Selected Vasculitides

Vasculitis is defined by inflammation within blood vessel walls that can affect vessels of all sizes (small, medium, or large) and can have a broad array of presentations. Specialist involvement (e.g., rheumatologists, nephrologists, pulmonologists, and/or others) should be routine. Vasculitis can be broadly classified as primary (i.e., diseases in which the primary clinical manifestations are due to vasculitis), secondary to other autoimmune diseases (e.g., rheumatoid vasculitis associated with rheumatoid arthritis), secondary to other systemic diseases (e.g., infectious vasculitis, paraneoplastic vasculitis), or drug-induced. Vasculitides are also categorized by the vessel size involved, as this largely determines the clinical manifestations patients exhibit:

• small (capillaries, arterioles, and venules): cutaneous leukocytoclastic vasculitis (typically appearing as palpable purpura), alveolar hemorrhage, glomerulonephritis

• medium (arteries within organs): renal or mesenteric infarctions, mononeuritis multiplex

• large (aorta and its branches): aortitis, limb claudication, jaw claudication

(Source: 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheumatol 2013.)

A full review of vasculitis is beyond the scope of this guide. Instead, we review the following conditions that residents are likely to encounter:

• Giant-cell arteritis(GCA; also known as temporal arteritis) is a large-vessel inflammatory vasculitis and the most common type of vasculitis in adults in North America.

• Polymyalgia rheumatica(PMR) is not a vasculitis but occurs in approximately 50% of patients with GCA. PMR is an inflammatory rheumatic condition that is more common than GCA and affects women more often than men.

• Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) is a rare multisystem autoimmune disease that is more common in older people and in men.

Giant-Cell Arteritis and Polymyalgia Rheumatica

Giant-cell arteritis (GCA) and polymyalgia rheumatica (PMR) are immune-mediated diseases that can occur simultaneously or in isolation in people aged 50 or older, with peak incidence between ages 70 and 80. Diagnoses of GCA and PMR are made based on clinical history and examination, laboratory studies, imaging, and (for GCA) confirmation by pathology.

GCA is a vasculitis that typically, but not exclusively, affects large arteries. Vasculitis can lead to luminal occlusion and therefore ischemic complications. The arteries affected generally include:

• branches of the external carotid arteries (e.g., temporal and occipital arteries)

• posterior ciliary or ophthalmic arteries, which can lead to ischemic optic neuropathy and vision loss in 10% to 15% of patients

• vertebral arteries and posterior cerebral circulation, which can rarely lead to posterior circulation strokes

• subclavian arteries

• axillary arteries

• thoracic aorta, which can lead to complications including aneurysm formation and dissection

GCA has historically been referred to as temporal arteritis due to its frequent tendency to affect these arteries, which are the site of biopsy that confirms the diagnosis in most cases. However, this term has been replaced by GCA, as not all patients with GCA have involvement of the temporal arteries, and temporal arteritis can occur due to other systemic vasculitides (e.g., polyarteritis nodosa, AAV).

Clinical Features

GCA

• Changes in vision, including diplopia and transient vision loss (amaurosis fugax): Amaurosis fugax, usually due to ischemic optic neuropathy, is the most alarming symptom in patients with GCA and is considered an emergency because permanent vision loss may occur if not treated promptly, and treatment can prevent a similar complication in the contralateral eye.

• New-onset headache (the most common chief concern): No one particular location or description of headache is specific or especially typical of GCA, but new, worsening, or severe headaches in older adults should prompt consideration of GCA.

• Scalp tenderness: Patients often report this feature as pain while combing their hair. It can rarely lead to scalp necrosis.

• Jaw (or tongue) claudication: This feature is defined as pain, soreness, or fatigue in the jaw or tongue that emerges with eating or speaking and resolves with resting the mouth. Although this feature should be differentiated from pain related to temporomandibular joint dysfunction, when present, it has the highest positive predictive value for the diagnosis of GCA of all clinical symptoms and signs on physical exam.

