Overview of Vasculitis

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Chapter 41 Overview of Vasculitis

The vasculitides are a group of rare diseases linked by the pathological consequences of vascular inflammation, including bleeding, ischemia, and infarction of downstream organs (Box 41-1). However, the clinical spectrum of these diseases is wide ranging and includes a myriad of clinical and pathological findings. Not all disease phenotypes that occur in the vasculitides are due to true “vasculitis” (i.e., inflammation of vascular structures). Some damage in vasculitis is due to nonvascular inflammation. For example, arthritis, uveitis, and pulmonary nodules are parts of different vasculitides but are not due to interruption of vascular flow. The pathophysiology of vasculitis is covered in Chapter 9 and in individual chapters on Takayasu’s arteritis (TA) (Chapter 42), giant cell arteritis (GCA; Chapter 43), and Kawasaki disease (Chapter 45).

Box 41-1 Classification of Vasculitis *by Predominant Size of Vessel Involvement

Large Vessel

GCA

Behçet’s disease

Relapsing polychondritis

Cogan’s syndrome

Aortitis associated with spondyloarthropathies

Retroperitoneal fibrosis

Idiopathic aortitis

Medium Vessel

^* Most of these diseases can involve vessels of varying sizes but are listed here by the size of the most commonly affected arteries for convenience purposes. This is not an exhaustive list of vasculitides.

The diseases outlined in this chapter are rare, and all are considered “orphan” diseases, with fewer than 200,000 cases in the United States at any time. As with most rare diseases, few well-controlled clinical treatment trials have been performed for this group of disorders. Much of the clinical investigation stems from studies of patient cohorts at large referral centers. In the past 2 decades, however, increasing international cooperation among vasculitis centers has resulted in several important randomized controlled treatment trials that have had significant impacts on the care and management of patients with vasculitis. Similarly, advances in diagnostic imaging and laboratory testing have improved clinicians’ ability to diagnose and evaluate patients with vasculitis.

This chapter reviews the major types of vasculitis, discusses evaluation of suspected cases of vasculitis, and outlines approaches to treatment and management of these disorders. There is a focus on differentiating inflammatory from noninflammatory disease as it relates to the types of patients physicians specializing in vascular medicine are likely to encounter in a consultative practice (Table 41-1). The newest advances in diagnosis and treatment are also reviewed briefly.

Table 41-1 Manifestations of Vasculitis That Mimic Noninflammatory Cardiovascular Disease

Classification of Vasculitis

The classification and nomenclature of vasculitis can be unnecessarily confusing. The most important first step in approaching these disorders is for clinicians to consider the possibility of “some sort of vasculitis” and, once clinical proof is found, to narrow down the specific type. Nevertheless, knowledge of the classification criteria is quite useful when considering treatment and clinical follow-up. Establishing a treatment plan for a case of vasculitis relies on both an understanding of the prognosis of a specific type and applying results of clinical trials that always include patients who meet specific classification criteria. For example, a patient with arthritis, purpura, and abdominal pain might well be treated with glucocorticoids alone if believed to have Henoch-Schönlein Purpura HSP, but would also receive an additional immunosuppressive drug (e.g., methotrexate, cyclophosphamide) if determined to have granulomatosis with polyangiitis (GPA [Wegener’s]). Similarly, the nature of follow-up visits, examinations, and subsequent evaluations are also heavily influenced by the specific type of vasculitis. For example, new-onset hemoptysis in a patient believed to be in remission after treatment for GCA would be concerning for infection or malignancy, whereas the same finding in a patient with GPA would usually prompt immediate reinstitution of high-dose glucocorticoids to treat potential alveolar hemorrhage while further evaluations, including for infection, are put in place.

