Posted: May 2007
Dennis K. Ledford, MD
The term vasculitis identifies complex medical conditions characterized by blood vessel inflammation and damage. Serious complications result when the vascular lumen is compromised and ischemia results. Vasculitis may be a primary disease or a manifestation of another disease (Table 1). Typically, vasculitis is systemic. Most vasculitis syndromes affect some tissues or organs more than others. Occasionally the disorder is confined to a single organ, such as the skin.
The diversity of vasculitis syndromes make these conditions a clinical concern for general-medicine physicians as well as specialists. Vasculitis syndromes most likely to be encountered by allergists/immunologists are hypersensitivity vasculitis; ANCA associated vasculitis, including Wegener’s granulomatosis and Churg-Strauss vasculitis (allergic angitis and granulomatosis); and temporal arteritis.
Because the etiology of most vasculitic syndromes is unknown, the development of definitive therapy for these conditions is hampered. Nevertheless, progress continues in refining immunosuppressive treatment and in improving the monitoring of therapy. In addition, diagnostic classification schemes continue to evolve and new testing modalities—particularly antineutrophil cytoplasmic antibody (ANCA) testing—are proving to be clinically useful.
Clinical features of many vasculitis syndromes overlap, and these abnormal conditions are heterogeneous—complicating the diagnosis and classification of affected subjects. Both this heterogeneity and lack of causal identification have hindered the development of a classification system. Available classification schemes are chiefly descriptive, and consensus is occasionally lacking on essential features of each condition.
|Figure 1. Classification scheme suggested by the Chapel Hill conference|
The Chapel Hill conference provided an organization and classification of vasculitis based principally on the size of the affected vessel (Figure 1). Controversy continues about small-vessel necrotizing arteritis, currently considered microscopic polyangiitis (MPA) in the Chapel Hill classification scheme. Some authorities believe MPA is a component of polyarteritis nodosa. However, MPA should not be confused with small-vessel necrotizing vasculitis, which characterizes Wegener’s granulomatosis and Churg-Strauss syndrome. Neither should MPA be confused with leukocytoclastic vasculitis, typically seen in Henoch-Schonlein purpura or hypersensitivity vasculitis. Usually, small-vessel necrotizing vasculitis affects arterioles, venules, and capillaries. Leukocytoclastic vasculitis affects capillaries and venules generally found in the skin. MPA affects vessels of various sizes, including small arteries, but not muscular arteries as in polyarteritis nodosa. Two series of randomized controlled trials have helped to define the classification of vasculitic syndromes, using ANCA and effective therapeutic regimens.
Epidemiology and pathophysiology
Hypersensitivity vasculitis is the most common vasculitic syndrome encountered in the clinical practice of allergy and immunology. Hypersensitivity vasculitis is comprised of a broad group of diseases which share a histological pattern of post-capillary venulitis with leukocytoclastic vasculitis (Leukocytoclasis refers to the nuclear debris remaining after neutrophils fragment as they infiltrate the affected blood vessel.) (Figure 2).
Figure 2. Hypersensitivity Vasculitis
These diseases tend to affect the skin and occasionally the kidney. Neutrophil fragmentation is associated with inflammation resulting in extravasation of red blood cells. Together these features distinguish hypersensitivity vasculitis from urticaria.
Red cell extravasation is responsible for the purpuric appearance of hypersensitivity vasculitis. Low-pressure, post-capillary venules cause a predilection for vessel involvement at sites of increased hydrostatic pressures. Hydrostatic pressures are greatest in dependent portions of the body—the distal legs in individuals who are upright and the sacral area in bedridden subjects. This distribution of cutaneous involvement is highly suggestive of hypersensitivity vasculitis.
The majority of hypersensitivity vasculitis is secondary to another, primary disorder. These secondary syndromes include drug hypersensitivity, for example penicillin allergy with serum sickness; autoimmune diseases such as systemic lupus erythematosus; and chronic hepatitis with cryoglobulinemia and malignancy.
The hallmark of the cutaneous reaction associated with hypersensitivity vasculitis is palpable purpura. Other cutaneous manifestations include a macular or papular rash, vesicles, bullae, subcutaneous nodules, ulcers, and urticaria. Skin lesions may be pruritic but more often are slightly painful or produce a burning sensation. Edema may accompany the lesions, and hyperpigmentation results from the hemosiderin presence caused by extravasation of red blood cells.