• Asymmetric enlargement, tenderness, or beading of temporal arteries: The pulse may be decreased or absent.

• Fatigue: Owing to the systemic inflammatory nature of the disease, fatigue and other constitutional symptoms are common.

• Fever: Fever may be the main presenting symptom in some patients, and GCA should be considered in cases of fever of unknown origin in older adults.

PMR

• symmetric pain and stiffness in selected joints (e.g., shoulders, pelvic girdle, neck), with symptoms most pronounced in the morning and improving throughout the day

• fatigue

• anorexia

• weight loss

• consider differential diagnosis of cancer and conduct additional investigation as deemed necessary

Evaluation

Laboratory studies:

• Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are common in both GCA and PMR. Although the lack of specificity of elevated inflammatory markers limits their utility, the negative predictive value of a normal CRP and ESR is fairly high. Nevertheless, if the clinical presentation is highly suspicious for GCA or PMR and CRP and ESR are normal, rare cases can present with normal inflammatory markers.

• Testing for antibodies when PMR is suspected can help rule out other diagnoses, such as rheumatoid arthritis (e.g., rheumatoid factor [RF], anti-cyclic citrullinated peptide [CCP]). Further assessment should be performed to exclude alternative diagnoses and establish a baseline for monitoring therapy (refer to 2015 European League Against Rheumatism/American College of Rheumatology [EULAR/ACR] recommendations for the management of PMR).

Imaging studies:

• Computed tomography angiography (CTA), magnetic resonance angiography (MRA), and ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) can help assess the extent of large-vessel (i.e., extracranial) vasculitis in GCA. In patients with newly diagnosed GCA, the 2021 American College of Rheumatology/Vasculitis Foundation (ACR/VF) guidelines conditionally recommend this type of imaging for all patients.

• Temporal artery ultrasound is increasingly used for diagnosing GCA. European League Against Rheumatism(EULAR) and British Society for Rheumatology guidelines recommend using ultrasound prior to considering biopsy in most cases. In contrast, ACR/VF guidelines recommend temporal artery biopsy over ultrasound. The use of temporal artery ultrasound is limited by availability of clinicians trained in its use and its operator dependence.

Temporal artery biopsy:

Temporal artery biopsy has historically been considered the gold standard for diagnosing GCA, although temporal artery ultrasound is, in part, replacing it in centers where it is available.

• Changes suggestive of GCA are visible in the figures below and are summarized as follows:

  • normal segments of the temporal artery, also called skip lesions, representing unaffected segments of the artery

  • granulomatous inflammation

  • multinucleated giant cells

  • disruption of the internal elastic lamina

  • thinning of the media

  • scarring of the intima

• GCA is not the only type of vasculitis that can involve the temporal arteries, hence the distinction between the terms “temporal arteritis” and “GCA.”

  • Features on temporal artery biopsy that are inconsistent with the diagnosis of GCA and warrant consideration of other causes of temporal arteritis such as AAV and polyarteritis nodosa include prominent neutrophilic inflammation, fibrinoid necrosis, or prominent vasculitis of the vasa vasorum (small vessels that provide blood supply to the larger temporal arteries).

(Source: An Unusual Cause of Leg Pain. N Engl J Med 2017.)

(Source: Polymyalgia Rheumatica and Giant-Cell Arteritis. N Engl J Med 2003.)

Note: In cases of suspected GCA, treatment should not be delayed for confirmation of diagnosis. Immediate intervention is required to provide the best chance of preserving vision, even in patients without visual symptoms at the time of presentation. However, glucocorticoids may affect diagnostic tests for GCA. The CRP may decrease within hours. The usefulness of ¹⁸F-FDG PET/CT may diminish within 24 to 72 hours of starting glucocorticoids. The sensitivity of temporal artery ultrasound diminishes after about 7 days of glucocorticoids, and the sensitivity of biopsy diminishes after 1-2 weeks of glucocorticoids. For this reason, the evaluation should be expedited to the extent it is possible, especially after initiating glucocorticoids. If symptoms are localized to one side, that side should be biopsied.

