ANCA-associated Vasculitis

Granulomatosis with Polyangiitis (GPA)

Hannah Angle

Background

  • Necrotizing vasculitis of small vessels characterized by granulomatous inflammation

Presentation

  • Constitutional symptoms: fevers, fatigue, weight loss
  • Vasculitis: pulmonary hemorrhage, mononeuritis multiplex, glomerulonephritis (hematuria, proteinuria)
  • Granulomatous inflammation: sinus and/or middle ear involvement, rhinorrhea, epistaxis, pulmonary nodule, cavitary pulmonary lesions (dyspnea, cough, hemoptysis)

Evaluation

  • ANCA + (typically PR3-cANCA)
  • ESR/CRP, ANA, anti-GBM, C3/C4, cryoglobulins, HBV/HCV, HIV
  • UA with microscopy (hematuria, proteinuria, RBC casts, dysmorphic RBCs)
  • CT chest if pulmonary symptoms
  • Biopsy: necrotizing granulomatous vasculitis, pauci-immune glomerulonephritis
  • Clinical Pearl: If you suspect renal disease (elevated Cr, hematuria), ask the renal or rheum fellow to help spin the urine to evaluate for RBC casting or dysmorphic cells. Quick way to confirm active GN, since renal biopsy takes time to arrange.

Management

  • Mild-moderate disease: MTX + prednisone 0.5 mg/kg/day followed by steroid taper
  • Severe disease: rituximab (first line) + prednisone 1mg/kg/day (60-80mg max)
  • If failed response to rituximab, cyclophosphamide can be used.
  • For pts with RPGN, pulmonary hemorrhage, mononeuritis multiplex or optic neuritis: IV methylprednisone 7-15mg/kg/d (1000mg max) x3d for induction therapy
  • DVT ppx (high risk for DVT/PE)

Microscopic Polyangiitis (MPA)

Hannah Angle

Presentation

  • Similar to GPA, but without granulomatous involvement (no upper respiratory tract involvement or pulmonary nodules); classically only involves lungs and kidneys

Evaluation

  • ANCA + (typically MPO-pANCA)
  • ESR/CRP, ANA, anti-GBM, C3/C4, cryoglobulins, HBV/HCV, HIV
  • UA with microscopy (hematuria, proteinuria, RBC casts, dysmorphic RBCs)
  • CT chest if pulmonary symptoms
  • Biopsy: necrotizing vasculitis (no granulomas), pauci-immune glomerulonephritis

Management

  • Same as GPA, see above

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Hannah Angle

Presentation

  • Similar to GPA/MPA. Predominant symptoms include atopic symptoms (asthma, rhinosinusitis) and peripheral eosinophilia.
  • Vasculitis manifestations are more rare, and when they occur, mononeuritis multiplex is the most common, unlike pulmonary hemorrhage or renal involvement in GPA/MPA.
  • Cardiac involvement (accounts for 50% deaths from EGPA): coronary arteritis, myocarditis, heart failure, arrhythmias
  • Skin involvement (>50%): tender subcutaneous nodules

Evaluation

  • ANCA + (typically MPO-pANCA, positive in about 50-60% of pts)
  • Peripheral eosinophilia
  • IgE, ANA, RF, C3/C4
  • Biopsy: necrotizing granulomatous vasculitis, eosinophilic infiltrates with fibrinoid necrosis, pauci-immune glomerulonephritis

Management

  • Mild-moderate disease: prednisone 0.5-1 mg/kg/day for 6-12 weeks followed by steroid taper
  • Severe: cyclophosphamide + prednisone 0.5-1 mg/kg/day for 6-12 weeks followed by steroid taper
  • For pts with life-threatening multiorgan involvement (cardiac, pulmonary, renal, neurologic): IV methylprednisone 1000mg daily x 3 days for induction therapy
  • ACR guidelines now also recommendd mepolizumab for non-severe disease (instead of rituximab or cyclophosphamide) plus steroids as initial induction therapy. Severe disease still requires rituximab or cyclophosphamide)
  • DVT ppx (high risk for DVT/PE)

