History

Vasculitis is a heterogeneous set of diseases characterized by blood vessel inflammation. Variabilities in clinical and pathological findings depend on the type and size of the blood vessels affected.1 Vasculitis can present either as a primary vasculitides or secondary to other underlying disorders. Systemic vasculitides are classified according to the American College of Rheumatology (ACR) 1990 criteria.2 The most common nomenclature applied for vasculitis is given by the International Chapel Hill Consensus Conference (CHCC).3

Purpura was the earliest vasculitis manifestation identified in vessels smaller than arteries and was later differentiated into infectious and noninfectious purpura.4,5 

Vasculitic neuropathy was described in 1866 and accompanied by abdominal pain, tachycardia, and cutaneous nodules noted over the trunk. An autopsy of cutaneous nodules showed the presence of nodules along medium-sized arteries. This disease was termed periarteritis nodosa and later renamed polyarteritis nodosa due to widespread vessel involvement.6 In 1897, the description of a disease with a necrotizing vasculitis, respiratory tract granulomatous lesions, and glomerulonephritis was given along with 2 cases that detailed the anatomic pathology of this disease with the cause of death as systemic vasculitis.6,7

In 1954, criteria for diagnosing Wegener’s granulomatosis (WG) was published8. Corticosteroids, cyclophosphamide, and trimethoprim/sulfamethoxazole were later recommended for the treatment of Wegener’s granulomatosis.9,10 Another major development was made by van der Woude who found sensitive and specific autoantibodies reacting with the cytoplasm of ethanol-fixed neutrophils and monocytes, known as anti-neutrophil cytoplasmic autoantibodies (ANCA).11

The 1994 International Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitides (CHCC1994) suggested names and definitions for common vasculitis types.12 Later, CHCC1994 concentrated on a limited number of vasculitides, and in 2012, the second International CHCC was held. The objectives were to provide appropriate definitions and names along with adding other important categories of vasculitis not included in CHCC1994.3

According to the 2012 International Chapel Hill Consensus Conference, large vessel vasculitis includes takayasu arteritis and giant cell arteritis (GCA); medium vessel vasculitis includes polyarteritis nodosa (PAN) and Kawasaki disease; small vessel vasculitis includes antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), which is further grouped into microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and esosinophilic granulomatosis with polyangiitis (EGPA); and variable vessel vasculitis includes Behcet disease and Cogan syndrome.

Epidemiology

Vasculitis as a whole affects approximately 38 to 40 people per million and is generally more common in adults than in children.13 Accurate estimation of incidence and prevalence is hindered by the rarity of certain forms of vasculitis. 

Large Vessel Vasculitis

The highest incidence of GCA is seen in Scandinavian (21.6 per 100,000 individuals) and Northern American (10.89 per 100,000 individuals) populations. In North America, data from Olmsted County, Minnesota, suggest that the prevalence of GCA is 204 per 100,000 individuals. The prevalence of Takayasu arteritis is approximately 8.4 per million individuals in the United States.14 

Medium Vessel Vasculitis 

Hepatitis B is a potential trigger for PAN and this form of vasculitis may occur in association with familial Mediterranean fever. In European countries, the annual incidence rate is between 0.9 and 8.0 per million individuals and prevalence rate is approximately 31 per million individuals.14 

The annual incidence of Kawasaki disease in the United States is estimated to be 20 per 100,000 children under 5 years of age and more likely to be seen in boys than girls. Children of Asian or Pacific Islander descent have a higher incidence of the disease. Myocarditis is also seen during the acute phase of Kawasaki disease.14,15

Small Vessel Vasculitis

The incidence of AAV is approximately 33.0 per million individuals in the United States. The incidence has increased in the last 40 years, likely due to improved and widespread testing. Individuals of Japanese, Chinese, and Southern European descent have an increased risk of being diagnosed with MPA compared with individuals of Northern European descent. The rarest form of ANCA is EGPA, with the universal incidence ranging from 0.14 to 4.0 per million individuals.15

Henoch-Schönlein purpura, also known as immunoglobulin A (IgA) vasculitis, is the most common type of vasculitis observed in children and adolescents. The annual incidence ranges from 3.5 per 100,000 individuals in Japan to 26.7 per 100,000 individuals in Scotland in children younger than 15 years of age, and is highest among children 4 to 6 years of age (70.3 per 100,000 individuals).15

