Systemic Vasculitis Syndromes Part 1

The diagnosis of a primary vasculitic syndrome is dependent on documentation of vasculitis and the exclusion of diseases that can cause secondary vasculitis. The diagnosis of a specific primary vasculitic disorder depends on the pattern of organ involvement, the histopathology, and the size of affected blood vessels.

The major determinants of prognosis and therapy include the type of vasculitis, the severity and extent of critical organ involvement, the rate of disease progression, and the etiology, if identifiable. The inflammatory process is often associated with nonspecific symptoms and laboratory abnormalities (e.g., elevated erythrocyte sedimentation rate, anemia, and fevers) that do not distinguish vasculitic diseases from other inflammatory, infectious, or neoplastic diseases. The toxic nature of the therapies for systemic vasculitis dictates the need for an accurate diagnosis.

Approach to the Patient with Suspected Vasculitis


The physician should not be reluctant to pursue invasive testing in the diagnostic evaluation of patients with a multisystem illness, but biopsy of clinically uninvolved tissue and the use of less specific tests should be eschewed. An approach directed toward "ruling in" a specific form of vasculitis and ruling out reasonable specific alternatives should be pursued.

The first step in the diagnosis of vasculitis is to perform a detailed patient history and physical examination to document specific organ involvement. Special attention should be paid to the skin, eyes, ears, upper airway, joints, urinalysis, lymph nodes, peripheral nerves, and large vessels. A few laboratory tests [see Table 1] should be selectively included in the initial evaluation. Specialized studies, including serologies, should be obtained only after a differential diagnosis is formulated. If the urine dipstick test indicates blood, leukocytes, or protein, the physician must promptly examine several fresh urine sediments. Urine that has been sitting for several hours before analysis is not as useful for identification of cellular casts, which rapidly degenerate ex vivo. The presence of red blood cell casts is highly suggestive of glomerulonephritis, but white cell casts may also be seen. Glomerulonephritis is usually asymptomatic. On the basis of the pattern of organ involvement, a differential diagnosis that includes specific types of systemic vasculitis and other disorders can then be generated.

Table 1 Selected Laboratory Tests for Patients with Multisystem Disease and Possible Vasculitis



Platelet count

Thrombocytosis may parallel the acute-phase response

Thrombocytopenia is not expected in primary vasculitic syndromes; consider SLE, marrow infiltration, hairy-cell leukemia, TTP, DIC, hypersplenism, APLS, HIV, scleroderma renal crisis, and heparin-induced thrombocytopenia

White blood cell count

Leukopenia is not expected in primary vasculitis; consider SLE, leukemia, hypersplenism, sepsis, myelo-dysplasia, and HIV

Eosinophilia is common in Churg-Strauss syndrome; it may occur in WG, rheumatoid arthritis, or normo-tensive scleroderma renal crisis

Erythrocyte sedimentation rate

Relatively low ESR is seen in DIC, liver failure, and hyperviscosity; ESR is frequently normal in HSP, may be low in Takayasu arteritis, and is normal in s 20% of giant cell arteritis


ALT or AST is elevated in liver disease, myositis, rhabdomyolysis, hemolysis, or myocardial necrosis

Anti-glomerular basement membrane

Useful for evaluation of alveolar hemorrhage, with or without glomerulonephritis; also useful for evaluation of normocomplementemic glomerulonephritis

Antinuclear antibody

Order when there is clinical suspicion of SLE, not as a general screening test for sick patients; negative test makes SLE very unlikely

Antineutrophil cytoplasmic antibody

Order when there is clinical suspicion of WG or MPA; order specific anti-PR3 and antimyeloperoxidase

Drug screen

Order for unexplained CNS symptoms, myocardial ischemia, vascular spasm, panic attacks with systemic features, or tachycardia; urine screen should be done

Blood cultures

Useful for any patient with febrile, multisystem, or wasting illness; pulmonary infiltrates; or focal ischemia/infarction. Cultures are easy to obtain


Order for unexplained venous or arterial thrombosis or thrombocytopenia

Purified protein derivative (± anergy)

Use in any patient who may require steroid therapy or who has unexplained sterile pyuria or hematuria, granulomatous inflammation, chronic meningitis, or possible exposure to tuberculosis

Examination of fresh urinary sediment

Perform in all patients with an unexplained febrile or multisystem illness

Hepatitis serologies

Order for abnormal transaminases or elevated hepatic alkaline phosphatase; portal hypertension; PAN or MPA syndrome; or unexplained cryoglobulinemia, polyarthritis, or cutaneous vasculitis

Complement C3, C4

Not a screening test for vasculitis; useful in the differential diagnosis of glomerulonephritis; low in cryo-globulinemia; may be low in endocarditis; usually normal in PAN, MPA, HSP, WG; may be low in viral hepatitis-related glomerulonephritis or vasculitis


Aldolase has no organ specificity; it has similar organ distribution as lactic dehydrogenase

ALT—alanine aminotransferase

APLA—antiphospholipid antibody

APLS—antiphospholipid antibody syndrome

AST—aspartate aminotransferase

DIC—disseminated intravascular coagulation

ESR—erythrocyte sedimentation rate

HSP—Henoch-Schonlein purpura

MPA—microscopic polyangiitis

PAN—polyarteritis nodosa

PR3—proteinase 3

PTT—partial thromboplastin time

RVVT—Russell viper venom test

SLE—systemic lupus erythematosus

TTP—thrombotic thombocytopenic purpura

WG—Wegener granulomatosis

Classification of the systemic vasculitis syndromes.