Currently there is no definitive laboratory diagnosis of hypersensitivity vasculitis other than a skin biopsy demonstrating leukocytoclastic vasculitis (Figure 2). Positive immunofluorescence for immunoglobulin and complement may be seen but is not required for diagnosis. Mild leukocytosis—with or without eosinophilia—and increased acute-phase indicators, such as erythrocyte sedimentation rate (ESR) or C-reactive protein, are typical but non-specific in hypersensitivity vasculitis. Laboratory tests and physical examination should focus on evaluating underlying diseases we know to be associated with this syndrome.
Treatment for hypersensitivity vasculitis should follow a protocol for relatively benign prognosis if no renal involvement is found. The syndrome is frequently limited to the skin and usually does not lead to life-threatening complications. If a specific antigen is detected, treatment should be targeted at eliminating any responsible infection or terminating administration of any identified causal drug. Antihistamine therapy for pruritus, treatment with nonsteroidal anti-inflammatory drugs for painful lesions, and—rarely, but with caution—short courses of systemic glucocorticoids may prove useful.
Vasculitis Associated with Antineutrophil Cytoplasmic Antibody (ANCA)
Vasculitis varieties associated with Antineutrophil Cytoplasmic Antibody (ANCA) include Wegener’s granulomatosis, Churg-Strauss Vasculitis, and microscopic polyangiitis. The description of ANCA and its association with specific vasculitis syndromes have modified our clinical evaluation of vasculitis and proposed pathophysiologic mechanisms. Cytoplasmic immunofluorescence of fixed neutrophils (c-ANCA)— demonstrating human autoantibody binding—is manifest in cases of Wegener’s granulomatosis. Perinuclear staining (p-ANCA) is characteristic in Churg-Strauss syndrome, microscopic polyangiitis, and progressive glomerulonephritis with vasculitis. Exceptions occur with staining patterns. For example, p-ANCA may be seen in about 5% of Wegener’s granulomatosis cases. ANCA occurs in subjects without vasculitis and is absent in some individuals with these conditions. Thus, the detection of ANCA supports but does not establish a diagnosis, and the absence of ANCA does not eliminate the diagnosis of vasculitis of these types. Measuring antibodies to specific neutrophil antigens enhances the specificity of ANCA results and improves the prognostic value of titer changes in predicting changes in disease activity.
Antimyeloperoxidase antibodies are characteristic in microscopic polyangiitis or Churg-Strauss syndrome (associated with p-ANCA), and anti-proteinase 3 is more specific for Wegener’s granulomatosis (associated with c-ANCA). The concentration of ANCA may be used to monitor disease activity and assist decision-making related to therapeutic dose reduction. The addition of monitoring levels of antibodies to specific neutrophil enzymes—such as elastase, proteinase 3 or myeloperoxidase—may enhance the reliability of ANCA changes in predicting changes in disease activity.
ANCA may activate neutrophils, resulting in initiation or augmentation of immunologic response and blood-vessel damage. Therefore, treatments directed toward reducing ANCA may minimize disease activity. The importance of ANCA in the pathophysiology of the associated vasculitis is unproven but suspected.
Wegener’s granulomatosis typically affects the upper airway, lung, and kidney. Involvement of the airway is the main reason that allergists/immunologists will encounter this vasculitic syndrome. Ninety percent or more of affected subjects will have ear, nose, or throat involvement including persistent sinusitis, nasal crusting or bleeding, otitis media, hearing loss, and ear pain. Pulmonary involvement occurs in more than 80% of affected subjects, usually showing nodules, infiltrates, or hemoptysis.
Symptoms of Churg-Strauss vasculitis are likely to help in the differential diagnosis of persistent sinus disease, difficult-to-treat asthma, allergic bronchopulmonary aspergillosis, eosinophilia, and increased blood IgE. Churg-Strauss vasculitis usually occurs in individuals with a history of asthma and allergy or allergic-like disease, overlapping with the majority of patients seen by an allergist or immunologist (Figure 3).
Figure 3. Churg-Strauss Vasculitis
Microscopic polyangiitis or small-vessel necrotizing vasculitis is characterized by pulmonary involvement, often with hemorrhage. Asthma is not characteristic of microscopic polyangiitis.
Since all three of these syndromes share a tendency for ANCA positivity and airway involvement, allergists/immunologists are likely to encounter individuals in which these syndromes are considered in the differential diagnosis. The prognosis of all three is poor without suitable treatment. So, allergists/immunologists emphasize the need for awareness and prompt diagnosis.
Treatment of ANCA Associated Vasculitis
Mean survival time of untreated subjects with Wegener’s granulomatosis (WG) is 5 months. Allergists/immunologists see more than 90% mortality rate within 2 years of diagnosis for patients without therapy. Similarly, the 5-year prognosis for survival of untreated Churg-Strauss vasculitis and microscopic polyangitis is 25% or less. With treatment, patients in all three vasculitis syndrome groups experience a 5-year survival rate of greater than 70%.
