Ross Milner and Robert B Smith III

Emory University School of Medicine, Department of Surgery

Introduction

Vasculitis is an inflammatory disorder that affects blood vessels in characteristic locations throughout the body. More than 30 types of vasculitis have been described by separate names. Although vasculitis has a characteristic distribution based on the affected vascular structures, it remains a systemic disease with systemic manifestations. Patients present with fever, weight loss, fatigue, tachycardia, and diffuse "aches and pains." In addition to these constitutional symptoms, almost every organ system can be affected.

Unfortunately, the cause of many of the disorders discussed in this chapter is unknown. It is clear, though, that the immune system plays a large role in the tissue damage caused by vasculitis. Inflammation in the affected blood vessels leads to critical stenosis creating an end-organ destructive process.

This chapter provides an overview of some of the most common vasculitides. In addition, a review of the mechanism of the immunologic development of vasculitis will be discussed.

Common Vasculitides

Behçet's Disease

This triad of aphthous oral ulcers, genital lesions, and recurrent eye inflammation was first described by a Turkish dermatologist, Hulusi Behçet, in the 1930s. Patients are most commonly affected in the Far East and Mediterranean regions. In fact, it is the leading cause of blindness in Japan. This disease occurs infrequently in the United States.

The vascular involvement is unusual in that it includes arterial structures of all sizes and venous structures as well. The variety of vascular beds affected allows for a diversity of involved organs, but the eyes, mouth, skin, lungs, joints, brain, genitals, and gastrointestinal tract are the most commonly reported systems.

Behcet's is one of only a few of the vasculitides in which a genetic predisposition has been described. The presence of the gene, HLA-B51, is a risk factor for development of the disease. Importantly, many people possess this gene and do not develop the disease. In fact, familial cases are not the rule and represent only about 5 percent of the total cases. Therefore, additional factors, such as environmental exposures, must play a large role. In fact, the mechanism for development of the disease is not understood.

Buerger's Disease

Also known as thromboangiitis obliterans, Buerger's disease was initially described in 1908. It is characterized by acute inflammation and thrombosis of arteries and veins, usually affecting the hands and the feet. The classic patient is a young male who is a heavy smoker. It most commonly occurs in Southeast Asia, Orient, India, and the Middle East; Buerger's disease does not commonly occur in African-Americans.

The disorder causes manifestations of peripheral vascular occlusive disease including claudication, rest pain, and the development of ulcerations. Despite the severity of the extremity manifestations that can develop, Buerger's usually spares other organ systems. The pathophysiology of this organ distribution is not known.

The association with tobacco use, including smokeless tobacco, is crucial for the development of this disease. It is postulated that the mechanism is autoimmune in nature and triggered by a factor in the tobacco. Interestingly, antiinflammatory medications and anticoagulation lack efficacy in treating Buerger's disease; abstinence from tobacco use is the only effective therapy.

Central Nervous System Vasculitis

Many forms of vasculitis can involve the central nervous system. Central nervous system vasculitis (CNSV) is a specific form of vasculitis in which the disease is confined to the central nervous system and no infectious etiology can be identified. CNSV can be difficult to diagnose because the symptoms of the disease are subtle and a brain biopsy is required for accurate diagnosis. The diagnosis can sometime be suggested findings on magnetic resonance angiography (MRA).

CNSV is also known as isolated angiitis of the central nervous system (IACNS) and granulomatous angiitis of the nervous system (GANS). The current preferred name of the disorder is primary angiitis of the central nervous system (PACNS). This disease process affects the small and medium blood vessels of the brain and spinal cord. Some patients appear to have a milder form of the disorder that is described as an angiopathy rather than an arteritis, in other words, benign angiopathy of the central nervous system (BACNS).

PACNS occurs in an equal distribution of men and women and can occur in any age group. It is most common, though, in the fifth decade. BACNS occurs in young women with a history of migraines. Although the exact mechanism is unclear, these patients tend to have exposure to caffeine, nicotine, and oral contraceptive medications.