The following criteria have been developed to help distinguish GCA from other vasculitides:

(Source: Giant-Cell Arteritis and Polymyalgia Rheumatica. N Engl J Med 2014.)

Treatment

Glucocorticoids are used for the treatment of both GCA and PMR, although at much different doses. GCA treatment usually begins with1 mg/kg daily of prednisone or prednisolone, whereas PMR treatment begins with 15 to 20 mg/kg daily. Rapid improvement of PMR symptoms within a few days after starting treatment with glucocorticoids is characteristic of the condition; lack of improvement should call into question the diagnosis of PMR.

The following algorithms provide more-specific treatment recommendations for GCA and PMR:

(Source: Giant-Cell Arteritis and Polymyalgia Rheumatica. N Engl J Med 2014.)

Other Treatments and Considerations:

• Tocilizumab is a monoclonal antibody against interleukin-6 receptor alpha that gained FDA approval in treatment of GCA in 2017. The ACR/VF management guidelines recommend routine use of tocilizumab, in addition to glucocorticoids, for all patients with newly diagnosed GCA.

• The GiACTA trial showed improved sustained glucocorticoid-free remission at one year and reduced cumulative glucocorticoid doses, but the optimal duration of treatment with tocilizumab is not known. (View a NEJM Quick Take video and read a NEJM Journal Watch summary about the trial.)

• Intravenous (IV) glucocorticoids may be necessary for induction therapy when visual symptoms are present.

• Despite patient exposure to prolonged courses of high-dose glucocorticoids, studies have indicated that Pneumocystis jirovecii pneumonia (PJP) is exceedingly rare in patients with GCA and PMR. The role of PJP prophylaxis in these diseases is therefore not clear.

• Treatment with bisphosphonates should be considered to prevent glucocorticoid-induced osteoporosis, when appropriate.

ANCA-Associated Vasculitis

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to the following diseases:

• microscopic polyangiitis (MPA)

• granulomatosis with polyangiitis (GPA; formerly referred to as Wegener granulomatosis)

• eosinophilic granulomatosis with polyangiitis (EGPA; formerly referred to as Churg-Strauss syndrome)

These three entities are grouped together because they are associated with the presence of ANCA by immunofluorescence assay and antibodies directed against proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA), although some patients with these diseases are ANCA-negative.

Clinical Features

The presentation of all ANCA-associated vasculitides can include constitutional features of fever, weight loss, malaise, and fatigue. The clinical features of the three diseases overlap substantially, as detailed below.

MPA/GPA: The presenting features of MPA and GPA can be remarkably similar and differentiating them can be difficult. In general, MPA and GPA diseases target primary blood vessels of a small- to medium-sized caliber. Typical manifestations include:

• petechial/purpuric rash due to cutaneous leukocytoclastic vasculitis

• inflammatory arthritis (typically a migratory oligoarthritis)

• sinusitis, often with bony destruction, epistaxis, or bloody nasal crusting (in GPA more often than in MPA)

• sensorineural hearing impairment

• pulmonary hemorrhage

• pulmonary interstitial fibrosis (in MPA more often than in GPA)

• mononeuritis multiplex

• glomerulonephritis (often rapidly progressive crescentic glomerulonephritis)

• inflammatory eye disease, especially scleritis and peripheral ulcerative keratitis

• eye, ear, nose, and throat manifestations (in GPA more often than in MPA)

Additional laboratory testing in patients with GPA is likely to show PR3-ANCA antibodies with a cytoplasmic (c-ANCA) staining pattern on immunofluorescence microscopy of neutrophils. MPA and EGPA are associated with MPO-ANCA antibodies and perinuclear ANCA (p-ANCA) patterns on immunofluorescence microscopy of neutrophils.

