Vasculitis

by Lanny J. Rosenwasser, M.D.

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Diagnosing vasculitis ... Pathogenesis ... Treatment ... Specific drugs ...
Cyclophosphamide ... References ... Faculty

Vasculitis--Inflammation and necrosis of blood vessels--is not an everyday disorder, but it enters into the differential diagnosis of a number of disorders that the average physician encounters. Although the most common cause of vasculitis is a secondary hypersensitivity reaction that resolves when the primary disease is treated, other vasculitides are primary diseases that require aggressive immunomodulatory therapy. In all cases, timely diagnosis and resolution of the vasculitis is required to avoid the possibility of the patient developing fatal renal failure or other significant complications.

Categorizing vasculitis

The vasculitides are divisible into four main categories that each have a distinct pathologic picture.

• Hypersensitivity vasculitides such as those associated with serum sickness, drug reactions, connective tissue disease, and cancer. Usually the skin of the feet and lower legs is a major site of involvement.

• The systemic necrotizing vasculitis group, which includes classic polyarteritis nodosa, and allergic granulomatosis and angiitis (Churg-Strauss syndrome). This disorder tends to occur in renal or visceral arteries, usually sparing pulmonary and splenic arterioles and other small vessels. Patients with allergic granulomatosis usually have a history of atopy or asthma, and involvement of their pulmonary arteries. Some patients present with elements of both disorders. This termed systemic necrotizing vasculitis overlap syndrome..

• The granulomatous vasculitides, including Wegener's granulomatosis, lymphomatoid granulomatosis, and the giant cell arteritides. Wegener's granulomatous is characterized by a granulomatous necrotizing vasculitis of the upper and lower respiratory tracts, and renal involvement in about 90% of patients. Lymphomatoid granulomatosis is blood-vessel-destroying vasculitis that primarily affects the lungs. Up to 45% of these patients develop a fatal neoplastic lymphoproliferative disease that destroys blood vessel. The giant cell arteritides affect medium or large-sized arteries. The classic syndrome involves infiltration of the vessel walls with mononuclear cells, formation of giant cells, and fragmentation of the internal elastic lamina.

• Other conditions, such as Kawasaki's syndrome, erythema nodosum, and Behcet's syndrome.

Diagnosing vasculitis is a clinical challenge because it is a syndrome, not a specific disease. A variety of pathologic states result in vasculitis; what ties them together is the end result of blood vessel inflammation.

The initial presentation of vasculitis can be as varied as the syndrome. Some patients have persistent constitutional symptoms, such as lingering cold. In some cases the lungs are markedly involved, in the form of pneumonia or asthma. Other associated organ-system-based infections include sinusitis, otitis, and other sites of infection. A patient with hypersensitivity vasculitis may initially present with a skin rash. Physicians may find that a suspicion of vasculitis often enters into differential diagnosis of many patients.

Signs and symptoms that characteristic of vasculitis include abnormal liver function, fever, neurologic complaints, hypertension, and renal disorders. Simple laboratory tests, including a white blood cell count and sedimentation rate, are useful for ruling out the most serious vasculitides.

Biopsy of the affected blood vessel is the best way to confirm a diagnosis.

Biopsy of the affected blood vessel is the best way to confirm a diagnosis. The exact nature of the vascular pathology depends on the disease involved. For example, polyarteritis nodosa affects medium-size arteries, resulting in fibrinoid necrosis of blood vessels with the formation of multiple aneurysms or nodules along the vessel. Hypersensitivity vasculitis results in a fibrinoid necrosis with a pleomorphic cellular infiltrate, known as leukocytoclastic changes, in the post-capillary venules.

Pathogenesis

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Immune mechanisms play the key role in the pathogenesis of all forms of vasculitis. Although the exact nature of the immunopathogenesis of most vasculitis syndromes has not been identified, immune complexes and anti-blood-vessel antibodies are believed to contribute to the process. In addition, the cells that line vascular walls contain antigens and likely act as accessory cells in mediating and amplifying immune damage.

A series of studies over the past six years has identified a specific association between systemic vasculitis and circulating autoantibodies against neutrophil cytoplasmic proteins. For example, antibodies to proteinase 3 have linked to Wegener's granulomatosis, and antibodies to myeloperoxidase have been linked to several vasculitides including ulcerative colitis and lupus. The notion of vasculitides-specific autoantibodies is further strengthened by an apparent correlation between the level of these serum factors and changes in disease activity, such as in response to treatment.

Treatment

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In the early 1970s, treatment for the vasculitides was revolutionized by the introduction of cytotoxic immunosuppressive drugs, such as cyclophosphamide. In fact, this novel therapeutic strategy that was initially pioneered in some of the most severe vasculitides, such as Wegener's granulomatosis, was later successfully applied to other, more common immunologic disorders such as rheumatoid arthritis and systemic lupus erythematosus.

For patients with sever vasculitis the definitive diagnosis, classification, and initial management of their disease is a job best done at a referral medical center, such as National Jewish. Once a patient's treatment regimen is begun, the patient can then be successfully managed on an ongoing basis by a community-based primary care physician.

In some cases, most notably a hypersensitivity reaction, vasculitis is a secondary disease that can be managed by identifying and eliminating the offending antigen or agent. However, some hypersensitivity vasculitides may also require corticosteroid treatment even after the offending antigen is eliminated. If no offending agent can be identified, other management approaches are necessary.

Vasculitis may also be associated with a primary illness, including rheumatic and connective tissue diseases, cancer, infectious diseases, and inflammatory bowel disease. In these cases the vasculitis often improves when the primary disease is treated. If the vasculitis is a major cause of morbidity, specific treatment may be necessary regardless of the underlying condition.