The pathophysiology is not understood. It is presumed that infectious agents, such as a viral infection, may stimulate the inflammatory process. This initial process then somehow becomes self-sustaining. It appears that genetics do not play a role in the development of CNSV

Churg-Strauss Syndrome

Churg-Strauss is a systemic vasculitis described in 1951 by Jacob Churg and Lotte Strauss. They reported a syndrome combining asthma, eosinophilia, fever, and accompanying vasculitis of various organ systems. This disease shares features with polyarteritis nodosa (PAN) but can be differentiated by the presence of granulomas and the abundance of eosinophils. It affects men and women equally and begins in middle age with development of a new-onset diagnosis of asthma.

The cause is unknown, but appears to be multifactorial. Although genetics may play a small role in the disease, it appears that two individuals within a family unit are never affected. Environmental factors and infectious etiologies may contribute, but have not been definitively implicated in the causation of the disease.

Cryoglobulinemia

This name literally means cold antibody in the blood. Cryoglobulinemia is a disease state in which antibodies precipitate in the blood under cold conditions. These immunoglobulins resorb upon rewarming. Hepatitis C is a likely initiating event for the development of these antibodies.

Three types of antibodies exist in cryoglobulinemia. Type I is a monoclonal antibody that does not reflect rheumatoid factor activity. Because type I antibodies do not commonly activate complement, it takes a high level of antibody to develop a hyperviscosity syndrome. Types II and III antibodies are rheumatoid factors, meaning that they bind to the Fc fragment of IgG. In type II, the rheumatoid factor is monoclonal. In type III, it is polyclonal. It is understood that most patients with type II or III antibodies have an underlying diagnosis of hepatitis C.

Treatment depends upon the type of antibody present. Severe hyperviscosity requires plasmapheresis and the treatment of any underlying malignancy. Types II and III cryoglobulinemia usually responds to corticosteroid therapy, cyclophosphamide, or both.

Giant-Cell Arteritis

Giant-cell arteritis, also known as one of its variants, temporal arteritis, is the most common form of vasculitis in adults. This disease is a panarteritis of medium- and large-sized arterial structures, especially the extracranial branches of the carotid artery. This form of vasculitis causes facial pain, headaches, joint pain, fever, difficulties with vision, and the possibility of permanent blindness in one or both eyes. Women are affected three times more commonly than men. Most patients are in the eighth decade of life with onset of the disease.

Although the underlying reason for developing giant-cell arteritis is unclear, immunologic mechanisms have been well defined and will be discussed in more detail later in this chapter. Briefly, the immune system inappropriately attacks the target arteries and leads to significant inflammation with the accompanying symptoms. Laboratory blood tests are nonspecific, but almost every individual afflicted with temporal arteritis has an elevated erythrocyte sedimentation rate (ESR). A definitive diagnosis is made by temporal artery biopsy. If clinical suspicion is high and the initial biopsy is negative, the contralateral vessel can be biopsied for diagnosis. Prompt initiation of corticosteroid therapy is mandatory. Biopsies will likely remain positive for up to 2 weeks after initiation of therapy, and corticosteroid treatment should not be withheld while awaiting biopsy.

Polyarteritis Nodosa

Polyarteritis nodosa (PAN) was initially described in 1866 as periarteritis nodosa. The name was changed to recognize the inflammation that occurred throughout the entire arterial wall. PAN is also known as "systemic necrotizing vasculitis." It is a disease of small and medium sized arteries that commonly develops in the fourth and fifth decades. It is twice as common in men as compared to women. Once again, the cause is unknown. Hepatitis B and C are likely underlying causes of PAN, explaining the high incidence of the condition in substance abusers.

