Giant cell arteritis. The wall of this muscular artery is diffusely involved by granulomatous inflammation, including scattered multinucleated giant cells, with significant loss of the muscular media and internal elastic lamina due to the vasculitis. (Photo courtesy of Dr. Charles Eberhart, Johns Hopkins University School of Medicine, Department of Pathology)
Takayasu’s Arteritis
Takayasu’s arteritis is a large-vessel vasculitis that predominantly affects women under the age of 40, with an increased prevalence among individuals of Asian descent. There are two general phases to the condition: the systemic phase and the occlusive phase. The systemic phase may manifest with fever, fatigue, weight loss, and other nonspecific constitutional symptoms, while the occlusive phase reflects symptomatic ischemia due to arterial stenoses, such as with claudication pain in the limbs, vision loss, headache, or unequal or absent pulses in the upper extremities. Takayasu’s arteritis is thought to start at the aortic annulus and progress from there, with autopsy studies rarely finding arteritis that is confined only to the aorta and its branches. Takayasu’s arteritis appears to involve cell-mediated immunity, with Th1 CD4+ lymphocytes supporting granuloma formation via interferon-γ and HLA-DR+ circulating T lymphocytes that appear to be sensitized against aortal antigens [4]. The 1990 American College of Rheumatology (ACR) Classification Criteria for Takayasu’s arteritis include disease onset before the age of 40, arteriographic narrowing of the entire aorta documented with CT angiography, decreased brachial pulse in at least one brachial artery, and a difference of >10 mm Hg in systolic blood pressure between both arms [5]; a minimum of three of six possible criteria are required for classification, and, though the diagnosis is supported by a history of elevated acute phase reactants at presentation, normal values do not exclude the diagnosis [6]. CT angiography and magnetic resonance angiography are the preferred imaging modalities for diagnosing Takayasu’s arteritis. Reasonable initial treatment of the disease per EULAR treatment guidelines includes prednisone initially at 1 mg/kg/day up to 60 mg daily, maintained for at least 1 month, followed by a gradual prolonged taper [7]. Immunosuppressive adjunctive therapy aside from glucocorticoids is also strongly recommended because of a propensity for Takayasu’s arteritis to remain subclinically active even on glucocorticoids, with the possibility of relapse of the disease with steroid monotherapy; indeed, roughly 50% of patients with successfully induced remission suffer from relapse of disease [8]. Azathioprine 2 mg/kg daily or methotrexate 20–25 mg weekly can be used as steroid-sparing agents and, for refractory cases, alternative steroid-sparing adjuncts include anti-TNF agents or cyclophosphamide.
Cogan’s Syndrome
Cogan’s syndrome is a chronic inflammatory disease of unclear origin that manifests with ocular, vestibuloauditory, and vasculitic findings. These may include interstitial keratitis, episcleritis, uveitis, or other orbital inflammation; sensorineural hearing loss, tinnitus, or vertigo; and, in 10–30% of patients, aortitis or other similarly significant vasculitis. Atypical cases of Cogan’s syndrome have been reported to involve the cardiovascular, neurologic, and gastrointestinal systems as well. Research has focused on the possible underlying autoimmune etiology of the condition, including the identification of an immunodominant peptide that shows similarity with autoantigens such as SSA/Ro and with the reovirus III major core protein lambda 1 and also shows similarity with the cell-density enhanced protein tyrosine phosphatase-1 (DEP-1/CD148), which is expressed on the sensory epithelia of the inner ear and on endothelial cells [9]. Treatment of Cogan’s syndrome depends on the type of organ involvement and the severity of disease. Keratitis, episcleritis, and anterior uveitis can typically be treated with topical prednisone acetate for several weeks. Deeper ocular inflammation and vestibuloauditory symptoms should be treated with at least prednisone 1 mg/kg daily and typically for at least 2–6 months. Some clinicians may also choose to add cyclophosphamide, methotrexate, cyclosporine, or infliximab for recalcitrant cases.
