Other Selected Vasculitides

Vasculitis is the inflammation of blood vessels and a broad disease category that encompasses myriad conditions, each with a unique clinical presentation, disease course, and management strategy. A full review of vasculitis is beyond the scope of this guide. This section covers the following types of vasculitis in children:

• Henoch-Schönlein Purpura (HSP)/IgA Vasculitis (IgAV)

• ANCA-Associated Vasculitis (AAV)

• Polyarteritis Nodosa (PAN)

• Takayasu Arteritis (TA)

The above subtypes of vasculitis can be differentiated using the following characteristics:

• size of blood vessels involved

• organ systems most commonly affected

• presence of antineutrophil cytoplasmic (ANCA)-associated antibodies

• transient versus chronic disease course

• histologic features

Vasculitis should be suspected in a pediatric patient in the following four clinical scenarios:

• prolonged constitutional illness (fever, weight loss, fatigue, malaise) with systemic inflammation (e.g., high erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]) and persistent symptoms despite a thorough negative workup for oncologic and infectious etiologies

• multisystem organ disease (e.g., pulmonary and kidney disease, kidney and gastrointestinal disease)

• unusual patient age for the illness (e.g., 13-year-old with myocardial infarction, 10-year-old with intussusception, 6-year-old with peripheral neuropathy)

• vasculitic rash (petechiae; palpable purpura; nonblanching purple/dusky lesions; ulcerative lesions; fixed, painful, erythematous nodules) in a patient with normal platelet counts

In 2010, the European League Against Rheumatism, the Paediatric Rheumatology European Society, and the Paediatric Rheumatology International Trials Organization published EULAR/PRINTO/PRES criteria for HSP (now referred to as IgA vasculitis [IgAV]), childhood polyarteritis nodosa, childhood granulomatosis with polyangiitis (formerly referred to as Wegener granulomatosis), and childhood Takayasu arteritis.

Henoch-Schönlein Purpura (HSP)/IgA Vasculitis (IgAV)

HSP, now more commonly referred to as IgAV, is a small-vessel vasculitis that affects the skin, joints, gastrointestinal tract, and kidneys. IgAV is the most common childhood vasculitis in the United States and typically affects children ages 3 to 15 years (peak age, 7 years). It is mediated by immune complexes (typically IgA) that are deposited in end organs and lead to inflammation. IgAV can be associated with antecedent infection, especially group A beta-hemolytic streptococcus (GAS), and seems to have seasonal variation, with fewer cases in the summer.

Classification

EULAR/PRINTO/PRES criteria for HSP/IgAV:

• purpura or petechiae (mandatory) with lower-limb predominance not due to thrombocytopenia and at least one of the following:

  • abdominal pain

  • IgA deposition on histopathology

    • leukocytoclastic vasculitis (LCV) with IgA deposits and/or proliferative glomerulonephritis with IgA deposits on histopathology

  • arthritis or arthralgia

  • renal involvement

Clinical Manifestations

Classic presentation: nonthrombocytopenic palpable purpuric rash, musculoskeletal pain, and colicky abdominal pain

• Rash: most common presenting feature

  • nonblanching, purpuric lesions developing in gravity- or pressure-dependent areas, usually distal to the elbows and below the waist; can occur on the face and ears

  • early lesions appear erythematous, petechial, or urticarial and then evolve into hemorrhagic or ecchymotic lesions; can also be bullous

  • Koebner phenomenon (lesions appear at sites of skin injury) and can occur along sock line

(Source: Henoch-Schönlein Purpura. N Engl J Med 2004.)