Two major classification systems for vasculitis exist: the American College of Rheumatology (ACR) system ¹ and the Chapel Hill Consensus Conference definitions.² These systems were not meant to be strictly diagnostic systems, but rather classification systems. These are definitions to apply to established vasculitis and differentiate one vasculitis from another. The main use of these systems has been for clinical trials and other types of clinical research. Nevertheless, these systems have been adapted for use by clinicians as helpful guides to practice. Not all types of vasculitis are included in the ACR or Chapel Hill systems; both are currently undergoing reevaluation and revision.³

The practice of differentiating among the inflammatory vasculitides by associated diagnostic antibodies is at this time limited to use of antineutrophil cytoplasmic antibodies (ANCAs). Specifically, many authors refer to ANCA-associated vasculitis, which includes GPA, microscopic polyangiitis (MPA), renal-limited pauci-immune glomerulonephritis, and the Churg-Strauss’ syndrome (CSS). Although it is convenient to refer to these related diseases as “ANCA-associated” vasculitis, it is important to realize that patients may have any of these diseases and still test negative for the presence of ANCA.

Perhaps the simplest method of sorting out the vasculitides, albeit also incomplete and not fully accurate, is to list them according to the size of artery (predominantly but not necessarily exclusively) involved (see Box 41-1). This results in considering small-vessel, medium-vessel, and large-vessel vasculitides. This system, although not applied for clinical trials or even clinically for treatment purposes, is an easy one to use as a first approach to describing the diseases and their major manifestations, and is used to outline the descriptions of the vasculitides in this chapter. However, when specific diseases and results of treatment trials are mentioned, the ACR and Chapel Hill Consensus systems are applied.

Large-Vessel Vasculitis

The large-vessel vasculitides are disorders in which the aorta and its main branches are affected, including the subclavian, carotid, vertebral, renal, mesenteric, and iliac arteries ⁴ (Fig. 41-1). Because such vessels are so frequently involved in noninflammatory vascular diseases, and patients with these diseases are frequently encountered by specialists in vascular medicine, these disorders are particularly highlighted in this textbook. Also included are individual chapters on TA (Chapter 42), giant cell (temporal) arteritis (Chapter 43), and Kawasaki disease (Chapter 45). The vasculitides involving large arteries are briefly described in this section, but it is important to realize that many of them also involve smaller-sized vessels.

Figure 41-1 (See also Color Plate 41-1.) Large-vessel vasculitis with stenotic lesions of abdominal aorta and left subclavian, left carotid, and bilateral renal arteries as imaged using three-dimensional (3D) dynamic gadolinium-enhanced magnetic resonance angiography (MRA).

Giant Cell Arteritis

Giant-cell arteritis, also commonly known as temporal arteritis and described in detail in Chapter 43, is the most common of the idiopathic vasculitides.^4,⁵ Giant-cell arteritis affects men and women aged 50 and older but is especially prevalent after age 70. Many vascular and systemic manifestations are seen in this disease. Vascular disease occurs in the aorta and its branches, with predilection for the branches of the carotid arteries, especially the ophthalmic artery, with resulting headaches, jaw claudication, and visual impairment. Rapid-onset irreversible monocular blindness is the most feared complication, but stroke, limb ischemia, and aortic disease can occur, the latter more common than generally appreciated, especially several years after the initial presentation. Common systemic manifestations include fever, anemia, proximal arthralgias (polymyalgia rheumatica), and fatigue. Diagnosis is often established on finding arteritis on temporal artery biopsy, but this is not required for a diagnosis. Elevated acute phase reactants are seen in 90% of cases. Treatment with high-dose glucocorticoids is highly effective but often results in significant drug-related morbidity.

Takayasu’s Arteritis

Takayasu’s arteritis, described in detail in Chapter 42, is a vasculitis that involves the aorta and all its major branches and the pulmonary arteries, including but not limited to the brachiocephalic, carotid, vertebral, subclavian, renal, femoral, and coronary arteries. This disease often results in stenoses, occlusions, and ischemic damage to end organs and limbs.^4,⁶ Stroke, myocardial infarction (MI), limb claudication, and severe renovascular hypertension are all complications well known to occur in this disease. It is mostly seen in women and usually first presents clinically in the second or third decade, but it can occur at older ages. Many patients have associated systemic symptoms of fever, arthralgias, and malaise. The disease has a waxing and waning course, and delay in diagnosis is common. Treatment involves glucocorticoids in almost all patients and often the addition of immunosuppressive medications. Surgical bypass procedures may be necessary in some cases.