Variable Vessel Vasculitis

The annual incidence of Behçet syndrome ranges from 0.05 to 3.9 per 100,000 individuals depending on the country. The highest prevalence was observed along the ancient Silk Road, ranging from 10.0 per 100,000 individuals in China to 421 per 100,000 individuals in Turkey. In the United States, the prevalence of Behçet syndrome is between 0.33 and 10.6 per 100,000 individuals.14 

Cogan’s syndrome primarily affects young adults, with the average age of onset ranging from 3 to 50 years and the majority of patients are White. As of 2015, there were less than 250 cases reported in the literature, though the actual number of patients with the disease are expected to be much higher. Cogan’s disease may be incorrectly diagnosed as idiopathic hearing loss or deafness, autoimmune inner ear disease, or idiopathic recurring ketatitis.16

Etiology and Risk Factors

The exact cause of vasculitis remains unknown. Various risk factors have been linked with an increase in incidence and prevalence of the disease. 

These include age, geography, gender, and ethnicity along with genetic and environmental factors. Hepatitis B and C infection can trigger immune system disorders such as rheumatoid arthritis, lupus, or scleroderma and have also been implicated in disease risk.17 Some medications and infections are known to be linked with systemic vasculitis, such as hepatitis B with PAN and silica or dust with AAV.18

GCA is the most common systemic vasculitis in patients older than 50 years of age while Kawasaki disease is more prevalent in children younger than 5 years of age. Human leukocyte antigen (HLA)-DRB1*04 is associated with GCA, HLA-B51/55 is associated with Behçet disease, and Kawasaki disease has numerous genetic associations. Behçet disease shows increased severity among male patients, whereas Takayasu arteritis has a female preponderance of 9 to 1.14

Vasculitis Prognosis

Disease prognosis depends on the degree of end-organ involvement. The 5-year survival rate increased from 70% to 80% between the 1990s and 2000s, likely due to ANCA testing that led to earlier diagnosis and treatment. 

Factors that influence patient outcomes include: 

  • Age
  • Vasculitis damage index of at least 1
  • Birmingham vasculitis activity score
  • Serum creatinine
  • End-stage renal disease
  • First relapse within 1 year
  • Infection burden

Relapse incidence also helps determine AAV prognosis. In patients with GPA, the introduction of cyclophosphamide has led to a clinical response in 90% of patients. Relapses remain common in patients diagnosed with GPA, with upper or lower respiratory tract involvement, and with ANCA directed against proteinase 3.19 

Early mortality spike within 1 to 2 years of diagnosis has been observed in patients with GCA. Main etiologies for mortality include cardiovascular diseases (39%), cerebrovascular diseases (14%), infections (13%), malignancies (13%), and gastrointestinal complications (4%). The involvement of large vessels in GCA is another factor associated with greater rates of relapse; despite this, there is a lower incidence of visual complications with large vessel involvement.19

The 10-year overall survival for Takayasu arteritis is 97% and the 15-year overall survival is 86%. Cardiologic complications are common causes of death for patients with Takayasu arteritis.20

Vasculitis Diagnosis & Presentation

Physical Examination Findings

On physical examination, fever, malaise, weight loss, night sweats, myalgia, and arthralgia may be noted. These nonspecific systemic manifestations are inflammatory responses that occur due to chemical mediators released from inflamed blood vessels.24 Examination findings involving various systems are provided below.

Cardiovascular System

Arterial pulse assessment must be routinely performed bilaterally for radial, carotid, femoral, brachial, popliteal, dorsalis pedis, and posterior tibial pulses to evaluate for any changes in the contour, upstroke, and pulse amplitude.25

Skin 

Skin lesions presenting as palpable purpura, nonpalpable purpura, pinpoint papules, vesicle, pustules, splinter hemorrhages, and urticaria are indicative of small vessel vasculitis. It often presents as a hemorrhagic pattern, leading to ulcerations in the skin.25 