Figure 1 Classification of the systemic vasculitis syndromes.


Several classification schemes have been proposed for organizing the systemic vasculitic disorders into a consistent paradigm. These classifications are useful in distinguishing the clinical disorders that have distinct differences in prognosis and response to treatment.1 No scheme is universally accepted. They all reiterate the characteristics of fulminant or classic disease, placing an emphasis on specificity of diagnosis. If a classification scheme is strictly adhered to, the newly ill patient without fully expressed disease is frequently left without a definitive diagnosis. The physician must recognize that until specific etiologies are defined, diagnostic entities remain conceptual, and overlap between diseases is not unusual. This must not be a deterrent to instituting therapy in the patient at risk for rapidly progressive organ damage. Nonetheless, classification systems provide useful constructs for communication and the design of research protocols [see Figure 1]. The most widely used classification schemes are based on the caliber of affected blood vessels, the pattern of organ involvement, and the presence or absence of granulomas, significant immune complex deposition, and eosinophilic infiltrates. Some authors have proposed a diagnostic role for the presence or absence of specific serum anti-neutrophil cytoplasmic antibodies (ANCAs), particularly antibodies to proteinase 3 and myeloperoxidase. At present, the appropriate role of these tests is to support a rationally developed clinical diagnosis, not to define one. In patients who do not fit neatly into a well-defined diagnostic category, these serologic tests should not supplant an attempt to obtain a tissue diagnosis. The presence of ANCA is not sufficient to make a diagnosis of a primary vasculitic syndrome; ANCA is not a screening test.

When the dominant symptoms and findings (i.e., neuropathy and cutaneous vasculitis) do not suggest a single specific vas-culitic disorder, targeted physical examination and serologic testing may be helpful. Most valuable is biopsy confirmation of the specific disorder. The value of indiscriminate testing for anti-nuclear antibodies, ANCA, rheumatoid factor, and angiotensin-converting enzyme is arguable. Alternatively, infection with hepatitis B or C can be associated with a broad range of vasculitic syndromes, and these infections must be routinely excluded.2

Overview of treatment

The systemic vasculitides are potentially life threatening and may require potent anti-inflammatory and immunosuppressive therapy. Diagnoses should be made with as much certainty as possible. However, questions regarding alternative diagnoses or coexistent diseases may linger. Hence, even after therapy is initiated, physicians should maintain a high degree of vigilance to detect unrelated medical problems, complications of therapy, or both.

A Venn diagram illustrates the relations between the causes of small vessel ("hypersensitivity") vasculitis. (BE—bacterial endocarditis; HSP—Henoch-Schonlein purpura; MPA—microscopic polyangiitis; RA—rheumatoid arthritis; SLE—systemic lupus erythematosus)

Figure 2 A Venn diagram illustrates the relations between the causes of small vessel ("hypersensitivity") vasculitis. (BE—bacterial endocarditis; HSP—Henoch-Schonlein purpura; MPA—microscopic polyangiitis; RA—rheumatoid arthritis; SLE—systemic lupus erythematosus)

The signs and symptoms of unrecognized infection may transiently resolve with steroid therapy.3 With the initiation of potent immunosuppressive therapy, there is a prolonged window of increased susceptibility to opportunistic infection. The greatest risks occur in patients with marked neutropenia or those receiving high doses of corticosteroids. Physicians must be particularly wary about attributing new problems to "flares" in the underlying disease without first excluding a new or re-crudescent infection. Patients with varicella-zoster virus may present with fever and pain before appearance of the vesicles. Pneumocystis carinii, cytomegalovirus, and systemic fungal infections and reactivation of mycobacterial disease are observed more frequently in patients with systemic vasculitides than in the general population. Immunosuppression from steroids and other medications is frequently associated with mucosal can-didiasis, less commonly associated with molluscum contagio-sum, and rarely associated with Kaposi sarcoma.

Methotrexate, azathioprine, and cyclophosphamide may cause leukopenia and, less often, other cytopenias. In patients with decreased renal function, methotrexate must be used with caution, if at all; the dose of cyclophosphamide should be decreased and carefully monitored because the pro-drug (cy-clophosphamide) is renally excreted. Bladder-emptying dysfunction is a relative contraindication to the long-term use of cy-clophosphamide because increased exposure to toxic metabolites of the drug may predispose to bladder cancer or cystitis. The recent trend in the treatment of patients with certain potentially life-threatening systemic vasculitic syndromes has been to introduce therapy with a short course of corticosteroids (often with a second immunosuppressive agent), tapered from a high dose to a low dose, to induce remission and then, depending on the disease, to continue immunosuppressive therapy with an alternative regimen of corticosteroids to maintain remission. The second regimen may initially consist of cyclophosphamide, which is felt to be the most potent of these agents, but cy-clophosphamide is then replaced with an agent that has a better safety profile (e.g., methotrexate or azathioprine). Therapy with that agent is then continued for many months.