Cryoglobulinemic Vasculitis

Meridith Balbach

Background

  • Cryoglobulins = Circulating immunoglobulins precipitate in the cold
  • Classification of cryoglobulins:
    • Type I: monoclonal immunoglobulin (IgM or IgG); associated with lymphoproliferative disorders (Waldenström’s, MM, CLL, B cell lymphomas)
    • Type II: mixed (monoclonal IgM with +RF* polyclonal IgG); associated with chronic infection (particularly chronic Hepatits C)
    • Type III: polyclonal IgM + IgG with +RF; associated with autoimmune disease *RF activity by definition is the reactivity of an IgM component with the Fc portion of an IgG
  • Deposition of cryoprecipitate may result in small vessel vasculitis

Presentation

  • Systemic features (fatigue, arthralgia, myalgia) + organ-specific
    • Skin (most common): palpable purpura (usually in lower extremities/ colder areas), livedo reticularis
    • Renal: proteinuria, hematuria, HTN (MPGN)
    • Neurologic: peripheral neuropathy (mononeuritis multiplex)

Evaluation

  • General: Serum cryoglobulins (fastidious collection, see above), C3/C4 (hypocomplementemia), RF (positive in types II/III), ANA w/ reflex (evaluate for underlying autoimmune etiology), hepatitis B and C serologies, SPEP with immunofixation
  • End-organ specific: urinalysis +/- renal biopsy (if findings c/f MPGN), skin biopsy (leukocytoclastic vasculitis)

Management

  • Treat underlying etiology, if possible
  • For moderate-severe disease or end-organ disease, consider corticosteroids, rituximab, cyclophosphamide

Polyarteritis Nodosa (PAN)

Hannah Angle

Background

  • Necrotizing vasculitis of medium-sized muscular arteries, leading to segmental transmural inflammation with fibrinoid necrosis, aneurysm formation, thrombosis, and downstream ischemia
  • Incidence: onset usually in middle age/older adults (peaks in the 5th decade)
  • Often idiopathic but frequently associated with Hepatitis B (historically up to 30% of cases), Hepatitis C, hairy cell leukemia, monogenic forms

Presentation

  • Systemic + vessel-specific symptoms
  • Constitutional symptoms: fatigue, weakness, fevers, arthralgias, myalgias, rash, weight loss
  • Vasa nervorum: Asymmetric polyneuropathy with motor and sensory deficits (foot drop, radial/ulnar neuropathy)
  • Cutaneous: livedo reticularis, palpable purpura, ulcers, tender erythematous nodules, bullae, vesicles
  • Renal: HTN
  • Mesenteric: abdominal pain and melena
  • Coronary: ischemic cardiomyopathy
  • Testicular: orchitis

Evaluation

  • Elevated ESR/CRP, CBC (normocytic anemia and leukocytosis), Hepatitis B panel, Hep C with reflex, negative ANCA
  • Arteriography: MRI, CT, or angiogram with classic “string of pearls” appearance
  • Biopsy: segmental transmural inflammation of muscular arteries, fibrinoid necrosis of arterial wall (no granulomas, presence suggests another process)

Management

  • Mild disease (e.g. isolated cutaneous disease): prednisone 1mg/kg daily (max 60-80mg) for 4 weeks followed by steroid taper
  • Moderate disease: cyclophosphamide + prednisone 1mg/kg daily (max 60-80mg) for 4 weeks followed by steroid taper
  • Severe/life-threatening disease (renal failure, significant proteinuria, GI/cardiac/neurologic involvement): cyclophosphamide + 500-1000mg IV methylprednisolone daily for 3 days, followed by prednisone 1mg/kg daily (max 60mg) for 4 weeks followed by steroid taper

Giant Cell Arteritis (GCA)

Lauren Waskowicz

Background

  • Most common large-vessel vasculitis characterized by granulomatous inflammation of medium and large arteries, particularly the cranial branches of the carotid artery
  • Incidence: most commonly >50 years old, slight F > M predominance
  • Closely linked to PMR (up to 50% of patients with GCA have PMR, and ~15–30% of PMR patients develop GCA)
  • T-cell dysregulation, IL-6-mediated inflammation, and macrophage-driven vascular remodeling cause intimal hyperplasia and vessel occlusion

Presentation

  • Systemic + vessel-specific symptoms
  • Systemic: Fatigue, low-grade fever, malaise, weight loss
  • Extracranial arteries: temporal unilateral headache, scalp tenderness, jaw claudication, visual disturbance (blurred vision, amaurosis fugax, or sudden irreversible loss), diplopia
  • Large-vessel arteries: arm claudication, bruits, aortic aneurysm or dissection. 15-20% of patients will have large vessel involvement without extracranial arterial involvement.