Head and Neck

Examine for fever, nasal crusting, hearing loss (may be suggestive of AAV), uveitis (may be suggestive of hypocomplementemic urticarial vasculitis syndrome), and dry eyes or mouth. Nasal obstruction with septal crusts and saddle nose deformity may be suggestive of GPA and oral ulcers may be seen in Behçet disease.25,26 

Kidneys and Genitourinary System

Edema may be present in the periorbital, sacral, and lower extremities. Orthostatic hypotension may suggest acute prerenal kidney injury. Testicular pain suggests PAN.25 Adults with IgA vasculitis are at higher risk of significant kidney involvement.27

Liver Function and Gastrointestinal System

Oral ulcerations, gingival hyperplasia, jaundice, dyspepsia, abdominal pain, hematochezia or melena, gastroduodenal ulcers, peritonitis, and bowel perforation may be indicative of gastrointestinal vasculitis seen in PAN, MPA, GPA, EGPA, lupus enteritis, and rheumatoid arthritis-associated vasculitis.25

Central and Peripheral Nervous Systems 

Patient may present with depression, anxiety, and migraines localized in the temporal area. Swollen and sensitive temporal arteries during palpation are often seen in Takayasu arteritis.25 Peripheral neuropathy may be seen in AAV and asymmetric polyneuropathy with involvement of the central nervous system may be observed in PAN.27

Diagnostic Workup

Laboratory Testing

Normocytic and normochromic anemia, leukocytosis, thrombocytosis, and elevations in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are consistent with a systemic inflammatory response.24 

Blood cultures, echocardiograms, hepatitis B and C screenings, HIV tests, and antibody levels of antiglomerular basement membrane, antiphospholipid, and antinuclear can be used to exclude diseases that mimic vasculitis. Complement levels and serum cryoglobulin can be obtained to show an association with mixed cryoglobulinemia.24 Immunoelectrophoresis should be used to investigate monoclonal gammopathies that could be observed in hepatitis C-related vasculitis.27 These additional tests are required to exclude vasculitis mimics and infections.

Biopsy of the involved organs is required to confirm a vasculitis diagnosis. The pathological changes with vasculitis include the presence of inflammatory immune cells in the blood vessel walls. It is crucial for clinicians to identify the biopsy site accurately as the histopathological diagnosis is essential for confirmation. Common sites include the skin, kidney, temporal artery, nasal mucosa, lung, sural nerve, muscle, and testis.

Kidney biopsy is preferred over skin biopsy in cases where both kidney and skin are involved. Identification of necrotizing glomerulonephritis is helpful for vasculitis diagnosis and when determining how aggressive treatment should be. In cases with nonspecific systemic symptoms, blind biopsies to rule out vasculitis are generally are not useful.24

Imaging Studies

Radiological investigations include a chest x-ray and high-resolution computed tomography (HR-CT) in cases with respiratory complaints. HR-CT discloses focal or diffuse infiltrates with ground-glass opacities or alveolar occupation, making it the preferred imaging tool.25 An axillary ultrasound to temporal artery ultrasound may increase the diagnostic yield for GCA in routine practice. Vascular imaging, such as magnetic resonance imaging (MRI), MR angiography, CT angiography, and positron emission tomography (PET) prove useful for large vessel inflammation.28 

Endovascular ultrasound can delineate vascular wall swelling in patients with Kawasaki disease and PAN. Echocardiography is required for the assessment of coronary artery involvement, particularly in Kawasaki disease. Patients with EGPA typically show bilateral patchy ground-glass attenuation or areas of consolidation with predominant subpleural and lower lobe distribution on a HR chest CT.28

Differential Diagnosis

Many diseases can simulate vasculitis and should be differentiated based on clinical presentation.24 

Various infections can present like vasculitis, including hepatitis B and C viruses, HIV, herpes virus, cytomegalovirus, parvovirus B19, and parainfluenza virus.29 Nonspecific symptoms such as fever, malaise, myalgia, arthralgia, and weight loss, and laboratory findings of normocytic normochromic anemia, leukocytosis, thrombocytosis, elevated ESR, and elevated CRP are observed in vasculitis. It is essential to differentiate infections from vasculitis as treatment for vasculitis may involve immunosuppressants. A complete infection screening must be performed in all patients that present with systemic inflammatory features.24