• Musculoskeletal pain: second-most common manifestation

  • persistent or intermittent

  • arthritis (joint warmth, effusions, and limitation) or arthralgias (joint aches without signs of inflammation)

  • periarticular and lower-extremity edema

• Gastrointestinal (GI) manifestations: can precede other manifestations

  • colicky abdominal pain

  • vomiting

  • hematemesis, melena

  • small-bowel vasculopathy can lead to ulceration and massive GI hemorrhage

  • intussusception

• Renal involvement:

  • affects one-third of patients; 90% will develop within first 4-8 weeks; 97% will develop within 6 months of initial diagnosis

  • poorest prognosis in children with nephritic/nephrotic syndrome at onset

  • microscopic or macroscopic hematuria with or without proteinuria, hypertension, glomerulonephritis

• Less common (but important) manifestations:

  • scrotal swelling mimicking testicular torsion

  • central nervous system (CNS) involvement: headaches, seizures, intracranial hemorrhage, cerebrovascular thrombosis, peripheral neuropathies

  • pulmonary involvement: interstitial disease, alveolar hemorrhage

  • cardiovascular involvement: carditis, myocardial infarction

Clinical Course

• Most cases are relatively mild and self-limited.

  • average duration of symptoms is 4 weeks without treatment

• Up to 33% recurrence rate, usually within the first year after diagnosis, with each subsequent episode being briefer and milder than prior episodes.

  • often triggered by preceding infection

• Chronic IgAV is unusual but can occur, especially in older children (teenagers)

Diagnosis

Laboratory evaluation:

• complete blood count (CBC) with differential: may have moderate leukocytosis, normocytic anemia may be due to GI blood loss, platelet count normal to mildly elevated

• coagulation studies: normal

• inflammatory markers: normal to mildly elevated; significantly elevated ESR should raise concern for alternative systemic vasculitides such as ANCA-associated vasculitis

• kidney function: creatinine (Cr) and blood urea nitrogen (BUN) may be elevated with kidney disease

• urinalysis (UA): monitor for proteinuria, hematuria, casts

• stool: may be hemoccult-positive

• immunologic tests: not routine; consider ANCA testing if significantly elevated ESR or other atypical/uncommon features (e.g., pulmonary, CNS, severe renal involvement); IgA is elevated in 50% of patients with IgAV, but testing is not indicated; antinuclear antibody (ANA) is not helpful

Imaging: abdominal x-ray, ultrasound, and CT may be helpful if concern for abdominal complications (e.g., obstruction, bleed, intussusception)

Skin biopsy: can help confirm diagnosis in non-classic presentations; light microscopy demonstrates leukocytoclastic vasculitis and IgA deposition on immunofluorescence

Renal biopsy: warranted if proteinuria/hematuria is significant or does not resolve; primarily mesangial IgA deposition; may show crescentic glomerulonephritis. Renal evaluation should be done in close conjunction with a nephrology specialist.

Treatment

• analgesia: standing nonsteroidal anti-inflammatory drugs (NSAIDs) are first line but should be avoided if gastrointestinal or renal involvement; acetaminophen

• routine blood pressure checks and urinalyses with primary care physician (PCP) to monitor for renal involvement

  • should be continued weekly until symptoms resolve and then monthly for 6 months after diagnosis

• glucocorticoids: helpful for significant abdominal or musculoskeletal manifestations or for severe kidney disease (to reduce proteinuria/hematuria); no benefit for prevention of kidney disease or mild kidney disease

  • mild/moderate disease: prednisone or IV methylprednisolone tapered over 3-4 weeks

  • severe disease: consider pulse IV methylprednisolone up to 3 days before transition to oral prednisone with taper

• immunosuppressive therapy: should be considered in patients with chronic nephritis, pulmonary, and/or CNS manifestations, or chronic IgAV: cyclosporine, cyclophosphamide, azathioprine, methotrexate, rituximab

ANCA-Associated Vasculitis

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of vasculitides characterized by small- to medium-sized blood-vessel inflammation, clinically overlapping features, and the presence of ANCA. The most common organs involved include the kidneys, lungs, GI tract, and sinuses. AAV is rare in children; therefore, most knowledge of clinical presentation and management comes from small case series and adult studies.