PAN can affect nearly every organ, but has a predilection for the nerves, skin, kidney, and gastrointestinal tract. A large number of patients present with hypertension and an elevated ESR. Once again, there is no specific laboratory test to confirm the diagnosis of PAN. Urinalysis may reveal proteinuria in patients with affected kidneys.

The American College of Rheumatology (ACR) has designated 10 criteria that are diagnostic of PAN and assist with distinguishing it from other forms of vasculitis. Patients must have at least three of the following criteria to be given the diagnosis:

1. Weight loss of more than 4 kg since beginning of illness

2. Livedo reticularis

3. Testicular pain or tenderness

4. Myalgias, weakness, or leg tenderness

5. Mononeuropathy or polyneuropathy

6. Development of hypertension

7. Elevated blood urea nitrogen or creatinine unrelated to dehydration or obstruction

8. Presence of hepatitis B surface antigen or antibody in serum

9. Arteriogram demonstrating aneurysms or occlusions of the visceral arteries

10. Biopsy of small or medium-sized artery containing granulocytes

Confirmation of the diagnosis requires a biopsy specimen that includes small or medium-sized arteries. Also, a mesen-teric arteriogram with microaneurysms may be diagnostic, but arteriography is usually reserved for situations in which there is not a symptomatic site from which to obtain a biopsy. Without treatment, most patients die within 2 to 5 years of the initial diagnosis. A combination of cyclophos-phamide and prednisone has altered the course to a survival of 70 percent over 10 years.

Takayasu's Arteritis

Mikito Takayasu first described the disease in 1908 as an abnormal appearance of the blood vessels on retinal examination. Takayasu's arteritis is commonly known as "pulseless disease" because of the difficulty in palpating peripheral pulses secondary to the multiple arterial stenoses. The usual patient is a woman under the age of 40. In fact, there is a 9:1 distribution of women to men affected by Takayasu's. In addition, it appears to be more common in Asian women. Overall, it is a very rare disease with only two to three cases per 1 million people.

Takayasu's involves the larger arteries of the body. In fact, the aorta and its major branches are the most commonly afflicted vessels. The syndrome is clinically divided into two phases: (1) a systemic phase and (2) an occlusive phase. In the systemic phase, patients have classic constitutional symptoms associated with inflammatory diseases. Conversion to the occlusive phase occurs as patients proceed to chronic arterial stenoses leading to abnormal perfusion. It can be exceptionally difficult to obtain an accurate blood pressure in these patients using the standard cuff technique in the arms. Pulmonary arteries may also be affected by Takayasu's, and this arterial bed can develop beading of the vessels, occlusions, and aneurysms.

The exact cause of this arteritis is unknown. A hypothesis has been proposed that patients with a certain genetic predisposition develop the disease after a specific exposure occurs, such as a viral or bacterial infection. Anemia and an elevated erythrocyte sedimentation rate are markers of active disease. The diagnosis can be made by standard contrast arteriography or magnetic resonance angiography. The vast majority of patients respond in the systemic phase to corticosteroid therapy. If surgical intervention is required for complications of the disease and tissue is sent for pathologic analysis, the artery wall appears identical to that in giant-cell arteritis. Surgical interventions are usually reserved as a treatment modality until the disease is in an inactive state.

Wegener's Granulomatosis

A German medical student, Heinz Klinger, was the first to actually describe this disease in 1931. A few years later, Friederich Wegener, a German pathologist, reported three additional cases and recognized the disorder as a form of vasculitis. It occurs in an even distribution between sexes and in people of all ages, but is more common in the 40-year-old age group. As with the other vasculitides, Wegener's can affect any organ in the body. The most common sites of involvement are the upper respiratory tract, lungs, and kidneys.