Behçet’s Disease
Oral aphthosis, along with genital aphthosis, is a hallmark feature of Behçet’s disease, though recurrent oral aphthosis in and of itself has a long differential that includes certain vitamin deficiencies, herpes simplex and other infectious etiologies, autoimmune blistering diseases such as IgA pemphigus or pemphigus vulgaris, drug-induced causes, or paraneoplastic phenomena. Celiac Disease and inflammatory bowel disease can also present with aphthous-like ulcerated lesions. The International Study Group for Behçet’s Disease identified recurrent oral ulceration as the required criterion for diagnosis, with patients also needing at least two of the following minor criteria to indicate a diagnosis of Behçet’s disease: recurrent genital ulceration; characteristic inflammatory eye disease such as anterior or posterior uveitis, retinal vasculitis, or cells in the vitreous; characteristic skin lesions such as erythema nodosum; or positive pathergy test (hyper-reactivity of the skin to minor trauma) [10]. Research has identified a strong genetic underpinning in Behçet’s disease of the MHC-related allele HLA-B51/B5, and carriage of this allele has been shown to predominate in men and be associated with a higher prevalence of genital, ocular, and skin manifestations and with a lower prevalence of gastrointestinal manifestations [11]. Behçet’s disease is unusual among the vasculitides as it has been shown to affect small, medium, and large vessels and can also involve the central nervous system. Venous thromboembolism can also occur in Behçet’s disease, and there is some discussion in the literature as to whether immunosuppression without anticoagulation is sufficient to prevent recurrence of this manifestation [12]. Colchicine, dapsone, azathioprine, apremilast, thalidomide, and interferon have all been used in the treatment of mucocutaneous manifestations of Behçet’s disease, while azathioprine, methotrexate, and cyclosporine have been used for ocular manifestations. Cyclophosphamide, anti-TNF agents, and chlorambucil have been used for refractory, severe central nervous system disease or life-threatening complications of Behçet’s disease.
Medium-Vessel Vasculitis
Polyarteritis Nodosa
Polyarteritis nodosa (PAN) is a necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. The disease is not associated with antineutrophil cytoplasmic antibodies (ANCA). Hepatitis B infection is commonly associated with PAN and is present in 20–30% of cases [13]. Clinical presentations are heterogeneous, with end-organ effects resulting from perfusion defects caused by the vasculitis. Common symptoms include constitutional symptoms, weight loss, myalgias, arthralgias, and skin abnormalities such as necrotizing purpura or subcutaneous nodules, while peripheral nerve involvement including mononeuritis multiplex is also common and is seen in roughly 80% of cases [14]. Involvement of the gastrointestinal, cardiac, genitourinary, and renal systems is seen as well. Mortality over a mean follow-up period of 6 years has been estimated at 25%, with one third of deaths being due to uncontrolled or relapsed vasculitis [15]. There are no specific biomarkers for PAN, and it is reasonable to screen for hepatitis B (HBV) and hepatitis C (HCV), human immunodeficiency virus (HIV), and parvovirus B19 to exclude the presence of these infections. Testing for ANCA, Proteinase 3 (PR3) antibodies, Myeloperoxidase (MPO) antibodies, cryoglobulins, and rheumatoid factor also should be obtained to exclude the differential diagnoses of ANCA-associated small-vessel vasculitis and cryoglobulinemic vasculitis. Serologic screening and surveillance for end-organ involvement and damage with creatine kinase levels, troponin, liver function and renal function testing, spot urine protein:creatinine ratio, and urinalysis is important in disease management. Acute phase reactants should be followed to monitor disease activity and response to treatment. Conventional dye angiography can be used to assess for medium-vessel microaneurysms, stenoses, and luminal irregularities. In general, conventional angiography is the imaging gold standard for PAN since neither CT nor MRI angiography offer comparable sensitivity. Treatment selection should be based on HBV status, mortality risk as predicted by the Five-Factor Score, and the severity and degree of organ involvement [14]. For patients with HBV infection, lamivudine is the preferred antiviral agent of choice, with plasma exchange on a background of prednisone until HBeAb seroconversion occurs. For non-HBV cases with a Five-Factor Score > 0, which corresponds to a poorer prognosis and increased 5-year mortality, a combination of steroids and cyclophosphamide induction followed by azathioprine maintenance may be used. Plasma exchange has not been shown to be beneficial for non-HBV cases of PAN.