EPGA: EPGA is thought to present in three phases, either in order, potentially with years between phases, or with multiple phases simultaneously. The three phases are as follow:

• prodromal/atopic: characterized largely by adult-onset, refractory asthma; allergic rhinitis; and other atopic features

• eosinophilic: characterized by often profound peripheral eosinophilia and eosinophil-rich inflammatory infiltrates in multiple organs (e.g., eosinophilic myocarditis, eosinophilic esophagitis/gastroenterocolitis, eosinophilic pneumonia)

• vasculitic: presentation is similar to MPA and GPA

Diagnosis

Diagnosis of each of these vasculitides is clinical. In some cases, the diagnosis can be made on clinical grounds alone with a compatible clinical history and no alternative explanation. In most cases, biopsy of affected tissue or supportive serologic testing is required for diagnosis.

Serology: The following tests should be obtained in all cases of suspected ANCA-associated vasculitis:

• ANCA immunofluorescence is usually positive.

• p-ANCA staining pattern is commonly associated with MPA and EGPA. c-ANCA is primarily associated with GPA.

• Although ANCA-negative disease occurs in a minority of patients with GPA and MPA, up to 60% of patients with EGPA may be ANCA-negative.

• MPO-ANCA or PR3-ANCA antibodies are often present at high titers. Antibodies to MPO with a p-ANCA pattern are more frequently associated with MPA and EGPA; antibodies to PR3 with a c-ANCA pattern are more frequently associated with GPA.

Biopsy: When feasible, biopsy of affected tissue should be obtained to confirm the diagnosis. Typical findings include:

• kidney biopsy with pauci-immune glomerulonephritis

• non-kidney biopsy:

  • mixed inflammatory infiltrate including neutrophils, lymphocytes, plasma cells, and eosinophils

  • small-to-medium-vessel vasculitis

  • fibrinoid necrosis

  • granulomatous inflammation, typically without well-formed epithelioid granulomas (GPA and EGPA only)

  • substantial eosinophil-rich inflammation (EGPA only)

    • The presence of granulomatous inflammation with vasculitis and the absence of microorganisms is supportive of GPA and EGPA. The same histopathology without granulomata is supportive of MPA. EGPA is usually differentiated on clinical grounds and by the presence of eosinophilia of peripheral blood or eosinophil infiltration in the tissue sample.

Imaging: No diagnostic imaging tests are available for AAV, although imaging of lung parenchyma (with plain radiographs, computed tomography) is helpful to identify pulmonary involvement, such as ground-glass opacities (GGOs) and cavitating lung nodules (typical of GPA). Other organ-specific diagnostic tests should be guided by clinical presentation (e.g., electromyogram and nerve conduction studies for workup of foot or wrist drop, echocardiogram and cardiac MRI for workup of eosinophilic myocarditis).

Management

AAVs can manifest with organ-threatening disease, requiring prompt diagnosis and therapy with immunosuppressive drugs, or they can manifest over time with non-organ-threatening features. Depending on the manifestations, the treatment may differ.

In general, for organ-threatening or serious AAV, induction therapy with high-dose glucocorticoids and another immunosuppressive agent (typically rituximab) is necessary. Maintenance therapy is usually a combination of tapering glucocorticoids and another agent (most often with rituximab, although azathioprine and mycophenolate mofetil are occasionally used). The optimal approach to induction and maintenance agent is still under investigation and is often individualized to the patient. The novel C5a-complement receptor antagonist avacopan has been found to be effective in the treatment of AAV with a glucocorticoid-sparing effect, and it received FDA approval for this indication.

For non-organ-threatening AAV, such as sinus congestion with nasal crusting or arthritis, less-intensive therapy may be appropriate. In such cases, weekly methotrexate with adjunctive glucocorticoids is often used.

Importantly, AAV is most often a relapsing-remitting disease. Patients who have PR3-ANCA antibody-associated disease are much more likely to relapse compared to those who do not. The titer of the antibody on serial testing does not consistently correlate with the risk of relapse. Those patients who are on tapering doses of immunosuppressive therapy are at high risk for relapse and need to be monitored clinically for signs and symptoms that suggest that disease activity has increased.