The diagnosis of Wegener's can be made by a blood test or direct biopsy of the affected organ. Anemia, mild leuko-cytosis, and an elevated erythrocyte sedimentation rate are nonspecific markers of the disease. Anti-neutrophil cyto-plasmic antibody (ANCA) is the blood test used to diagnose Wegener's, specifically C-ANCA. This agent is directed against serine proteinase-3 and is relatively sensitive and highly specific for Wegener's. If positive, the test is useful to diagnose the disease early and to allow rapid institution of therapy, but it can be inaccurately interpreted and lead to misdiagnosis and mistreatment. Even with positive results from an ANCA, a biopsy proven diagnosis is still prudent. Lung biopsy and kidney biopsy are commonly performed in an attempt to confirm the diagnosis. The pathologic specimen is considered positive if a triad of granulomata, vasculitis, and tissue necrosis are observed.

Wegener's was almost uniformly fatal until the 1970s. Now, it is well treated with a combination of cyclophosphamide and prednisone. Even when successfully treated initially, patients can develop "flares" of the disease again in the future. With the described regimen, more than 90 percent of patients are successfully managed.

Immunologic Mechanisms of Disease

Giant-cell, or temporal, arteritis has provided the basis for a majority of the understanding of the immunologic mechanisms in the destructive processes of vasculitis. Three key observations have recently been made in defining this process. The first is that this vasculitis is a T-cell-dependent process. The second is that T-cell activation in the nonlym-phoid environment of the arterial wall requires the activation of antigen-presenting cells, otherwise known as dendritic cells. And the third observation is that the blood vessel determines the site specificity of giant-cell arteritis.

The CD4+ T cell is the predominant cell in the vasculitic lesion. These data arise from animal models using mouse chimeras. It is also supported by observations in humans that clonally expanded populations of CD4+ T cells from isolated vascular lesions have identical receptors.

This concept of a T-cell response leading to arterial injury and the initiation of giant-cell arteritis is dependent on three crucial events: (1) T cells arrive and gain access to a site in which they do not normally reside; (2) there is an inciting antigen that is accessible to these T cells; and (3) antigen-presenting cells that are capable of T-cell stimulation go through a differentiation process. The site of entry for T cells in giant-cell arteritis is thought to be the vasa vasorum, but, before T-cell entry, dendritic cells play a large role. In fact, endothelial cells and dendritic cells together lead to recruitment of T cells into the vessel wall.

Dendritic cells were only recently recognized to reside in medium-sized vessels, and they appear to be isolated to the adventitia of these vessels. In healthy arteries, these cells remain immature and help maintain T-cell unresponsive-ness. In fact, if T cells encounter antigen on an immature dendritic cell, an inhibitory signal is provided to the T cell. Therefore, one of the postulated roles of dendritic cells in the adventitial location is to prevent the activation of T cells. This finding of an immature dendritic cell is not seen in arteries of patients with giant-cell arteritis. Such lesions have mature, activated dendritic cells. These mature dendritic cells now foster and activate T cells as opposed to the unresponsiveness in their immature state. Therefore, it is reasoned that the activation of dendritic cells is an initiating step in the development of giant-cell arteritis.

A difference in the activated dendritic cells seen in temporal arteritis versus other inflammatory disorders also explains the pathophysiology of the disease. Usually, acti vated dendritic cells migrate to the regional lymph nodes and stimulate other cells by the production of chemokines when they reach that location. This function does not occur in temporal arteritis in which the dendritic cells stay localized to the arterial wall and elaborate chemokines activating migration of cells to the affected vessel.

The formation of granulomas is dependent on T cells and is a result of their response to indigestible antigens. It also appears that interferon-g is required for the development of a granuloma. The media of the arterial wall is the location of the formation of granulomas in temporal arteritis. This development is dependent on the production of interferon-g by T cells located in the adventitia of the arterial wall. The granulomatous reaction can wall off immunogens, but leads to damage of the surrounding tissue. Tissue necrosis that occurs from the release of lytic enzymes is seen in other vasculitides, such as Wegener's granulomatosis and Churg-Strauss syndrome. Interestingly, necrosis is not a feature of giant-cell arteritis, and its presence excludes this diagnosis. Thinning of the arterial wall can occur and has been implicated in the development of aneurysmal formation in these patients.

