label all vessels and pathologic findings.</image>

### Diagnosis

#### Laboratory

The ESR is typically elevated above 50 millimeters per hour and frequently exceeds 100, though a normal ESR does not exclude GCA, as approximately 5 percent of patients present with normal values. CRP is more sensitive than ESR and is often elevated above 50 milligrams per liter. The complete blood count commonly reveals a normocytic anemia and reactive thrombocytosis. Liver function tests show elevated alkaline phosphatase in approximately 30 percent of patients. IL-6 levels are elevated but are not routinely measured in clinical practice.

#### Imaging

Temporal artery ultrasound has emerged as the first-line imaging modality in many centers, endorsed by the 2018 EULAR recommendations. The halo sign, defined as a hypoechoic, non-compressible circumferential wall thickening, demonstrates a sensitivity of approximately 77 percent and specificity of approximately 96 percent. The compression sign, indicating a non-compressible temporal artery, is an additional supportive finding. Critically, ultrasonography must be performed before or within days of starting glucocorticoid therapy, as the halo sign resolves quickly with treatment. MRI of the cranial vessels or large vessels detects mural enhancement and thickening of the temporal arteries or the aorta and its branches. PET-CT with 18F-FDG detects large-vessel inflammation with a sensitivity of 80 to 90 percent for large-vessel GCA and should ideally be performed before or within 3 days of glucocorticoid initiation. PET-CT is particularly useful for extracranial and large-vessel GCA but cannot reliably assess cranial vessels due to interference from brain uptake. CT angiography detects vessel wall thickening, stenosis, and aneurysm formation and is useful for long-term follow-up.

#### Temporal Artery Biopsy (TAB)

Temporal artery biopsy remains the traditional gold standard and is still recommended by the ACR when clinical suspicion is intermediate. The biopsy specimen should be at least 1 centimeter in length, ideally 2 centimeters or more, and should be processed with attention to skip lesions. Characteristic histopathologic findings include transmural granulomatous inflammation, giant cells in the media present in 50 to 75 percent of positive biopsies, fragmented internal elastic lamina best demonstrated with Verhoeff-van Gieson staining, and intimal hyperplasia. The sensitivity is approximately 85 to 90 percent, with skip lesions accounting for potential false negatives. Biopsy can be performed within 2 weeks of starting glucocorticoids without significant loss of sensitivity, and bilateral biopsy increases the diagnostic yield by 5 to 10 percent. The 2018 EULAR recommendations acknowledge that imaging with ultrasound or MRI can replace biopsy in experienced centers when imaging findings are positive.

### Management

#### Acute Treatment

Glucocorticoid treatment must not be delayed when GCA is suspected, particularly in the presence of visual symptoms. For patients without visual symptoms, prednisone at 40 to 60 milligrams daily, approximately 1 milligram per kilogram per day, is the standard initial dose. For patients with visual symptoms or impending visual loss, treatment begins with intravenous methylprednisolone 1000 milligrams daily for 3 days, followed by oral prednisone 60 milligrams daily, along with urgent ophthalmology consultation, with the primary goal of preventing contralateral eye involvement. Low-dose aspirin at 75 to 100 milligrams daily may reduce ischemic events and is conditionally recommended by the ACR.

#### Glucocorticoid Taper

The typical total duration of glucocorticoid therapy is 1 to 2 years, though some patients require longer courses. A representative taper schedule begins with the initial dose of 40 to 60 milligrams for 2 to 4 weeks, followed by reductions of 10 milligrams every 2 weeks until reaching 20 milligrams, then reductions of 2.5 milligrams every 2 to 4 weeks until reaching 10 milligrams, and finally reductions of 1 milligram every 1 to 2 months below 10 milligrams. Monitoring at each visit should include symptom assessment along with ESR and CRP measurement, initially every 2 to 4 weeks and then monthly. Relapse occurs in approximately 50 percent of patients during the taper, most commonly when prednisone drops below 10 milligrams daily.

#### Tocilizumab (GC-Sparing Agent)

The landmark GiACTA trial demonstrated that tocilizumab 162 milligrams subcutaneously weekly combined with a 26-week prednisone taper achieved sustained remission at 52 weeks in 56 percent of patients compared to only 14 percent with prednisone taper alone. Tocilizumab received FDA approval for GCA in 2017 and allows faster glucocorticoid tapering with substantially lower cumulative glucocorticoid exposure. The 2024 ACR/EULAR recommendations conditionally recommend tocilizumab for all patients with new or relapsing GCA. An important monitoring consideration is that tocilizumab suppresses CRP regardless of disease activity, rendering CRP unreliable as a disease activity marker. Clinicians must rely instead on clinical symptoms and imaging for monitoring. The minimum duration of tocilizumab therapy is 1 year, though the optimal duration remains uncertain, and relapse is common after discontinuation, occurring in approximately 50 percent of patients.