Besides infections, rare diseases such as thrombotic thrombocytopenic purpura, antiphospholipid antibody syndrome, sickle cell disease, cholesterol emboli from atheroma, noninflammatory vessel wall disorders, amyloidosis, scurvy, and ergotamine-induced vasospasm can confuse the diagnosis due to similar presentations, systemic symptoms, or ischemic manifestations.24 

Approximately 50% of patients with GCA will present with symptoms similar to polymyalgia rheumatica. Patients with polymyalgia rheumatica will display shoulder and hip inflammation on an ultrasound.28

Vasculitis Management

Nonpharmacologic

Surgical treatments for vasculitis. Vascular procedures for vasculitis should be performed only during inactive disease periods.​​ In Takayasu arteritis, angioplasty with stenting of constricted vessels is done to improve blood flow as the aorta and renal arteries get involved. Repeat procedures also show good response as many vessels are prone to restenosis. Reconstructive surgery with graft implantation can be considered.34

In GPA, endoscopic management with local corticosteroid injection and/or mitomycin-C application can be done for subglottic stenosis. Repeated procedures are usually required.35

Pharmacologic

Large vessel vasculitis 

  • Giant cell arteritis
    • Glucocorticoids
    • Tocilizumab
    • Azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil
    • Aspirin
  • Takayasu arteritis
    • Glucocorticoids
    • Tocilizumab
    • Azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil
    • Infliximab, adalimumab, etanercept
    • Aspirin

Medium vessel vasculitis

  • Kawasaki disease
    • Corticosteroids
    • IVIG
    • Aspirin
    • Infliximab
    • Cyclosporine
    • Cyclophosphamide
  • PAN
    • Glucocorticoids
    • Azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil
    • Rituximab

Small vessel vasculitis

  • GPA/MPA
    • Glucocorticoids
    • Azathioprine, cyclophosphamide, leflunomide, methotrexate, mycophenolate mofetil 
    • Rituximab
    • Sulfamethoxazole/trimethoprim
  • EGPA
    • Glucocorticoids
    • Azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil
    • Rituximab
    • Mepolizumab

Glucocorticoids. Glucocorticoids are the cornerstone of vasculitis treatment. Oral prednisone is the drug and route of administration of choice, while IV pulse methylprednisolone is an alternative option for the treatment of GCA, Takayasu arteritis, and AAV. High-dose oral glucocorticoids is often combined with non-glucocorticoids immunosuppressive therapy to induce remission in large vessel vasculitis.

Due to the side effects seen with prolonged dose, the drug dose is tapered when the inflammation is controlled. The usual approach is to begin with a daily dose comparable to 1 mg/kg of prednisone up to a maximum dosage of 80 mg/day.

Moderate-dosing is comparable to 0.5 mg/kg of prednisone, and low-dosing is comparable to less than 10 mg/day.30 There are significant risks of side effects with chronic glucocorticoid use, including Cushingoid changes, osteoporosis, glaucoma, and metabolic abnormalities such as diabetes and hypercholesterolemia.36

Corticoid-sparing immunosuppressants include azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide. These agents are used in large, medium, and small vessel vasculitis. It is also given in cases of refractoriness to prednisone and other drugs.30-33 

Cyclophosphamide. Cyclophosphamide is an alkylating agent that blocks DNA replication. Low doses of cyclophosphamide with concomitant glucocorticoids are used in the treatment of vasculitis. A combination of high-dose glucocorticoid and cyclophosphamide improved survival rates from 20% to over 80% in patients with AAV, making this combination the standard treatment.36

Use of cyclophosphamide is also associated with a lowering of concomitant steroid use in 80% of patients,37 though there is limited data to support its use in patients with Kawasaki disease.33 It is also given in cases of refractoriness to prednisone and other drugs.

Methotrexate. Methotrexate inhibits dihydrofolate reductase and activation of nuclear factor-κB. It is used to treat various large, medium, and small vessel vasculitis as well as Behçet disease. Methotrexate or azathioprine are either first or second line options for remission maintenance in patients with AAV.37 Methotrexate with glucocorticoids is often used as the initial corticoid-sparing immunosuppressant for GCA and Takayasu arteritis and as the drug of choice to induce remission for patients with active GPA, MPA, and PAN.30,31

TNF inhibitors approved by the US Food and Drug Administration (FDA) and utilized for vasculitis treatment include infliximab, adalimumab, and etanercept.38,39 

Rituximab. Rituximab is an anti-CD20 monoclonal antibody that has been found to be effective for the treatment of many autoimmune disorders. 