AAV includes the following diseases:

• microscopic polyangiitis (MPA)

• granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis)

• eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome): extremely rare in children and not covered in this guide (see Diagnosis and Management of ANCA-Associated Vasculitis for more information)

Overview of MPA and GPA

• necrotizing vasculitis with few or no immune deposits (pauci-immune)

• in pediatric AAV, age of onset is between 10 and 20 years

• pathophysiology is not entirely clear, but presence of ANCAs implicates neutrophils as key effector cells and success of B-cell depletion therapy with rituximab argues for a pathogenic role of antibodies

Clinic Features of AAV

General:

• fatigue, fever, weight loss

Pulmonary:

• alveolar hemorrhage leading to hemoptysis

• nodules, cavitation

Renal:

• abnormal urinalysis/creatinine

• pauci-immune glomerulonephritis on biopsy

Head, eyes, ears, nose, and throat (HEENT):

• upper airway involvement is distinguishing feature of GPA; MPA usually limited to lower respiratory tract

  • saddle-nose deformity, nasal septal perforation, dacryocystitis, erosive sinusitis

  • subglottic stenosis is a significant cause of morbidity

  • conjunctivitis, scleritis

Gastrointestinal:

• abdominal pain, nausea

• biopsy difficult to distinguish from inflammatory bowel disease

Musculoskeletal:

• arthritis, arthralgias, myalgias

Neurologic:

• mononeuritis multiplex

Diagnosis of AAV

Based on clinical features:

• pulmonary-kidney disease, sinus disease, GI involvement

• presence of serologic markers

• characteristic histopathologic findings

Laboratory evaluation:

• CBC with differential: leukocyte count may be elevated, anemia of chronic disease, thrombocytosis

• inflammatory markers: significantly elevated ESR and CRP; very unusual to have active AAV with normal inflammatory markers

• kidney function: elevated BUN/Cr in kidney disease

• UA: evaluate for proteinuria, microscopic hematuria, and red blood cell casts

• immunologic testing

  • ANCA positive in 95% of children with AAV; GPA is most commonly associated with cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) or antiproteinase 3 antibodies (PR3-ANCA, 73%), and MPA is most commonly associated with perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) or antimyeloperoxidase (MPO-ANCA, 75%)

Imaging:

• pulmonary screening: important because pulmonary involvement is often asymptomatic; confirmation of pulmonary involvement changes management and often requires escalation of therapy

  • chest x-ray: nodules and cavitations can often be seen in GPA, but are less common in MPA

  • high-resolution chest CT: detects small nodules and perivascular densities; ground-glass opacities more common in MPA than in GPA due to capillary involvement

  • sinus CT: thickening of sinus lining, sinus opacification, cavitation

  • MRI: helpful to visualize active mucosal disease and soft tissue changes involving nose, orbits, mastoids, and upper airways (i.e., subglottic stenosis)

Pathology:

• GPA is distinguished from MPA by granulomatous inflammation on biopsy (renal, pulmonary, sinus).

  • pulmonary

    • necrotizing vasculitis involving predominantly small arteries and veins in lungs

  • renal

    • focal and segmental pattern of extracapillary proliferation and crescent formation with progression to necrotizing glomerulonephritis

    • immunofluorescence demonstrates pauci-immune pattern with scant deposition of immunoglobulins and complement

    • electron microscopy with dense subendothelial deposits

Classification Criteria for GPA

Neither adult nor pediatric diagnostic criteria exist for MPA.

EULAR/PRINTO/PRES criteria for childhood GPA:

The presence of at least three of the following six criteria confirms the diagnosis of GPA with a sensitivity of 93.3% and a specificity of 99.2%.

