The Vasculitides

Yusuf Yazici

Michael D. Lockshin

KEY POINTS

The major ischemic manifestations of vasculitides are defined by the type and size of the blood vessels involved and the tissue and organ damage caused by ischemia related to vascular occlusion.
Most diagnoses are defined by clinical rather than laboratory findings.
Treatment of most vasculitides involves corticosteroids usually along with immunosuppressive agents, especially when there is major organ involvement.
When there is a high suspicion of vasculitis, treatment should be started right away before waiting for definite laboratory or tissue evidence because major organ complications can develop quickly.

The vasculitides are a heterogeneous group of systemic inflammatory disorders that have as their common manifestation the inflammation of blood vessels with demonstrable structural injury to the vessel walls.

The major ischemic manifestations are defined by the type and size of the blood vessels involved and the tissue and organ damage caused by vascular occlusion.

ETIOPATHOGENESIS

Although the specific cause of many of these disorders is not known, the inciting agents and disease mechanisms have been characterized in many. Infectious organisms, drugs, tumors, and allergic reactions are some of the defined triggers.

Pathogenetic factors include immune complex disease, antineutrophil cytoplasmic antibodies, antiendothelial cell antibodies, and cell-mediated immunity.

CLINICAL MANIFESTATIONS

Although each of the vasculitic disorders has its own clinical signature (see the specific disease discussions in subsequent text), they share clinical manifestations to one degree or another.
When the physician deals with a patient who has a multisystem disorder, and once infection and neoplasm have been ruled out appropriately, a vasculitic disorder should be strongly considered if combinations of the following manifestations are prominent:
- Constitutional symptoms, including fatigue, weight loss, fever, weakness, and failure to thrive.
- Skin rash.
- Joint inflammation.
- Muscle inflammation.
- Neuropathy or central nervous system disjunction.
- Pulmonary infiltrates or nodules.
- Sinus or nasal inflammation.
- Kidney inflammation or insufficiency.
- Gastrointestinal or liver inflammation.
- Laboratory abnormalities, including anemia, leukocytosis, thrombocytopenia, and elevated erythrocyte sedimentation rate (ESR), or C-reactive protein (CRP).

CLASSIFICATION

Although many clinical overlap syndromes may exist, the following clinical parameters can be employed to diagnose the disorder, define its severity, and then construct the correct therapeutic plan.

I. VESSEL SIZE

The occlusion of blood vessels as a consequence of inflammation leads to different clinical manifestations defined by the type and size of blood vessel involved and the tissue bed that is perfused by the vessel. Therefore, the physician can employ the findings the patient presents with as a diagnostic tool. For example, large-vessel involvement might cause blindness, stroke, or a myocardial infarction; medium-vessel disease can lead to renal or bowel dysfunction; and small-vessel disease can cause skin lesions and ischemia (Table 37-1).

II. PATHOLOGY AND TYPE OF INFLAMMATION

The types of inflammation involving blood vessels fall into two broad categories: necrotizing and granulomatous; however, overlaps can exist. In the necrotizing type, seen classically in polyarteritis nodosa (PAN), inflammatory lesions are focal and segmental and consist of macrophages, CD4+ T lymphocytes, and polymorphonuclear leukocytes. Fibrinoid necrosis may or may not exist, but disruption of the internal elastic lamina is expected. The granulomatous lesion of Wegener’s granulomatosis (WG) in the lung reveals focal necrotizing lesions with or without granulomatous inflammation or multinucleated giant cells. It is important to note that vasculitides are commonly segmental, with areas skipped between active vessel inflammation and normal vessel. This demands multiple tissue sections. In PAN,
inflammation can also occur in one section of the vessel and it is this asymmetry of vessel wall damage that can lead to aneurysms.

Table 37-1 Clinical Manifestations of Vasculitis According to Vessel Size

Vessel size	Disorder
Large vessels (aorta and its branches)	Giant cell arteritis Takayasu’s arteritis Primary angiitis of the central nervous system
Medium-sized vessels (main visceral arteries)	Polyarteritis nodosa Kawasaki’s disease
Small vessels (venules, capillaries, arterioles, and small arteries)	Churg-Strauss syndrome Wegener’s granulomatosis Henoch-Schönlein purpura Microscopic polyangiitis Mixed cryoglobulinemia

III. CHARACTERISTIC CLINICAL PATTERNS

WG—lung, sinus, and kidney; PAN—aneurysms and neuropathy; Henoch-Schönlein purpura (HSP)—rash, abdominal pain, and joint problems.