The combined use of these three treatment strategies has led to a dramatic turnaround in the prognosis for vasculitis patients. Before cytotoxic therapies were introduced, a five-year mortality rate of about 90% was typical for patients with some of the sever necrotizing vasculitides, such as Wegener's granulomatosis or polyarteritis nodosa. In contrast, patients with vasculitis today who undergo appropriate immunomodulatory therapy have a remission rate of about 95%.

Treatment duration depends on the type and severity of vasculitis. For the more severe vasculitides, treatment for one year after remission may be necessary to achieve a sustained response.

Few controlled trials have been conducted to prove the efficacy of most immunomodulatory treatments. Much of the data on using these therapies for vasculitis were collected retrospectively, which weakens the reliability of any conclusions based on these data.

Corticosteroids

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Corticosteroids are the treatment of choice for patients with hypersensitivity vasculitis who need specific therapy. These drugs are also, in general, the primary treatment for giant cell arteritides and temporal arteritis. Corticosteroids are also used as an adjunctive agent along with a cytotoxic drug to treat Wegener's granulomatosis, lymphoid granulomatosis, and the systemic necrotizing arteritis diseases.

At the doses usually used to treat the vasculitides, corticosteroids have both anti-inflammatory and immunosuppressive effects. In most cases, several doses a day are required to suppress acute inflammation in a patient. However, after a brief period this regiment is scaled back to larger doses administered on alternate days. This change in dosing schedule is critical for minimizing the significant adverse effects of chronic corticosteroid use, such as hypothalamic pituitary adrenal suppression and increased risk of infection. An 80 mg dose of prednisone given on alternate days will cause dramatically fewer adverse effects than a 10 mg dose administered four times a day.

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Cyclophosphamide is the primary cytotoxic drug used for treating vasculitis. When used chronically at low daily doses, cyclophosphamide results in immunosuppression without a substantial anti-inflammatory effect. It takes 12-14 days for cyclophosphamide to exert an immunosuppressive effect, so the drug is initially given along with a multiple daily-dose corticosteroid regimen. Once the patient is stable, the corticosteroid is scaled back to alternate-day dosing.

Daily, low dose treatment with cyclophosphamide causes bone marrow suppression and leukopenia. The chronic cyclophosphamide dose should therefore be adjusted based on a patient's peripheral leukocyte counts. In general, the white cell count should be maintained at more than 3500 cells per mm3. It is critical to closely follow a patient's white cell count when cyclophosphamide therapy is begun. Other major adverse effects include hemorrhagic cystitis, gonadal dysfunction, development of lymphoma or leukemia, and pulmonary and bladder fibrosis.

Because cytotoxic drugs cause such significant adverse effects, patients should be treated with the minimum dose required to induce a lasting remission. Despite the need to keep treatment as brief as possible, many vasculitis patients have to remain on a cytotoxic drug regimen for as long as a year after a treatment starts.

Azathioprine is another cytotoxic drug that is often used to treat the vasculitides, although it is not as effective as cyclophosphamide in patients with Wegener's granulomatosis. However, for young patients for whom the possibility of gonadal dysfunction is a significant consideration, axathioprine may be a reasonable alternative.

Although combined therapy with cyclophosphamide and a corticosteroid induces remission in about 95% of patients with severe vasculitis, such as Wegener's granulomatosis or poly arteritis nodosa, about a third of patients will have relapse and require a second course of treatment. A smaller fraction of patients may require a third or fourth course of therapy to manage subsequent relapses, but eventually about 95% of all patients stay in remission for five or more years and can be considered cured.

References

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1. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Int Med 116:488-98, 1992.

2. Hoffman GS, Sechler Jmg, Gallin JI, et al. Brocnchoalveolar lavage analysis in Wegener's granulomatosis. A method to study disease pathogenesis. American Review of Respiratory Disease 143:401-07, 1991.

3. Hunder GG, Arend WP,et al. The American College of Rheumatology criteria for the classification of vasculitis. Arthritis Rheumatism 33:1065-136, 1990.

4. Hoffman GS, Leavitt RY, Fleisher TA, Minor JR, Fauci AS. Treatment of Wegener's granulomatosis with intermittent high-dose intravenous cyclophosphamide. Am J Med 89:403-10, 1990.

5. Jenne DE, Tschopp J, Ludemann, et al. Wegener's autoantigen decoded. Nature 346:520, 1990.

6. Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic antibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. New Engl J Med 318:1651, 1988.

7. Rosenwasser LJ, Wolff SM. Systemic vasculitis. In: Current Therapy in Internal Medicine. Second Edition. TM Bayless, MC Brain, RM Cherniack, eds, BC Decker, Inc, Philadelphia. pp. 68-72, 1987.

8. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener's granulomatosis prospective clinical and therapeutic experience with 85 patients for 321 years. Ann Int Med 98:76, 1983.

9. Fauci AS, Haynes BF, Katz P, The spectrum of vasculitis. Ann Int Med 89:660, 1978.

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Lanny J. Rosenwasser, M.D. Head, Division of Allergy & Clinical Immunology, National Jewish; Professor of Medicine, UCHSC

Terri Finkel, M.D., Ph.D. Assistant Faculty Member, National Jewish; Assistant Professor, Department of Microbiology and Immunology, UCHSC

Donald Y.M. Leung, M.D., Ph.D. Head, Division of Pediatric Allergy/Immunology, National Jewish; Professor, Department of Pediatrics, UCHSC

The Medical Scientific Update, a publication of the Office of Professional Education at National Jewish, provides information to physicians about our clinical and research programs in allergic, respiratory, and immune system disorders. The Web edition of the Medical Scientific Update published by the Gerald Tucker Memorial Medical Library.