• upper airway involvement: chronic purulent or bloody nasal discharge, or recurrent epistaxis/crusts/granulomata; nasal septal perforation or saddle-nose deformity; chronic or recurrent sinus inflammation

• pulmonary involvement: chest x-ray or CT scan showing the presence of nodules, cavities, or fixed infiltrates

• renal involvement: protein level >0.3 grams per day; hematuria or red blood cell casts; necrotizing pauci-immune glomerulonephritis

• granulomatous inflammation: within wall of artery or in perivascular or extravascular area of artery or arteriole

• laryngotracheobronchial stenosis: subglottic, tracheal, or bronchial stenosis

• ANCA: ANCA positivity by immunofluorescence or by enzyme-linked immunosorbent assay (ELISA; MPO/p or PR3/cANCA)

Treatment of AAV

In 2017, EULAR, together with the Euroepan Renal Association (ERA) and Euroepan Vasculitis Society (EUVAS) published a recommended treatment algorithm for AAV.

• Severe disease:

  • induction with cyclophosphamide or rituximab along with glucocorticoids

    • rituximab is now heavily favored in the pediatric population

  • consider plasma exchange for life-threatening disease (e.g., pulmonary hemorrhage, renal failure)

  • maintenance with azathioprine, methotrexate, or rituximab alongside a prolonged glucocorticoid taper

• Mild-to-moderate disease

  • induction with methotrexate or mycophenolate mofetil (MMF) along with glucocorticoids

  • maintenance with azathioprine or methotrexate alongside a prolonged glucocorticoid taper

Polyarteritis Nodosa (Systemic)

Polyarteritis nodosa (PAN) is a necrotizing vasculitis involving small- and medium-sized arteries. The organs most often involved include the skin, muscles, kidneys, and gastrointestinal tract. PAN is generally considered the third-most common systemic vasculitis in children (after IgAV and Kawasaki disease). A number of infectious triggers have been implicated in PAN, with streptococcal infection being most frequently cited. Genetic studies have shown an association between childhood PAN and mutations in the familial Mediterranean fever (MEFV) gene in Turkish children. Mutations in the gene encoding adenosine deaminase 2 (ADA2) result in a systemic, PAN-like vasculopathy characterized by intermittent fevers, early-onset lacunar strokes, livedoid rash, and hepatosplenomegaly.

Classification Criteria

EULAR/PRINTO/PRES classification criteria for childhood PAN:

• evidence of necrotizing vasculitis in medium or small arteries or an angiographic abnormality showing aneurysm, stenosis, or occlusion of a medium- or small-sized artery plus one of the following five criteria:

  • skin involvement (livedo reticularis, skin nodules, or infarcts)

  • myalgia or muscle tenderness

  • hypertension

  • peripheral neuropathy

  • renal involvement

Clinical Features

Constitutional symptoms:

• fever

• malaise

• weight loss

• pain (testicular or abdominal)

Skin lesions:

• can resemble IgAV lesions; can also be necrotic and associated with peripheral gangrene

• fixed, tender, subcutaneous nodules of upper and lower limbs (i.e., erythema nodosum)

  • note: PAN should always be on the differential for erythema nodosum)

• skin infarctions

Musculoskeletal involvement:

• arthralgias and myalgias common, especially calf pain with activity (claudication)

• arthritis less common, but when present is often more painful compared to other types of inflammatory arthritides (e.g., juvenile idiopathic arthritis, or JIA)

Renal involvement:

• hematuria, proteinuria, hypertension due to renal arterial necrotizing vasculitis, resulting in areas of infarction

Neurologic involvement:

• mononeuritis multiplex; strokes should raise suspicion for deficiency of adenosine deaminase type 2 (DADA2)

Diagnosis

Laboratory evaluation:

• CBC with differential: leukocytosis and thrombocytosis

• inflammatory markers: ESR and CRP should be elevated in active disease

• UA: to screen for kidney disease

• kidney function: elevated BUN/Cr may indicate kidney disease

Imaging:

• conventional angiography: the gold standard but invasive; multiple saccular aneurysms can appear as “beads on a string” or “rosary signs”

• magnetic resonance angiography (MRA) or CT angiography: noninvasive initial screening imaging exam, but will miss small aneurysms or microaneurysms; detects areas of renal ischemia/infarction

Biopsy:

• Classic histopathology is fibrinoid necrosis of the walls of medium or small arteries with marked inflammatory response within or surrounding the vessel wall.