The chief target of oxidative attack in patients with giant-cell arteritis is the medial smooth muscle cell. In normal blood vessels, the media is inaccessible to inflammatory cells because of the lack of capillaries in this location. The formation of neocapillaries in an inflamed artery leads to the recruitment of cellular activity causing arterial damage. The cell responsible for this response is the macrophage.

Macrophages in the media of blood vessels produce reactive oxygen intermediates resulting in the oxidative attack just mentioned. Oxygen-derived free radicals injure tissue through several mechanisms, the most important of which is the oxidation of membrane lipids. This results in structural disintegration of the cell and cellular death. Another mechanism is the interruption of intracellular signaling pathways. This interruption can affect the balance between the destructive and protective mechanisms characteristic of the pattern of response to injury in giant-cell arteritis. The usual course of the injury process is to cause intimal hyperplasia with resultant ischemic complications (Figure 1). The most feared complication of temporal arteritis, blindness, is produced by severe vascular stenoses caused by the oxidative process of injury to nutrient arteries. The variable response seen among patients is not well understood.

Conclusions

Vasculitic disease remains poorly understood for the majority of the subtypes. Interestingly, therapeutic regimens have been developed that can significantly alter the course of the diseases despite a lack of advancement in full understanding of the pathophysiology of the vasculitis process. It is hoped that the growing knowledge of the inflammatory mechanisms seen in giant-cell arteritis will further assist with the management of all types of vasculitis.

Figure 1 Adaptive immune responses in vasculitis and the consequences of arterial-wall injury. (A) Activation and trapping of dendritic cells in the arterial adventitia generate the conditions required for the recruitment and stimulation of antigen-specific T cells. CD4+ T cells that enter the microenvironment of the arterial wall interact with dendritic cells and begin secreting cytokines. Interferon-g is a critical cytokine that regulates the differentiation and function of macrophages. The functional commitment of the macrophages in the vascular infiltrates is closely linked to their location in the arterial wall. Macrophages in the adventitial layer supply the inflammatory cytokines interleukin-1 and interleukin-6. Macrophages in the media secrete metallopro-teinases and play a critical part in oxidative injury through the production of reactive oxygen intermediates. (B) Three aspects of oxidative damage in the media. Protein nitration occurs in endothelial cells lining neocapillaries. Toxic aldehydes are formed in the process of lipid peroxidation, and smooth-muscle cells undergo apoptosis. In parallel, reactive oxygen intermediates also trigger cellular activation, as exemplified by the induction of aldose reductase. The response of the artery to injury is shown in panels C and D. Arteritis does not necessarily result in luminal stenosis and may proceed without compromising blood flow (C). In patients with ample production of platelet-derived growth factor and vascular endothelial growth factor, rapid and exuberant intimal hyperplasia ensues, causing lumen-occlusive arteritis (D). Accordingly, the clinical presentation of arteritis may or may not include ischemic complications. From Weyand, C. M., and Goronzy, J. J. (2003). Medium- and large-vessel vasculitis. N. Engl. J. Med. 349(2), 160-169.