Kawasaki Disease
The most common systemic vasculitis among children worldwide is Kawasaki disease, a vasculitis that affects medium caliber vessels. Kawasaki disease occurs most frequently in children under the age of 5. While Kawasaki disease can affect children of all ethnicities, its highest prevalence is found in Asian populations, particularly Japanese children. Kawasaki disease typically presents with acute onset fevers and acute phase reactant elevation without an infectious source. Additional features may include cervical lymphadenopathy, generalized or palmoplantar rash, lesions of the mucus membranes (including strawberry tongue) and ocular disease including conjunctivitis and uveitis. The most feared complication of KD is cardiac disease: myocarditis in the early phase of the disease, and coronary artery aneurysms which develop in later stages. For this reason, echocardiography is a mandatory diagnostic study in the evaluation of suspected cases of Kawasaki disease and is performed serially to monitor for the development of aneurysms in confirmed cases. Ophthalmologic exam should also be obtained due to the high prevalence of uveitis. Additional studies should be undertaken to exclude infectious etiologies with similar presentations, including scarlet fever, parvovirus and herpesviruses, and other inflammatory conditions (JIA, periodic fever syndromes). Once the diagnosis of Kawasaki disease is made, therapy with IVIG is standardly implemented. The implementation of IVIG early in the disease course has demonstrated significant benefit in reducing the risk of coronary artery aneurysms [16] Additional therapies considered in refractory or severe Kawasaki disease include aspirin, glucocorticoids, and repeat courses of IVIG. With timely diagnosis and treatment, Kawasaki disease can be limited to a monophasic illness with minimal long-term sequelae in many patients.
Small-Vessel Vasculitis
Granulomatosis with Polyangiitis (GPA)
Granulomatosis with polyangiitis, formerly known as Wegener’s granulomatosis, is an ANCA-associated necrotizing vasculitis with granulomatous inflammation, predominantly affecting small to medium vessels and usually involving the upper and lower respiratory tracts. The varied clinical presentations of GPA are driven by the presence of granulomatous inflammation that can manifest as orbital pseudotumor, chronic sinusitis, Eustachian tube dysfunction, subglottic stenosis, and cavitary pulmonary lesions, or by the small- or medium-vessel vasculitis, which can result in pulmonary hemorrhage, glomerulonephritis, palpable purpura or mononeuritis multiplex. Abnormalities of the upper airway, including chronic rhinitis with or without nasal crusting, epistaxis, chronic sinusitis, and serous otitis, are typically the earliest presenting features and are estimated to be present in over 90% of cases [17]. Anti-PR3 antibody positivity with a C-ANCA pattern by indirect immunofluorescence microscopy has a high specificity and positive predictive value for GPA, but the absence of ANCA or PR3 does not exclude the diagnosis, and isolated granulomatous disease of the upper or lower respiratory tract in particular has a propensity to be associated with PR3 and C-ANCA negativity. PR3-ANCA is thought to be present in 80–95% of GPA cases, with the remaining 5–20% exhibiting atypical MPO-ANCA positivity or no ANCA [18]. GPA can be divided into the categories of limited disease, which tends to be characterized by predominance of necrotizing granulomatous manifestations, and severe disease, which is disease threatening the function of life or a vital organ, usually secondary to the vasculitis. The term “limited” may be misleading since patients with non-life-threatening forms of GPA often suffer from chronic morbidity and can require several years of continuous immunosuppression to adequately treat the mass lesions associated with this form of GPA. In general, patients with limited GPA are treated with an antimetabolite agent such as methotrexate, azathioprine, mycophenolate mofetil, or leflunomide. Rituximab may have a role for patients who have been refractory to this class of agents or are intolerant of these drugs. Patients with severe GPA should be treated with induction with pulse intravenous methylprednisolone 1000 mg daily for 3 days, thereafter converted to oral prednisone, used in conjunction with cyclophosphamide or rituximab. Concurrent cyclophosphamide as an induction agent can be given either orally at 2 mg/kg daily to a maximum dose of 200 mg daily for 6 months or as a series of IV pulses of 15 mg/kg to a maximum of 1.2 grams initially every 2 weeks for the first three pulses, followed by spacing to every 3 weeks for the next 3–6 pulses [19]. As an alternative to cyclophosphamide induction, rituximab is FDA-approved for induction in patients and should be administered according to the RAVE trial protocol at a dose of 375 mg/m2 weekly for 4 weeks [20]. Among patients with the severe forms of ANCA-associated vasculitis, rituximab is commonly considered to be the treatment of choice for younger patients (who are concerned about preserving fertility), older patients (who may not be able to tolerate traditional cytotoxic agents), or patients who have previously been treated with cyclophosphamide. Remission induction with cyclophosphamide should be followed by 18–24 months of immunosuppressive therapy in accordance with the 2008 EUVAS Management Guidelines [19]. Azathioprine 2 mg/kg daily is preferred, but options may also include methotrexate 20–25 mg per week if creatinine is <1.5 mg/dL, mycophenolate mofetil 1000 mg twice daily, or leflunomide 20–30 mg daily as second-line options. Rituximab can also be used as a long-term maintenance agent.