#### Other Steroid-Sparing Agents

Methotrexate provides modest benefit as a steroid-sparing agent, with a meta-analysis of three randomized controlled trials showing reduced relapse rates and cumulative glucocorticoid doses. It is used primarily when tocilizumab is unavailable or contraindicated. Abatacept showed reduced relapse risk in the ABAGART trial, though Phase III data are awaited. Secukinumab, an anti-IL-17 agent, is under investigation. Tocilizumab biosimilars represent emerging options for cost reduction.

#### Monitoring for Complications

Glucocorticoid-related side effects require proactive monitoring and management, including osteoporosis assessment with DEXA scanning, calcium and vitamin D supplementation, and bisphosphonate therapy when indicated, as well as monitoring for diabetes, hypertension, infection, cataracts, and adrenal insufficiency. Aortic aneurysm screening with CT or MR angiography should be performed at diagnosis and periodically thereafter, with expert opinion suggesting annual screening for the first 2 years followed by every 2 to 5 years. Relapse monitoring relies on symptoms, ESR and CRP (acknowledging their unreliability on tocilizumab), and imaging when needed.

## Polymyalgia Rheumatica

### Epidemiology

Polymyalgia rheumatica has an incidence of 50 to 100 per 100,000 in individuals over 50 years of age, making it the most common inflammatory rheumatic disease in the elderly. The female-to-male ratio is 2 to 3 to 1, matching the demographics of GCA. Approximately 15 percent of PMR patients have coexistent GCA, and 40 to 60 percent of GCA patients have PMR features, highlighting the close relationship between these conditions.

### 2012 ACR/EULAR Classification Criteria

The 2012 ACR/EULAR classification criteria require an age of 50 or older, bilateral shoulder aching, and an abnormal CRP and/or ESR. The scoring system without ultrasound assigns points for morning stiffness exceeding 45 minutes (2 points), hip pain or restricted range of motion (1 point), negative RF and anti-CCP (2 points), and absence of other joint involvement (1 point), with a score of 4 or greater classifying as PMR. When ultrasound is incorporated, additional points are available for bilateral subdeltoid bursitis, biceps tenosynovitis, or glenohumeral synovitis (1 point) and bilateral hip synovitis or trochanteric bursitis (1 point), with a threshold of 5 or greater for classification.

| Criterion | Finding | Points (without US) | Points (with US) |
|-----------|---------|---------------------|-------------------|
| **Required** | Age ≥50, bilateral shoulder aching, abnormal CRP and/or ESR | Entry criterion | Entry criterion |
| Morning stiffness | >45 minutes | 2 | 2 |
| Hip pain/limited ROM | Hip pain or restricted range of motion | 1 | 1 |
| RF and anti-CCP | Both negative | 2 | 2 |
| Absence of other joint involvement | No other joints involved | 1 | 1 |
| Shoulder US | Bilateral subdeltoid bursitis, biceps tenosynovitis, or glenohumeral synovitis | — | 1 |
| Hip US | Bilateral hip synovitis or trochanteric bursitis | — | 1 |
| **Classification threshold** | | **Score ≥4** | **Score ≥5** |

### Clinical Features

Bilateral shoulder pain and stiffness is present in more than 95 percent of patients and is often severe, with significant difficulty raising the arms above the head. Hip and pelvic girdle pain and stiffness occur in approximately 70 percent and produce difficulty rising from a seated position and climbing stairs. Morning stiffness exceeding 45 minutes, and often exceeding 1 hour, is characteristic. Constitutional symptoms including fatigue, malaise, low-grade fever, and weight loss are common. A dramatic response to low-dose glucocorticoids, with significant improvement within 24 to 72 hours, is itself a diagnostic feature of PMR. Peripheral synovitis is mild when present, affecting the knees and wrists, and is rarely erosive. Distal extremity swelling resembling RS3PE (remitting seronegative symmetrical synovitis with pitting edema) should prompt consideration of an underlying malignancy.

### Imaging

Ultrasound of the shoulders reveals bilateral subdeltoid or subacromial bursitis, biceps tenosynovitis, and glenohumeral synovitis, while hip ultrasound may demonstrate synovitis and trochanteric bursitis. PET-CT shows increased FDG uptake in the shoulders, hips, spinous processes, and interspinous bursae and can additionally detect large-vessel GCA. MRI demonstrates a bursitis and synovitis pattern similar to that seen on ultrasound.