Glucocorticoid therapy alone is marginally effective in suppressing these diseases, with median survival of slightly more than one year for patients with Wegener’s granulomatosis. Controlled trials have demonstrated that a combination of oral prednisone, 1-1.5 mg/kg/day and oral cyclophosphamide, 2mg/kg/day, is effective in inducing remissions and permitting tapering of therapy over several years in the majority of Wegener’s granulomatosis studies. Prednisone dosage is tapered to every other day and the cyclophosphamide gradually also tapered over 6-24 months. Conversion to alternative immunosuppressive therapy, particularly with weekly methotrexate after 6 months of successful induction therapy, may maintain clinical response without increasing the risk of bladder cancer—a side effect of oral cyclophosphamide treatment. Recommendations for therapy of other forms of ANCA-associated vasculitis, such as Churg-Strauss syndrome or microscopic polyangiitis, are less secure because we lack sufficient controlled trials. However, many clinicians use treatments similar to those studied in Wegener’s granulomatosis.
Relapses of Wegener’s granulomatosis after remission, along with the cumulative adverse effects produced by both the prednisone and cyclophosphamide administration, have stimulated the search for alternative treatments. A randomized study demonstrated clinical benefits of monthly, pulse-therapy with cyclophosphamide. This study showed a reduction of side effects and a 57% reduction of total cyclophosphamide dose needed for disease control. The intravenous treatment group experienced significantly fewer infections, less leukopenia, and a possible reduction of gonadal toxicity as a result of decreased levels of follicle-stimulating hormone. Also, intermittent, intravenous cyclophosphamide is associated with less bladder toxicity than daily, oral therapy. Recent onset of disease, presence of renal involvement and absence of granulomas in the lung and airway characterize a cohort of subjects that shows better response to intravenous cyclophosphamide. Daily treatment with oral cyclophosphamide appears to be more effective than monthly treatment with intravenous cyclophosphamide. An oral combination of trimethoprim and sulfamethoxazole reduces relapse rates in Wegener’s granulomatosis, sparing additional cytotoxic and glucocorticoid therapy. Intramuscular, depot-injections of corticosteroid may also reduce corticosteroid side effects without significantly compromising clinical response. Weekly, oral, pulse–administration of methotrexate is also effective in controlling Wegener’s granulomatosis and is a potential consideration if cyclophosphamide toxicity or adverse effect to gonads is an overriding concern. Methotrexate is also recommended after the first 6 months of cyclophosphamide administration to ease tapering of the cyclophosphamide, thereby minimizing bladder toxicity. Methotrexate therapy is not recommended for severe, immediately life-threatening disease. Limited data support the efficacy of mycophenolate mofetil and calcineurin inhibitors, such as cyclosporine and tacrolimus, in the treatment of necrotizing vasculitis. Inhibitors of tumor necrosis factor—such as etanercept—have not been found to be effective in Wegener’s granulomatosis. Intravenous gamma globulin may be of some value in Churg-Strauss vasculitis.
Giant-cell vasculitis typically affects large arteries that have an elastic lamina (Figure 4).
Figure 4. Temporal Arteritis
Most commonly, these vessels are part of the carotid artery or its branches. But this is a systemic disorder, and any large artery may be affected. Giant-cell arteritis is histologically characterized by features of a panarteritis. This panarteritis is accompanied by inflammatory, mononuclear infiltrates inside the vessel wall, which usually focus on the internal, elastic lamina. Multinucleated giant cells are typical. This pathophysiology suggests a cell-mediated immune response, probably specific for antigens in the elastic lamina. The pathophysiology is supported by distinct cytokine patterns; detection of increases in tumor necrosis factor, IL-6, IL-1β, IL-2 and IFN-γ; and identification of T lymphocytes expressing specific antigen receptors with restricted clonal expansion. Temporal arteritis or cranial arteritis occurs almost exclusively in individuals more than 50 years of age and is more common in Caucasian women of northern-European heritage. Familial aggregation and an association with select human leukocyte antigen (HLA) alleles, particularly HLA-DR4, support a genetic predisposition for the disease. Polymyalgia rheumatica, a syndrome accompanied by symmetrical musculoskeletal aching, often occurs with giant-cell vasculitis, but this condition may occur alone and is twice as common as giant- cell vasculitis.