IV. CLUES TO PATHOGENIC MECHANISMS

Virus/immune complexes (hepatitis B and C)—PAN; cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and antiproteinase 3—WG; perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) and antimyeloperoxidase—microscopic angiitis.

V. LABORATORY ABNORMALITIES

VI. INCITING AGENTS

Hepatitis B virus—PAN; hepatitis C virus—mixed (IgG–IgM) cryoglobulinemia; human immunodeficiency virus—PAN, leukocytoclastic vasculitis (LV).

DIAGNOSTIC INVESTIGATIONS

Most patients with vasculitis have nonspecific systemic symptoms, involvement of multiple organ systems, or both. They commonly present as diagnostic challenges. The diagnosis is based on a combination of clinical, serologic, histologic, and, for medium and large vessel disease, angiographic findings. A complete history and physical examination are mandatory, because most diagnoses are optimally defined by clinical rather than by laboratory findings. Although the diagnosis of the vasculitides is usually based on the clinical presentation, certain supporting data are employed in solidifying the diagnosis, defining the extent of the disease and the degree of tissue damage, and guiding therapeutic choices. However, it must be appreciated that if the clinical picture dictates immediate therapeutic action, awaiting the results of more sophisticated tests or biopsies may not be appropriate.

LABORATORY TESTS

I. The level of inflammation

can be defined by the presence of anemia, leukocytosis, thrombocytosis, and elevation of the ESR or CRP levels. All values may be abnormal on disease presentation and improve or normalize after therapy is instituted.

II. ORGAN-SPECIFIC LABORATORY TESTING

Testing for the presence and extent of organ involvement is often guided by the clinical manifestations and also includes routine blood testing and imaging.

Renal involvement can be clarified best with measurement of serum creatinine, urinalysis, and possibly a 24-hour urine collection for determination of creatinine clearance and protein. An elevated creatinine level and active urinary sediment with red blood cells, casts, and proteinuria commonly reflect active kidney inflammation, characteristic of small vessel vasculitis.
Muscle inflammation. An elevated creatine kinase level could represent muscle damage resulting from inflammation or myocardial infarction resulting from coronary vasculitis.
Lung involvement. A posteroanterior and lateral chest radiograph or computed tomography (CT) scan can be quite helpful in defining a pulmonary infiltrate cavity, nodule, pleural involvement.
Liver involvement. Abnormal results of liver function tests may reflect liver inflammation or associated infectious hepatitis.
Sinus involvement. A routine sinus series radiograph or CT scan may help define the presence and extent of mucosal inflammation.

III. TESTING FOR TYPE OF VASCULITIS OR ITS ETIOLOGY

These tests are used in specific clinical circumstances, as guided by the disease presentation and the results of the above routine tests.

Consider an infectious trigger. Hepatitis B or C and human immunodeficiency virus.
Consider an immune complex disorder. Complement consumption with low C3 and C4 levels and presence of cryoglobulins (e.g., hepatitis C).
Consider an autoimmune disorder such as systemic lupus erythematosus (SLE). Antinuclear antibody (ANA) and anti-dsDNA testing.

IV. DISEASE-SPECIFIC LABORATORY TESTING

Antineutrophil cytoplasmic antibody (ANCA). These antibodies are found in the serum of patients with specific types of vasculitis and are helpful as adjunctive diagnostic tools in the setting of a clinical picture consistent with WG, microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS). Two different indirect immunofluorescence staining patterns characterize these antibodies: cytoplasmic (c-ANCA, reflecting antibodies to serine proteinase 3) and perinuclear (p-ANCA, reacting with myeloperoxidase). A few points about ANCA that are important are listed below.
- Most, but by no means all, patients with WG have c-ANCA positivity and most with MPA or CSS have p-ANCA positivity.
- The definite diagnosis of WG continues to be based on biopsy results, not on ANCA positivity.
- Decisions regarding disease activity should be based on clinical signs, not on the ANCA titer or the biopsy.
- Ten percent of patients may be negative for ANCA in the setting of active vasculitis.
Tissue biopsy. Like any test, a tissue biopsy should be considered if it is needed to define a diagnosis, guide a therapy, or clarify the prognosis. In general, the simplest and safest procedure with the highest yield should be chosen, as defined by the specific clinical setting. At times, the severity of the disease and the comorbidities are such that one employs the clinical picture alone in guiding the treatment.