• Depending on organs involved, tissue can be obtained from muscle, sural nerve, kidney, liver, testis, or gastrointestinal tract.

Treatment

Permanent remission is often achieved with treatment.

• Induction:

  • glucocorticoids: initial intravenous (IV) pulses for severe disease, followed by oral prednisone 1 to 2 mg/kg/day with a slow taper

  • IV cyclophosphamide (CYC): typically used for 3 months as induction therapy in severe disease

  • mycophenolate mofetil (MMF): In a 2021 randomized, controlled trial, children treated with MMF or CYC for induction had similar rates of remission (71% vs. 75%, respectively) but the MMF group reported better quality of life.

• Maintenance:

  • azathioprine: often used for maintenance

  • MMF

  • tumor necrosis factor (TNF) inhibitors: can be effective; patients with DADA2 (PAN-like systemic illness with prominent CNS involvement) have an excellent response to TNF inhibitors

  • penicillin prophylaxis: for streptococcal-induced PAN

Takayasu Arteritis

Takayasu arteritis (TA) is a rare, chronic, granulomatous vasculitis affecting large vessels, including the aorta and its main branches. The estimated incidence in adults is 0.50 per 100,000. Although TA can occur in very young children, it more often presents in adolescents in the pediatric population.

Classification Criteria

EULAR/PRINTO/PRES classification criteria for childhood TA:

In addition to angiographic abnormalities (on conventional angiography or CTA/MRA), patients should have at least one of the following five criteria:

• decreased peripheral artery pulse and/or claudication of extremities (“pulseless disease”)

• blood-pressure difference between limbs of >10 mm Hg

• bruits over aorta and/or its major branches

• systolic/diastolic hypertension

• ESR >20 or CRP above the upper normal limit

Clinical Manifestations

Determined by the patterns of blood vessel and stage of disease (acute, stenotic, fibrotic):

• systemic features: fever, weight loss, fatigue (up to 83% of patients)

• cardiac disease: myocardial infarction, valve disease, or cardiomyopathy

• abnormal four-extremity blood pressures

• hypertension: due to renal artery involvement (may be only manifestation in early stage of disease)

• claudication

• the midaortic syndrome: hypertension, abdominal bruits, abdominal pain

• bloody diarrhea and abdominal pain: due to mesenteric artery involvement

• CNS manifestations: due to involvement of supradiaphragmatic aortic arch; headaches, ischemic strokes, syncope

Diagnosis

Laboratory evaluation:

• inflammatory markers: usually elevated in active disease

• CBC with differential: anemia of chronic inflammation, often see leukocytosis and thrombocytosis

• autoantibodies: usually not present, not a helpful diagnostic tool

Pathology:

• intramural multinucleated giant cells in the walls of affected large-size arteries

Imaging:

• MRI/MRA: preferred imaging test in children; vessel wall thickness and edema with active inflammation; most common finding in children with TA is stenosis of aorta with both fusiform and saccular aneurysms

• positron emission tomography (PET): the role is still being studied but may help identify areas of active inflammation in vessel walls when concerned for disease recurrence vs. sequalae of past disease

Treatment

• Treatment should be managed by an interdisciplinary team including rheumatologists, nephrologists, and cardiologists, as needed.

• Treatment strategies are generally extrapolated from evidence in adults with TA.

• The most commonly used immunosuppressive agents are glucocorticoids (universal use), TNF inhibitors (infliximab, etanercept, adalimumab), tocilizumab, cyclophosphamide; use of rituximab is less common given lack of autoantibodies.

• Antihypertensives are often employed for patients with persistent hypertension.

• Depending on the degree and location of vessel involvement, surgical and endovascular procedures may be needed, especially in patients with refractory hypertension, abdominal angina, and/or claudication.