at: inbox

Rheumatology - Selected Vasculitides - Fast Facts | NEJM Resident 360

Vasculitis is inflammation within blood vessels 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, and management is usually outpatient. 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 can occur simultaneously in patients with GCA. PMR is an inflammatory rheumatic condition that is more common than GCA and affects women more often than men.

• Antineutrophil Cytoplasmic Antibody (ANCA)–associated vasculitides (AAV) are rare multisystem autoimmune diseases that are more common in older people and in men.

Giant-Cell Arteritis and Polymyalgia Rheumatica

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

GCA is an inflammatory 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)

• ophthalmic arteries; can lead to ischemic optic neuropathy and vision loss in 10% to 15% of patients

• vertebral arteries

• distal subclavian arteries

• axillary arteries

• thoracic aorta; can lead to complications of aneurysm formation and dissection

Clinical Features

GCA

• changes in vision, such as transient vision loss (amaurosis fugax), is the most alarming symptom and, usually due to ischemic optic neuropathy, is considered an emergency because permanent vision loss may occur if left untreated and treatment can prevent a similar complication in the other eye

• new-onset headache (the most common chief complaint)

• scalp tenderness

• asymmetric enlargement, tenderness, or beading of temporal arteries (pulse may be decreased or absent)

• fatigue

• fever

• jaw claudication

PMR

• pain, aching, or stiffness or all three in selected muscle groups (e.g., shoulders or pelvic girdle), with symptoms most pronounced in the morning

• fatigue

• anorexia

• weight loss

A differential diagnosis of cancer must be considered, with additional investigation undertaken 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 generally quite high.

• When PMR is suspected, testing for antibodies can help rule out other diagnoses, such as rheumatoid arthritis (e.g., rheumatoid factor [RF], anti–cyclic citrullinated peptide [CCP]).

• 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 vasculitis in GCA.

  • Temporal artery ultrasound is a potentially useful modality for assessing the presence of inflammation. European League Against Rheumatism (EULAR) and British Society for Rheumatology guidelines recommend ultrasound prior to considering biopsy in most cases.

• Temporal artery biopsy is the gold-standard test for GCA. Changes suggestive of GCA are visible in the biopsy specimen shown below.

  • Panel A shows a normal segment of the temporal biopsy — also called a “skip lesion” as it has been skipped and is unaffected.

  • Panel B shows some of the typical findings in GCA:

    • disruption of the internal elastic lamina

    • thinning of the media

    • scarring of the intima

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

Note: In cases of suspected GCA with ischemic optic neuropathy, treatment should not be delayed for diagnosis confirmation. Immediate intervention is required to provide the best chance for preserving vision. Diagnostic tests for GCA may be affected by glucocorticoids, however, especially the CRP, which may decrease within hours. The usefulness of 18F-FDG PET/CT may diminish within 24 to 72 hours of starting glucocorticoids. Other imaging modalities will decline in diagnostic effectiveness in a similar time frame. Although the sooner a biopsy can be performed, the better, a biopsy may still be interpretable for up to a week or more after starting glucocorticoids. If symptoms are localized to one side, that side should be biopsied.

Classification Criteria for GCA and PMR from the American College of Rheumatology 

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

Treatment

Both GCA and PMR are treated with glucocorticoids, although at much different doses. GCA treatment usually begins with prednisone or prednisolone 1 mg/kg daily, whereas PMR treatment begins with 15 to 20 mg daily. Some experts recommend low-dose aspirin in patients with GCA unless contraindicated to (possibly) lower the risks of vision loss and stroke.

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 (Actemra) is a monoclonal antibody against interleukin-6 receptor alpha that gained FDA approval in treatment of GCA in 2017.

• The GiACTA trial showed improved sustained glucocorticoid-free remission at one year and reduced cumulative glucocorticoids doses, but longer follow-up is needed to assess for adverse effects. (View a NEJM Quick Take video or read a NEJM Journal Watch summary about the trial).

• Currently, its optimal role in clinical practice is uncertain, but it may be helpful in patients who have trouble tapering glucocorticoids or who are at high risk of steroid-related adverse events.

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

• Patients on long-term high-dose glucocorticoids should receive Pneumocystis jirovecii pneumonia prophylaxis (although this strategy is not well studied among patients with GCA).

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 frequently accompanied with positive tests for ANCA by immunofluorescence. They may have autoantibodies against proteinase 3 (anti-PR3) or myeloperoxidase (anti-MPO), although some patients with these diseases are ANCA-negative.

Clinical Features

Microscopic polyangiitis/granulomatosis with polyangiitis:

The presenting features of MPA and GPA can be remarkably similar so that differentiating them can be difficult. In general, these diseases target primary blood vessels of a small caliber. Consequently, their manifestations have a tendency to affect body organs with a predominance of small vessels, particularly the lung parenchyma and the kidneys. Typical manifestations include:

• petechial/purpuric rash

• inflammatory arthritis (symmetrical small joints primarily)

• sinus congestion

• sensorineural hearing impairment

• bloody nasal crusting/epistaxis

• pulmonary hemorrhage

• interstitial fibrosis

• mononeuritis multiplex

• glomerulonephritis with acute kidney injury

Eye, ear, nose, and throat manifestations occur more commonly in patients with GPA than in those with MPA. Additional laboratory work in patients with GPA is likely to show positive testing for antibodies to proteinase 3 (anti-PR3) with a cytoplasmic-staining pattern on immunofluorescence microscopy of neutrophils (c-ANCA). On the other hand, MPA and EGPA are associated with antimyeloperoxidase (anti-MPO) antibodies and perinuclear ANCA (p-ANCA) pattern on immunofluorescence microscopy of neutrophils.

Eosinophilic granulomatosis with polyangiitis: 

Unlike MPA and GPA, the primary presentation of EGPA is that of difficult-to-control asthma. The vasculitic phase of the disease usually comes later in the natural history. In addition to the features seen in MPA and GPA, the following manifestations are also seen in EGPA:

• steroid-dependent asthma

• hypereosinophilic syndrome with associated organ dysfunction from eosinophil infiltration

Nasal hemorrhage is uncommon in EGPA.

Diagnosis

Diagnosis of each of these vasculitides can largely be made on clinical grounds alone with a compatible clinical history and no likely alternative explanation. In addition, the following tests are of value:

• ANCA immunofluorescence is mostly positive but occasionally negative. Perinuclear ANCA (p-ANCA) staining pattern is commonly associated with MPA and EGPA. Cytoplasmic-staining pattern on immunofluorescence microscopy of neutrophils (c-ANCA) is mostly seen with GPA.

• Anti-MPO or anti-PR3 antibodies are often present at a high titer. 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.

• Kidney biopsy with pauci-immune glomerulonephritis

• Targeted (nonkidney) tissue biopsy: 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: There are no diagnostic imaging tests for AAV, though imaging of lung parenchyma (plain radiographs, computed tomography) is helpful to identify pulmonary involvement, such as ground-glass opacities (GGOs) and cavitating lung nodules (typical of GPA).

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 (such as cyclophosphamide or rituximab) is necessary. Maintenance therapy is usually a combination of tapering glucocorticoids and another agent (such as azathioprine or mycophenolate). The optimal choice of induction and maintenance agent is still unclear and is often individualized to the patient. Although avacopan was recently found to be effective in the treatment of AAV with a steroid-sparing effect, its role remains uncertain.

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, patients with AAV can relapse. Those who have a PR3 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.

inbox