Certain procedures are associated with both a high yield and low risk: skin biopsy in patients with dermatitis, temporal artery biopsy in giant cell arteritis (GCA), and muscle biopsy in PAN. Others entail a higher risk with a high diagnostic yield: lung biopsy in WG, kidney biopsy in MPA, muscle and nerve biopsy in PAN, and brain biopsy in primary angiitis of the brain.

IMAGING STUDIES

I. MAGNETIC RESONANCE IMAGING (MRI) AND COMPUTED TRANSAXIAL TOMOGRAPHY (CTT)

These procedures may be needed to define the presence of specific organ involvement or extent of disease. Examples include MRI of the brain to assess for infarcts or CTT of the chest to characterize lung disease.

II. ANGIOGRAPHY

In special circumstances, this procedure can add greatly to diagnostic accuracy and to the definition of the type and the extent of vascular involvement. This is particularly true when diagnostic questions remain after the initial clinical evaluation of PAN and Takayasu’s arteritis (TA). Magnetic resonance angiography (MRA) can be employed as a noninvasive method of evaluating vessel involvement. Angiograms are not helpful in small vessel vasculitis.

III. Positron-emission tomography (PET) scanning

can be used in select cases for showing aortic and other vascular inflammation as part of a fever of unknown origin or vasculitis workup.

GIANT CELL ARTERITIS

GCA is a disease of aging adults, usually starting after the age of 50 years. It affects primarily whites, and women are twice as likely to be affected. GCA can accompany polymyalgia rheumatica (PMR), a syndrome characterized by proximal muscle aches and stiffness that is usually symmetric.

I. CLINICAL MANIFESTATIONS

Common presenting symptoms are fatigue, headache, and tenderness of the scalp, particularly around the temporal and occipital areas. Jaw claudication (pain when chewing) is seen in two-thirds of patients. Headache is the presenting symptom in
two-thirds of the patients, and half of them have the proximal soreness and stiffness, often severe, of PMR.
Physical examination. Temporal arteries can be palpable, tender, and nodular, with reduced pulsation. In some series, visual disturbances have been reported in 20% of patients, but the frequency has declined over the years, probably because of earlier diagnosis and treatment. Transient ophthalmologic symptoms can lead to permanent blindness if not treated promptly.

II. Diagnosis

of GCA should be considered in any patient older than 50 years with recent onset of headache, loss of vision, myalgia, fever of unknown origin, a high ESR, or anemia. It should be remembered that PAN can, but rarely, also affect the temporal arteries.

Laboratory tests. The ESR is usually elevated, often over 100 mm/hour. A normal ESR is unusual but does not rule out GCA. Anemia and thrombocytosis are common. Similarly, the ESR is usually elevated in PMR, but a normal ESR does not rule out PMR.
Temporal artery biopsy. Most rheumatologists recommend biopsy to define the presence of vessel inflammation. Some do bilateral biopsies initially and some recommend contralateral biopsy when the first side is negative. Things to keep in mind are as follows: Do not delay treatment awaiting the results of the biopsy; and remember that in one-third of patients biopsy results are negative because the lesions can involve the artery in a skipped fashion. Color duplex ultrasonography may have a place in the diagnosis of GCA; the most specific finding is a dark halo around the artery, which may represent edema. However, skill and experience of the ultrasonographer is important.
Pathology shows granulomatous arteritis with giant cells and destruction of the internal elastic lamina.

III. TREATMENT

Most rheumatologists use an initial dosage of 10 to 20 mg of prednisone daily for PMR and 40 to 60 mg of prednisone daily for GCA because of the higher risk of arteritic complications in GCA. There is usually a dramatic response to steroids in patients with PMR, seen within days.

Corticosteroid tapering begins after a month; most patients are on 5 to 10 mg of prednisone at 6 months. Although controversy exists over the length of treatment, patients will usually need to be on steroids for about a year, and some for as long as 2 years.
Relapses are defined on clinical grounds, not solely by an elevation of the ESR, and are managed by increasing the dose of steroid. Side effects of corticosteroids should be kept in mind and may necessitate the use of steroid-sparing agents such as methotrexate or azathioprine.
Low-dose aspirin (100 mg) has been shown to help prevent cranial ischemic complications of GCA.

TAKAYASU’S ARTERITIS