The clinical symptom that makes giant-cell vasculitis likely to be encountered by allergists/immunologists is headache. This headache is easily confused with the other facial and cranial complaints that are sometimes attributed to sinus disease. The headache is often more severe than a patient’s prior headaches, is described as somewhat boring in character, and may be unilateral. Scalp pain, particularly with hair brushing or with chewing, are highly suggestive of the diagnosis. Other manifestations include fatigue, malaise, anorexia, weight loss, subjective fever, or sweats, along with pain in the axial and proximal muscle extremities. Initial physical findings are limited and include tenderness of the temporal artery and occasionally over one or more branches of the affected arteries. As with other vasculitic syndromes, ischemia is the major complication. In this case, ischemia often affects the ophthalmic arteries—with blindness from optic nerve ischemia being the most common and severe complication.
Laboratory findings include increased erythrocyte sedimentation rate, normochromic or slightly hypochromic anemia, increased gamma globulin and complement, elevated C-reactive protein, increased blood IL-6 concentration, and mildly abnormal liver-function. Most of these findings reflect a systemic response to release of inflammatory cytokines, particularly IL-1, IL-6, and tumor necrosis factor.
Diagnosis is usually confirmed by microscopic examination of a temporal artery segment (Figure 4). A biopsy of 3-5 cm of vascular tissue will optimize diagnostic potential. Bilateral biopsies slightly increase diagnostic yield. Treatment may be initiated for as long as a week to 14 days before biopsy without significantly modifying pathologic findings. This may be important to a clinician who might begin treatment before obtaining a biopsy to minimize the chance of irreversible blindness if the biopsy is postponed.
Treatment of giant-cell vasculitis is similar to that for other forms of complicated vasculitis, except that oral glucocorticoids alone are more likely to be sufficient. Treatment is usually initiated at 40-60 mg/day until the disease is controlled, as manifested by resolution of symptoms and normalization of blood abnormalities—particularly anemia and ESR. Tapering of the glucocorticoid therapy should be started as soon as possible to minimize systemic side effects, as treatment may be necessary for up to 2 years, usually on an every-other-day schedule. Weekly methotrexate has permitted a reduction or discontinuation of glucocorticoid therapy in 2 randomized trials, allowing control of the disease with limitation of side effects such as osteoporosis. Giant-cell vasculitis has fewer tendencies to relapse following remission compared to ANCA-positive vasculitis. Polymyalgia rheumatica is best treated with low-dose prednisone (usually 10-15 mg daily) for 6-12 months.
Allergists/immunologists frequently see hypersensitivity vasculitis associated with viral infection and drug allergy. A consideration of this syndrome often enters into the differential diagnosis between urticaria and urticarial vasculitis. Allergists/immunologists commonly encounter ANCA-positive vasculitis because these conditions affect the lung and upper airway. Churg Strauss vasculitis occurs in subjects with a history of asthma and is characterized by pulmonary infiltrates and eosinophilia. Wegener’s vasculitis and Churg Strauss vasculitis often result in a persistent sinusitis. Microscopic polyangiitis is also associated with pulmonary infiltrates and hemoptysis. Finally, the headache found in giant-cell vasculitis may be confused with sinusitis, introducing this condition into the differential diagnosis of individuals being evaluated for sinus complaints.
Assessment and treatment of vasculitis remains empirical because of the absence of known etiologies and pathophysiology. The value of combining oral glucocorticoid therapy with cyclophosphamide has stood the test of time in Wegener’s granulomatosis, but disease relapse and efforts to limit side-effects greatly spur our search for other therapies.
Many alternatives for vasculitis treatment are available but inadequate experience prevents definitive recommendations. Since vasculitic syndromes are relatively rare, our potential of gathering sufficient numbers of patients for double-blind trials is low. Therefore, each clinician must weigh risks against benefits in various treatment options without the advantage of definitive trial data. Treatment choices remain a challenge in managing subjects diagnosed with vasculitis.
Primary Vasculitis Syndromes
Giant Cell arteritis
Idiopathic cutaneous vasculitis
Essential mixed cryoglobulinemia
Isolated vasculitis of the central nervous system
Secondary Vasculitis Syndromes
Drug induced vasculitis
Vasculitis associated with other primary diseases
Infection e.g. Hepatitis B associated polyarteritus nodosa
Autoimmune disease (e.g. systemic lupus erythematosus, Sjögren’s Syndrome)
WGET research group. Etanercept plus standard therapy for Wegener’s granulomatosis.
N Engl J Med. 2005;325:351-
Jayne D et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003;349:36-.
Salvarani C et al. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med 2002;347:261-
Weyand CM, Goronzy JJ. Medium- and large-vessel vasculitis. N Engl J Med 2003;349:160-
Hoffman GS et al. Wegener’s granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488-
Jennette FC et al. Nomenclature of systemic vasculitis. Proposal of an international consensus conference. Arthritis Rheum 1994:37:187-
Hoffman GS et al. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 2002;46:1 309-