Tocilizumab. Tocilizumab is a humanized recombinant anti-IL-6 receptor antibody that inhibits the binding of IL-6 to membrane-bound and soluble IL-6 receptors in a competitive manner. IL-6 supports the shift from acute to chronic inflammation and stimulates the release of ESR and CRP from hepatocytes. 

IVIG. High-dose IVIG has a low incidence of severe side effects. More common side effects include nausea, headache, fatigue, and febrile infusion reactions. Rare but serious side effects include thrombosis and embolism, pulmonary edema, renal failure, aseptic meningitis, and severe anaphylactic reactions.49

Aspirin. Adverse events include gastrointestinal and cerebral hemorrhage, which can be exacerbated when taken concomitantly with glucocorticoids.55 

Mepolizumab. Mepolizumab is an anti-IL-5 monoclonal antibody that reduces blood eosinophil counts.

Vasculitis Comorbidities

Accelerated atherosclerosis and cardiovascular mortality are noted in cases with AAV. Many patients also have hypertension, diabetes mellitus, and hypercholesterolemia either due to immunosuppression or in association with the underlying disease.62

Takayasu arteritis is associated with coronary heart disease, aortic incompetence, and myocarditis. Behçet disease usually can cause intracardiac mass lesions, thrombosis, or endomyocardial fibrosis. Kawasaki disease is associated with coronary artery aneurysms as the most common disease manifestation. Patients with Kawasaki disease are also predisposed to develop premature ischemic heart disease.63

Patients with GPA and MPA show an increased cancer risk, particularly skin, bladder, and hematologic malignancies. This risk increases with higher cumulative doses of cyclophosphamide.67

Vasculitis Complications

Complications due to infections and active vasculitis are the predominant risk factors for mortality within the first year of diagnosis. Cardiovascular complications such as myocardial infarction, stroke, and venous thromboembolism are usually the causes of death, followed by malignancies and infections. In spite of improvements in survival rates of AAV, the overall mortality rate has shown an increase by 2.7-fold over the general population.62 Complications can vary by type of vasculitis.

GCA

Vision loss occurs in 15 to 20% of patients, with anterior ischemic optic neuropathy the most common pathology. Vision loss can be halted if glucocorticoids are initiated promptly after diagnosis.64

Takayasu arteritis

Patients with Takayasu arteritis may experience new arterial occlusions, stroke or transient ischemic attack, new or worsening aneurysm, end-stage kidney disease, myocardial infarction, heart failure, and aortic regurgitation as a result of their diagnosis. These complications are more likely in patients with progressive disease, thoracic aorta involvement, and retinopathy.64

Kawasaki disease

The most severe complication for patients with Kawasaki disease is coronary artery abnormality development.

Behçet disease, AAV, and GCA

Inflammation-induced thrombosis is associated with Behçet disease, AAV, and GCA, especially during active disease. Both venous and arterial thrombosis can manifest in Behçet disease, though increasing research suggests that this may also be a characteristic of AAV and large vessel vasculitis.65

Patient Education

With vasculitis, a multidisciplinary management approach is needed that involves the primary care physician and rheumatologist. Patients with vasculitis encounter delays in obtaining an accurate diagnosis which can lead to substantial morbidity and increased mortality.66

Patients taking methotrexate should refrain from alcohol use and other hepatotoxic substances. Patients on corticosteroids should be wary of drug adverse effects like weight gain, hirsutism, hypertension, sleep disturbances, and glucose intolerance.

Patients on immunosuppressive therapies must be advised to see a doctor at any sign of infection. In patients of childbearing age on treatment with teratogenic medications such as methotrexate and warfarin, birth control measures should also be discussed.

Physicians should try to spend more time with patients of vasculitis in order to improve treatment outcomes. The interaction between patient and physician should be motivating and respond to the individual patient’s needs.67

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