Microscopic Polyangiitis (MPA)
Microscopic polyangiitis is a necrotizing vasculitis with few or no immune deposits that predominantly affects small vessels, but without the presence of necrotizing granulomas that is characteristic of GPA. The initial presentation of MPA typically is characterized by a long prodromal phase dominated by marked constitutional symptoms followed by rapidly progressive necrotizing glomerulonephritis presenting as a nephritic syndrome. Glomerulonephritis is present in roughly 80% of cases at diagnosis, but pulmonary involvement is less common, occurring in about 10–30% of patients [21]. Another important distinguishing feature of MPA from GPA is that fever is the presenting feature in 80% of cases of MPA, but is an initial feature in only of 20–25% of cases of GPA. Anti-MPO antibody positivity with a P-ANCA pattern by indirect immunofluorescence microscopy has a high specificity and positive predictive value for MPA, but the absence of ANCA or MPO does not exclude the diagnosis. Although MPA and GPA can appear similar in many aspects of presentation, more detailed analyses of pathophysiology indicate key differences in these conditions. While both anti-MPO and anti-PR3 antibodies can activate neutrophils in vitro, the evidence for in vivo pathogenicity of anti-MPO is more robust than that for PR3-ANCA. A recent genome-wide association study of patients with ANCA-associated vasculitides demonstrated a significant association of PR3-ANCA and human leukocyte antigen-DP and the genes encoding α1-antitrypsin and PR3 while MPO-ANCA were significantly associated with human leukocyte antigen-DQ [22]. Nevertheless, similar to GPA, MPA can be categorized as limited or severe disease, and the treatment modalities are quite similar, including pulse methylprednisolone converted to oral prednisone and used in conjunction with cyclophosphamide or rituximab for induction for severe disease. Azathioprine, methotrexate, mycophenolate mofetil, leflunomide, rituximab, and, though with significant potential side effects form long-term use, cyclophosphamide can be used for maintenance therapy.
Eosinophilic Granulomatosis with Polyangiitis (EGPA)
Eosinophilic granulomatosis with polyangiitis, formerly known as Churg-Strauss syndrome, is an ANCA-associated, eosinophilic necrotizing vasculitis affecting predominantly small to medium vessels that is associated with asthma and peripheral and tissue eosinophilia. Diagnosis of eosinophilic granulomatosis with polyangiitis is supported by a history asthma, peripheral eosinophilia with an absolute eosinophil count >1500/mm2 and biopsy showing evidence of necrotizing granulomas and eosinophilic small-vessel vasculitis. Asthma is the defining clinical feature of EGPA, being present in >90% of patients at diagnosis and preceding the onset of vasculitis in roughly 80% of cases [23]. EGPA is typically divided into three phases of the disease: the allergic phase, with occurrence of asthma, allergic rhinitis, and sinusitis; the eosinophilic phase, in which eosinophilic organ infiltration (e.g., lungs, heart, and gastrointestinal system) occurs; and the vasculitic phase, with purpura, peripheral neuropathy, and constitutional symptoms. ANCA-positive patients are at increased risk for otolaryngologic involvement (usually sinusitis); neurologic complications including peripheral neuropathy and mononeuritis multiplex; renal involvement (typically an interstitial nephritis rather than glomerulonephritis). An unusual feature of neurologic involvement in EGPA is the occurrence of bilateral wrist or foot drop in patients, which is not typically seen in individuals with other small- or medium-vessel vasculitides. Similar to the approach for GPA and MPA described above, corticosteroids with cyclophosphamide or rituximab are classically used for remission induction, while azathioprine and methotrexate are some of the main therapeutic options for remission maintenance in EGPA. Interestingly, IL5 plays a central role in regulating eosinophil proliferation, maturation, and differentiation and is present at increased levels in patients with eosinophilic granulomatosis with polyangiitis, indicating that this cytokine may be important in disease pathogenesis [24]. In 2017, a multicenter, double-blind, parallel-group, randomized phase 3 clinical trial of 136 participants demonstrated that treatment with mepolizumab, an anti-IL5 monoclonal antibody that binds to IL5 and prevents its interaction with its receptor on the eosinophil surface, resulted in significantly more weeks in remission and a higher proportion of participants in remission than did placebo, thereby allowing for reduced glucocorticoid use [25]. On the strength of this and other trials, the FDA approved mepolizumab in December 2017 for the treatment of EGPA, though it is important to note that the dose of the medication used in the trial was 300 mg administered every 4 weeks, as opposed to the 100 mg dose every 4 weeks typically used in asthma without concurrent EGPA.