Behçet’s Disease

Behçet’s disease is a systemic inflammatory disease with multiple mucocutaneous manifestations, especially including genital and oral ulcers and often severe sight-threatening inflammatory eye disease.⁷ Arthritis, gastrointestinal disease (including mucosal lesions), epididymitis, and secondary amyloidosis can also occur. Although its prevalence is markedly increased in countries in the Eastern Mediterranean, Middle East, and East Asia and descendents of people from these regions, Behçet’s disease is found in populations worldwide.

Vasculitis occurs in up to one third of patients with Behçet’s disease and is unique among the inflammatory vasculitides for the relatively common clinical involvement of venous disease. Both arterial and venous manifestations may occur in the same patients. Venous involvement includes superficial phlebitis, varices, and thromboses of deep veins, vena cava, cerebral sinuses, and other major veins.

The arterial lesions in Behçet’s disease are often in large vessels and frequently result in aneurysms, stenoses, or rupture. The most common sites of arteritis are the aorta and its branches and the pulmonary arteries; however, Behçet’s disease may also involve medium and small vessels.

Behçet’s disease can involve a huge range of different types of histopathologies, consistent with the protean disease manifestations. The oral and genital ulcers do not have specific pathognomonic features. Similarly, biopsy specimens of the gastrointestinal lesions cannot differentiate Behçet’s disease from inflammatory bowel disease. Although the vascular lesions can include large and small arteries as well as veins, these lesions are similar to those of other vasculitides.

Treatment of Behçet’s disease varies with the manifestation being addressed and may range from colchicine and topical glucocorticoids for aphthous ulcers to large doses of glucocorticoids for many problems including mucocutaneous, vascular, and eye lesions. The uveitis is treated with long-term immunosuppressive agents, including cyclosporine, azathioprine, chlorambucil, and cyclophosphamide. Inhibitors of tumor necrosis factor (TNF)-α are now also used to treat this disorder. Many treatment protocols are based on expert opinion, but in recent years an increasing number of controlled clinical trials have been performed, especially involving eye disease. Behçet’s disease can be a highly aggressive form of vasculitis that frequently results in significant morbidity and mortality.

Relapsing Polychondritis

Relapsing polychondritis is a rare connective tissue disease that predominantly affects the cartilaginous structures of the eyes, ears, nose, and subglottis/trachea, but may also affect a wide variety of other organ systems and is associated with vasculitis, especially of large vessels.⁸ The cardinal feature of polychondritis is auriculitis, inflammation of the outer ear, usually sparing the noncartilaginous lobe. Auriculitis, which is also a feature of GPA and CSS but virtually of no other diseases, is readily treated with glucocorticoids and can result in disfigurement if allowed to go untreated. Other common manifestations include inflammatory eye disease that can lead to blindness, destruction of nasal cartilage leading to internal derangement and external disfigurement, sensorineural hearing loss and vertigo, arthritis, and subglottic inflammation with resulting stenosis, a life-threatening condition. Each of these features can also be seen in GPA, although auriculitis is rare in this disease, and relapsing polychondritis is not associated with parenchymal pulmonary manifestations.

The vasculitis seen in relapsing polychondritis can affect vessels of any size, but large-vessel vasculitis is the most common. Aortitis with associated aortic valvular dysfunction and accompanied by thoracic or abdominal aortic aneurysms is fairly common and can lead to heart failure, aneurysmal rupture or dissection, and involvement of branch arteries. Small-vessel disease can affect nerves, eyes, kidneys, and other systems.

The histopathology of relapsing polychondritis includes destructive inflammation of various types of cartilage, necrotizing aortitis, vasculitis in small vessels (e.g., skin, glomeruli), and direct inflammatory infiltration of eye structures, heart valves, pericardium, skin, and other tissues.

Relapsing polychondritis has been associated with various other primary autoimmune diseases, such as inflammatory bowel disease, lupus, and others. The rarity of this syndrome has precluded comprehensive research that might help both better differentiate cases from other conditions and learn more about the pathophysiology. Treatment almost always involves systemic glucocorticoids, and immunosuppressive agents are frequently prescribed for this often rapidly progressive disease.