Small Vessel Vasculitis

Vasculitis that affects capillaries and venules is the most common form of vasculitis and almost invariably involves the skin. It can occur at any age and affects men and women with equal frequency.


Small vessel vasculitis can occur as an idiopathic disorder or secondary to drug allergy, bacterial endocarditis, viral infections such as those caused by hepatitis B or C, disseminated Neisseria, and rickettsiae; it can be part of a defined systemic autoimmune disorder such as Sjogren syndrome, systemic lupus erythematosus (SLE), or rheumatoid arthritis; or it can occur in association with hematologic, lymphoid, and solid-organ malignancies [see Figure 2]. Small vessel vasculitis can accompany diseases commonly associated with the involvement of larger vessels (e.g., Wegener granulomatosis [WG]).


Clinical Manifestations

Cutaneous involvement can occur in many of the primary or secondary vasculitic syndromes. Large, medium-sized, or small vessel occlusion can cause livedo, Raynaud phenomenon, or necrosis. Purpura is the most common manifestation of small vessel vasculitis. Small vessel vasculitis, particularly when associated with infections, is frequently associated with immune complex deposition. Vasculitis primarily involving the postcap-illary venules has been termed hypersensitivity vasculitis in older literature.4 Primary small vessel vasculitis may be limited to the skin or may be associated with visceral involvement, including alveolar hemorrhage, intestinal ischemia or hemorrhage, and glomerulonephritis.

Purpura tends to occur in recurrent crops of lesions of similar age and is more pronounced in gravity-dependent areas [see Figure 3]. When purpura is not primarily in gravity-dependent areas, cold agglutinin disease, cryoglobulinemia (which may be associated with an infection such as hepatitis C or with lym-phoma), embolism, and infiltrative diseases should be excluded. Cutaneous vasculitis of any etiology may be associated with striking dependent edema.

In a case series of cutaneous small vessel vasculitis,4 almost 100% of patients younger than 20 years had disease limited to the skin, whereas approximately 40% of the 172 patients older than 20 years had an associated or underlying systemic disorder. Seventeen adults had a systemic necrotizing vasculitis, four had malignancy, four had a bacterial infection causing the vasculitis, 11 had cryoglobulinemia, and 59 had Henoch-Schon-lein purpura. The prevalence of infection with hepatitis C virus, likely the most common cause of mixed cryoglobulinemia,2 was not reported in this series.

Palpable purpura of the distal extremities is the most common presentation of small vessel vasculitis.

Figure 3 Palpable purpura of the distal extremities is the most common presentation of small vessel vasculitis.

Table 2 Immunosuppressive Therapies for Vasculitis



Efficacy Rating



Often used at 1 mg/kg daily (split doses in severe disease) initially; tapered, with goal of discontinuance by 6 months or sooner if possible; utilize other drugs to enable this if possible

Primary therapy in all forms of life-or organ-threatening forms of vas-culitis; probably most rapid-acting therapy

Ideally, check baseline PPD status; consider prophylaxis against Pneumocystis (when using high doses) and osteoporosis; monitor for development of glaucoma in elderly patients


1-3 mg/kg p.o. daily; avoid neutropenia; nadir is usually 9-14 days after initiation of therapy or change in dose; decrease dose in setting of renal insufficiency; monthly "pulse" dosing has been used (0.5-1 g/m2), but there may be greater likelihood of relapse; give pulse dose after dialysis

Most potent nonsteroidal immuno-suppressive therapy; unclear onset of action but should be given when severe disease recognized, particularly rapidly progressive glomerulonephritis

Major side effects limit long-term use of this drug: leukopenia, myeloproliferative disease, bladder damage, and malignancy; current trend is to induce remission in WG and other severe forms of vasculi-tis with prednisone and cyclophosphamide, with tapering of prednisone and change of cyclophos-phamide to a less toxic (but likely less effective) medication (e.g., azathioprine or methotrexate)


2-3 mg/kg daily p.o.

Less potent than cyclophospha-mide; useful to maintain remission while trying to spare cortico-steroid dosing

Not usually given as primary induction therapy; avoid leukopenia; can cause a confusing hypersen-sitivity reaction that includes high fever, with or without rash and eosinophilia


Given once weekly (up to approximately 0.3 mg/kg/dose) along with daily folic acid (1 mg)

Less potent than cyclophosphamide; useful to maintain remission while trying to spare corticosteroid dosing; decrease dose for mild renal insufficiency; avoid in patients with creatinine > 2.5 mg/dl

Useful in maintaining remission; has been used as primary induction therapy with prednisone in patients with mild WG; significant frequency of relapse in WG patients maintained on this drug alone; monitor WBC, creatinine and transaminase levels (causes hepatitis and can cause cirrhosis; avoid any ethanol ingestion); can be given orally or by weekly injection; folic acid reduces "nuisance" side effects

PPD—purified protein derivative

WBC—white blood cell count

WG—Wegener granulomatosis 

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