Henoch-Schonlein Purpura
Henoch-Schonlein purpura (HSP) is a small-vessel vasculitis that is more common in children than in adults, is typically self-limited, and is notable for histology demonstrating IgA deposition in the walls of involved blood vessels. While monophasic in children, it can be relapsing in adults and may result in renal failure and gut ischemia. Purpura not due to thrombocytopenia should raise suspicion for this condition, as should concomitant arthritis, abdominal pain, and glomerulonephritis. From the pediatric literature, there is little evidence that immunosuppression is effective in the treatment of renal disease. For the cutaneous lesions of the condition, and possibly for the gastrointestinal symptoms as well, dapsone is often first-line therapy once glucose-6-phosphate dehydrogenase deficiency has been ruled out, given the possibility of significant hemolysis due to dapsone in such patients. Patients should be counseled that cutaneous vasculitis can be stimulated by activities that promote circulation to the lower extremities, including exercise, heat, and alcohol. Pressure stockings can be very effective for the treatment of the cutaneous manifestations of HSP and should be worn as much as possible, especially with regard to periods of activities such as those noted above. HSP is associated with a risk of renal insufficiency that remains even after initial recovery of renal function, thus routine monitoring of renal function should continue over a patient’s lifetime.
Single Organ Vasculitis
The Chapel Hill Consensus Conference definition for single-organ vasculitis defines this entity as “vasculitis in arteries or veins of any size in a single-organ that has no features that indicate that it is a limited expression of a systemic vasculitis.” Importantly, this definition is one that relies on vigorous exclusion of primary or secondary systemic rheumatic causes. When diagnosed, single-organ vasculitis by definition does not evolve into systemic vasculitis. Importantly, though, workup often reveals secondary non-rheumatic cause for the vasculitis such as cancer, environmental exposures, or infection.
Most available knowledge regarding single-organ vasculitis is based on small case series that have appeared in the literature over the last several decades [26]. Any organ system can be involved, but the most common targets are often skin, central and peripheral nervous system, muscle, gastrointestinal organs, the urogenital tract, breasts, and the eyes. In contrast, other visceral organs including the heart, liver, lungs, and the kidneys have never been established to be targets of single-organ vasculitis. The clinical presentation is a consequence of the specific end-organ that is involved. In general, however, constitutional symptoms are infrequently seen, acute phase reactants are usually normal to only slightly elevated, and the prognosis is often benign. The vasculitis itself is thought to follow a monophasic course in most cases. That being said, there is currently little evidence-based data to guide management of this group of vasculitides. Most experience with treatment has been based on retrospective series, and there are no randomized placebo-controlled trials of intervention for single-organ vasculitis to date.
High-Yield Review of Vasculitis
Key Points on Systemic Vasculitis
Systemic vasculitides share the pathogenic feature of inflammation focused in the walls of blood vessels.
Primary vasculitides are categorized according to the caliber of the blood vessels involved.
Secondary vasculitis can be due to underlying connective tissue disease, infection, drug-induced, or paraneoplastic causes.
Commonly used imaging modalities in suspected vasculitis include Doppler ultrasound, conventional angiography, computed tomography angiography, magnetic resonance angiography, and positron emission tomography.
Diagnosis of vasculitis is made based on tissue histopathology in concert with the appropriate clinical presentation.
Typical histologic findings of vasculitis include infiltration of the vessel wall by immune cells, fibrinoid necrosis of blood vessel walls, and leukocytoclasis.
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