Cogan’s Syndrome

Cogan’s syndrome is a rare disorder characterized by inflammatory eye and inner ear/vestibular disease that can also involve inflammatory vasculitis.⁹ It is a disease of young adults, usually first affecting patients before age 40, although both children and older patients have also been affected.

The characteristic clinical manifestations of Cogan’s syndrome are interstitial keratitis, sensorineural hearing loss, and vestibulatory dysfunction. Although interstitial keratitis is the most common eye problem in Cogan’s syndrome, uveitis, scleritis, and many other types of ophthalmological inflammation can occur. The eye and ear damage is often permanent and can be quite debilitating. The combination of inflammatory eye disease and inner ear problems is required for a diagnosis of Cogan’s syndrome, but these findings can occur in other diseases as well, such as infections, malignancies, sarcoidosis, and various autoimmune diseases, including other vasculitides (e.g., GPA, relapsing polychondritis, Behçet’s disease). Other organ systems are less commonly involved.

Vasculitis occurs in up to 15% of patients with Cogan’s syndrome and is mostly large-vessel disease, with some medium-vessel manifestations reported. The large-vessel disease in Cogan’s syndrome is similar to that of TA and includes aortitis with aortic insufficiency, stenoses of the carotid and subclavian and other aortic branch arteries, and even coronary artery disease (CAD). Treatment of Cogan’s syndrome includes both glucocorticoids and immunosuppressive drugs, appropriate rehabilitation (e.g., vestibular retraining), surgical correction of eye damage, and use of hearing aides or surgical correction of hearing loss.

Idiopathic Aortitis

Aortitis may be found in the absence of any other manifestations of a systemic inflammatory disease.¹⁰^–¹² These cases often come to the attention of vascular medicine specialists when patients undergoing surgical repair of aortic aneurysms and dissections are found to have inflammation consistent with aortitis on pathological specimens. Autopsies and studies of large numbers of surgical specimens have demonstrated that noninfectious aortitis occurs in 4% to 15% of cases. Although on detailed investigation, many of these patients are retrospectively found to have had evidence of GCA, TA, relapsing polychondritis, GPA, or another definable vasculitis, it is common among these cases to find no evidence of more systemic inflammatory disease. The majority of cases of so-called idiopathic aortitis involve thoracic lesions, in contrast to the overall predominance of abdominal aortic lesions for noninflammatory disease.

It is possible that cases of isolated inflammatory aortic aneurysms will be increasingly identified earlier as magnetic resonance imaging (MRI) technology continues to improve and helps demonstrate inflammation in the arterial wall. It can, however, be difficult to differentiate inflammation due to true idiopathic aortitis and vasculitis from the vascular and periaortic inflammations seen in association with atherosclerotic disease. Currently, in the absence of pathological specimens or other evidence of a vasculitis, MRI alone is not diagnostic for inflammation. The emergence of positron emission tomography (PET) scanning for large-vessel disease may also help in the evaluation of such patients.

The approach to treatment of idiopathic aortitis is unclear; many patients never develop other findings of vasculitis. However, new aneurysms and significant vascular disease do occur in some cases.¹¹ Comprehensive evaluation of evidence of systemic disease is necessary and should include a detailed physical examination, diagnostic imaging, laboratory studies, and other approaches outlined later in this chapter. Appropriate treatment should be given if inflammatory disease other than that seen in the surgical specimen is found, but not all patients require glucocorticoids, especially in the postoperative period. Furthermore, regular follow-up of such patients by a specialist knowledgeable about vasculitis is imperative because lesions may develop subtly and only years after the initial pathological diagnosis is made.

Miscellaneous Forms of Large-Vessel Vasculitis

Although large-vessel vasculitis is only rarely seen with other systemic inflammatory conditions, it is important to recognize these potential associations. Aortitis is rarely associated with long-standing seronegative spondyloarthropathies (ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and inflammatory bowel disease) and can result in aortic insufficiency. Retroperitoneal fibrosis, a rare disease of proliferating fibroblasts usually causing ureteral obstruction and at times aortic stenosis and periaortitis, is also associated with true inflammatory aortitis. There have been a few case reports of large-vessel vasculitis in patients with rheumatoid arthritis, systemic lupus erythematosus (SLE), and GPA.