### Differential Diagnosis

The differential diagnosis of PMR includes late-onset rheumatoid arthritis, which is distinguished by RF or anti-CCP positivity, erosive disease, and a lack of dramatic response to low-dose glucocorticoids. GCA features should always be screened for in PMR patients through careful questioning about headache, jaw claudication, and visual symptoms. Inflammatory myopathies produce proximal weakness rather than pain and have elevated CK levels. Paraneoplastic PMR-like syndromes may be seen with underlying malignancies, and cancer screening is indicated when atypical features are present. Hypothyroidism can cause proximal muscle aching and should be excluded with TSH testing. Bilateral rotator cuff disease produces shoulder pain but is not associated with elevated inflammatory markers. Fibromyalgia features normal ESR and CRP with widespread pain that is not limited to the proximal girdles.

### Management of PMR

Prednisone at 12.5 to 25 milligrams daily is the initial treatment per 2015 ACR/EULAR guidelines. At least 70 percent improvement within one week is expected, and failure to respond should prompt reconsideration of the diagnosis. The glucocorticoid taper reduces the dose to 10 milligrams daily by 4 to 8 weeks, then by 1 milligram every 4 weeks, with the goal of discontinuation by 1 to 2 years. Most patients require 1 to 2 years of treatment, and 30 to 50 percent experience relapse during the taper. Glucocorticoid-related morbidity is significant, with 60 to 80 percent of PMR patients experiencing at least one adverse effect.

Methotrexate at 7.5 to 10 milligrams weekly serves as a glucocorticoid-sparing agent that reduces relapse rates and cumulative glucocorticoid doses. The 2015 ACR/EULAR guidelines conditionally recommend early methotrexate for patients at high risk of relapse or those experiencing glucocorticoid side effects. Tocilizumab showed benefit in the PMR-GIA trial and is used off-label for refractory or relapsing PMR, though larger randomized controlled trials are needed. Leflunomide has been evaluated in small studies as an alternative steroid-sparing agent. Sarilumab, an anti-IL-6 receptor antibody, demonstrated in the SAPHYR trial that 200 milligrams subcutaneously every 2 weeks allowed faster glucocorticoid tapering, representing a promising emerging therapeutic option.

<image>A clinical comparison diagram of GCA and PMR showing their overlapping and distinct features. Use two overlapping circles (Venn diagram style). In the GCA circle: new headache, jaw claudication, visual symptoms, temporal artery abnormalities, large-vessel inflammation, high-dose GC treatment (40-60 mg). In the PMR circle: bilateral shoulder/hip girdle pain and stiffness, morning stiffness >45 min, subdeltoid bursitis on US, dramatic response to low-dose GC (12.5-25 mg). In the overlap: age >50, elevated ESR/CRP, constitutional symptoms, IL-6 elevation, responds to tocilizumab, aortic involvement possible. Below the diagram, show the key question: "Does this PMR patient also have GCA?" with red flag symptoms (headache, jaw claudication, visual symptoms, temporal artery abnormalities) that warrant further evaluation.</image>

## Key Clinical Pearls

- GCA with visual symptoms is a medical emergency; start IV methylprednisolone 1g daily immediately
- Do NOT wait for biopsy results before starting GC in suspected GCA; biopsy remains positive for up to 2 weeks
- Jaw claudication has the highest positive likelihood ratio (~4.2) of any clinical feature for GCA
- Tocilizumab suppresses CRP regardless of disease activity; use clinical symptoms and imaging for monitoring on TCZ
- PMR should respond to prednisone ≤25 mg/day within 1 week; if no response, reconsider the diagnosis
- All GCA patients need long-term aortic aneurysm surveillance (17x increased risk of thoracic aneurysm)

## References
1. Hellmich B, et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2020;79(1):19-30.
2. Stone JH, et al. Trial of tocilizumab in giant-cell arteritis (GiACTA). N Engl J Med. 2017;377(4):317-328.
3. Dejaco C, et al. 2015 Recommendations for the management of polymyalgia rheumatica: a EULAR/ACR collaborative initiative. Ann Rheum Dis. 2015;74(10):1799-1807.
4. Dasgupta B, et al. 2012 Provisional classification criteria for polymyalgia rheumatica: a EULAR/ACR collaborative initiative. Ann Rheum Dis. 2012;71(4):484-492.
5. Ponte C, et al. 2024 EULAR/ACR recommendations for the management of giant cell arteritis. Ann Rheum Dis. 2024.