Figure 1 Adaptive immune responses in vasculitis and the consequences of arterial-wall injury. (A) Activation and trapping of dendritic cells in the arterial adventitia generate the conditions required for the recruitment and stimulation of antigen-specific T cells. CD4+ T cells that enter the microenvironment of the arterial wall interact with dendritic cells and begin secreting cytokines. Interferon-g is a critical cytokine that regulates the differentiation and function of macrophages. The functional commitment of the macrophages in the vascular infiltrates is closely linked to their location in the arterial wall. Macrophages in the adventitial layer supply the inflammatory cytokines interleukin-1 and interleukin-6. Macrophages in the media secrete metallopro-teinases and play a critical part in oxidative injury through the production of reactive oxygen intermediates. (B) Three aspects of oxidative damage in the media. Protein nitration occurs in endothelial cells lining neocapillaries. Toxic aldehydes are formed in the process of lipid peroxidation, and smooth-muscle cells undergo apoptosis. In parallel, reactive oxygen intermediates also trigger cellular activation, as exemplified by the induction of aldose reductase. The response of the artery to injury is shown in panels C and D. Arteritis does not necessarily result in luminal stenosis and may proceed without compromising blood flow (C). In patients with ample production of platelet-derived growth factor and vascular endothelial growth factor, rapid and exuberant intimal hyperplasia ensues, causing lumen-occlusive arteritis (D). Accordingly, the clinical presentation of arteritis may or may not include ischemic complications. From Weyand, C. M., and Goronzy, J. J. (2003). Medium- and large-vessel vasculitis. N. Engl. J. Med. 349(2), 160-169.

References

Abril, A., Calamia, K. T., and Cohen, M. D. (2003). The Churg Strauss syndrome (allergic granulomatous angiitis): Review and update. Semin. Arthritis Rheum. 33(2), 106-114.

Frankel, S. K., Sullivan, E. J., and Brown, K. K. (2002). Vasculitis: Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, polyarteritis nodosa, and Takayasu arteritis. Crit. Care Clin. 18(4), 855-879.

Manna, R., Miele, L., La Regina, M., Grieco, A., and Gasbarrini, G. Cryoglobulinemia: A true internistic disease? Int. J. Immunopathol. Pharmacol. 16(1), 33-41.

Mills, J. L., Sr. (2003). Buerger's disease in the 21st century: Diagnosis, clinical features, and therapy. Semin. Vasc. Surg. 16(3), 179-189.

Nordborg, E., and Nordborg, C. (2004). Giant cell arteritis: Strategies in diagnosis and treatment. Curr. Opin. Rheumatol. 16(1), 25-30.

Parra, J. R., and Perler, B. A. (2003). Takayasu's disease. Semin. Vasc. Surg. 16(3), 200-208.

Shepherd, R. F., and Rooke, T. (2003). Uncommon arteriopathies: What the vascular surgeon needs to know. Semin. Vasc. Surg. 16(3), 240-251. An excellent review of the manifestations of the vasculitides as they affect the vascular surgeon. Surgical treatment is reviewed as well as the expected outcomes based on interesting case presentations.

Stone, J. H. (2002). Polyarteritis nodosa. JAMA 288(13), 1632-1639.

Tamargo, R. J., Connolly, E. S., Jr., McKhann, G. M., Khandji, A., Chang, Y., Libien, J., and Adams, D. (2003). Clinicopathological review: Pri mary angiitis of the central nervous system in association with cerebral amyloid angiopathy. Neurosurgery 53(1), 136-143; discussion 143. Weyand, C. M., and Goronzy, J. J. (2003). Medium- and large-vessel vasculitis. N. Engl. J. Med. 349(2), 160-169. The authors thoroughly review the most advanced understanding of the pathologic mechanisms of medium- and large-vessel vasculitis. This article is clearly written with excellent illustrations. Yazici, H. (2003). Behjet's syndrome: An update. Curr. Rheumatol. Rep. 5(3), 195-199.

Capsule Biography

Dr. Milner is an Assistant Professor of Surgery in the Division of Vascular Surgery at Emory University School of Medicine. He has a strong interest in the endovascular management of peripheral vascular disease.

Dr. Smith is John E. Skandalakis Professor of Surgery Emeritus and former Head of the Vascular Surgery Division, Emory University School of Medicine, where he has been a member of the faculty for more than 38 years. He is currently Associate Chairman of the Department of Surgery and Medical Director of Emory University Hospital. In addition, he serves on the Executive Committee of the Board of Commissioners, Joint Commission on Accreditation of Healthcare Organizations.

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