Medium-Vessel Vasculitis

Among the inflammatory vasculitides, the medium-vessel diseases have the greatest variety of clinical manifestations, which result from the broad range of vessel sizes actually involved in the process. As stated earlier, classifying the vasculitides by affected vessel size can be problematic, but particularly with the medium-vessel disorders.

Specialists in vascular medicine need to be aware of protean presentations of active medium-vessel disease and the lasting damage they can cause. As with large-vessel disease, these disorders can mimic noninflammatory cardiac, renal, cerebral, and other vascular problems. This fascinating set of diseases comprises the vasculitides for which the highest quality and quantity of clinical trial data are available to help guide therapy.

Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is among the “purer” vasculitides in that most of its manifestations are due to true vascular inflammation.¹³ With the identification of other types of vasculitis, the spectrum of what is now diagnosed as PAN has narrowed over the past 50 years. Although characterized as a medium-vessel disease, PAN may also involve small vessels such as those in the skin. Polyarteritis nodosa frequently involves inflammation leading to multiple small aneurysms that often appear angiographically as a “string of beads.” Ischemia and infarction of kidneys, intestines, and skin are common in PAN, with arthralgias, myalgias, and fevers also frequently seen. Diagnosis is based on angiographic appearance (Fig. 41-2) or tissue pathology, often from surgical specimens such as a resected ischemic bowel segment. Interestingly, PAN in one subset of patients is associated with either hepatitis B or hepatitis C infections.^13,¹⁴ Importantly, there is a difference between hepatitis C–associated PAN and hepatitis C–associated cryoglobulinemic vasculitis (CV, see later section). Cardiac manifestations of PAN are due to coronary arteritis or malignant hypertension (secondary to renal artery disease) and include myocardial ischemia, heart failure, and arrhythmias.

Figure 41-2 Polyarteritis nodosa (PAN) with stenotic lesions (A) and wall thickening and enhancement (B) of celiac and superior mesenteric arteries imaged using three-dimensional (3D) dynamic gadolinium-enhanced magnetic resonance angiography (MRA).

Treatment of PAN almost always involves high-dose glucocorticoids followed by a slow tapering of the dose. In more severe cases, an immunosuppressive agent is added. Hepatitis-associated PAN is now often treated with short courses of glucocorticoids and prolonged courses of antiviral agents. The rate of disease relapse in PAN is lower than that for many other types of vasculitis, and this relatively good prognosis is another important factor to take into consideration when deciding on a therapeutic regimen. Due to the rarity of the disease, controlled clinical trials for PAN are unlikely to occur; treatment is based on case series and expert opinion.

Granulomatosis with Polyangiitis (Wegener’s)

Granulomatosis with polyangiitis is characterized by the triad of inflammation and destruction of tissue in the upper airway and sinuses (Fig. 41-3), lower airway (Fig. 41-4), and kidneys (Fig. 41-5), as well as the development of ANCAs.^15,¹⁶ Approximately 70% of patients with GPA are positive for ANCA at diagnosis, although some will develop the antibodies later in the course of their illness. Among patients with GPA and glomerulonephritis, more than 90% are positive for ANCA. Although the combination of these features is common in GPA, many patients present with only a subset of these findings. Granulomatosis with polyangiitis also frequently involves many other organ systems. The upper airway lesions include destructive rhinitis, often leading to nasal bridge collapse and the “saddle nose” deformity, sinusitis, and subglottic inflammation that can lead to life-threatening tracheal stenosis. The most severe form of pulmonary disease in GPA is alveolar hemorrhage, and this is a common cause of early death. Other common pulmonary lesions include nodules, with or without cavitation, and tracheobronchitis. Other common features of GPA are retroorbital pseudotumor with resulting proptosis, conductive and sensorineural hearing loss, mononeuritis multiplex, arthritis, and purpura. Peripheral vascular involvement with gangrene is seen in GPA and may be the presenting feature (Fig. 41-6).