Evaluation

  • ESR/CRP (almost always elevated), CK, TSH
  • Evaluate for any temporal artery abnormalities (tenderness to palpation, presence of nodules)
  • Ophthalmology evaluation if any concern for ocular involvement
  • Temporal artery biopsy by vascular surgery (typical in the US) OR temporal artery ultrasound (evaluate for presence of Halo sign)
  • If high suspicion for GCA with negative biopsy or ultrasound, perform further imaging to evaluate for large vessel involvement (CT/CTA or MRI/MRA of aorta and/or branches)

Management

  • 1st line treatment: glucocorticoids ± steroid-sparing agent
    • Start glucocorticoids as soon as GCA is suspected, do not delay while awaiting biopsy; early treatment can prevent irreversible vision loss!
    • No vision symptoms: prednisone 1mg/kg daily (max 60 mg) for 2-4 weeks followed by taper over months
    • Vision symptoms: IV methylprednisolone 500–1000 mg/day × 3 days → then prednisone 1 mg/kg/day (max 60 mg) with taper
  • Consider tocilizumab as adjunctive in those with steroid-refractory disease or those at higher risk for glucocorticoid-related side effects (since most pts with GCA are elderly, this applies to most pts)
  • Bisphosphonates will be commonly indicated for prevention of glucocorticoid-induced osteoporosis. A bone density test should be obtained at baseline to assess if other anabolic therapies should be used in higher risk pts.

Takayasu's Arteritis

Hannah Angle

Background

  • Chronic large-vessel vasculitis that primarily affects the aorta and its major branches, often leading to vascular stenosis, occlusion, or aneurysm formation
  • Incidence: onset usually <30 years old; 80-90% cases in females; strong predilection for individuals of Asian, Middle Eastern, and Latin American descent
  • Etiology: T-cell and pro-inflammatory cytokines drive granulomatous inflammation of vessel wall

Presentation

  • Biphasic course initial systemic inflammatory phase followed by vascular occlusive phase
  • Subacute constitutional symptoms: fevers, arthralgias, myalgias, rash, weight loss
  • Cardiovascular: angina from coronary arteritis, HTN (renal a. involvement), discrepant BP between arms (arterial stenosis), diminished or absent pulses (“pulseless disease”), carotidynia (tenderness of the carotid a.), arterial bruits, limb claudication, carotid/vertebral arteritis (vertigo, headache, syncope, strokes), mesenteric ischemia

Evaluation

  • ESR/CRP: often elevated, though can be normal during active disease
  • Arteriography: MRA or CTA of head/neck, chest, and abdomen/pelvis

Management

  • New arterial stenosis or aorta/carotid artery involvement: 1mg/kg prednisone daily (max 60- 80mg) for 2-4 weeks followed by steroid taper
  • Organ threatening disease (coronary artery involvement, critical stenosis of carotid/vertebral arteries): 500-1000mg IV methylprednisolone daily for 1-3 days, then 1mg/kg prednisone daily for 2-4 weeks followed by steroid taper

Behcet’s disease

Meridith Balbach

Background

  • Chronic relapsing variable vessel (i.e. affects small, medium, large) vasculitis preferentially affecting veins with consequent wide-ranging mucocutaneous, ocular, neurologic, vascular, GI, and joint manifestations.
  • Incidence: usually onset age 20-40y (rare >40y); equally affects men and women (but men more likely to have severe disease); coined the “Silk Road disease” due to increased frequency in the Middle East and Central Asia
  • Etiology: genetic predisposition (strongest risk conferred by HLA-B*51 allele) + environmental factors results in (via unclear mechanisms) prominent neutrophil activation and MHC class I regulation defect and = dysregulated innate (auto-inflammatory) and adaptive (autoimmune) immunity
  • Differential diagnosis (consider very broad DDx given many nonspecific features): Sweet syndrome, IBD, HSV, reactive arthritis, erythema multiforme, bullous disease

Presentation

  • Initial relapsing-remitting course with symptoms dependent on vessels involved
    • Mucosa: painful, shallow oral ulcers (seen in >90%); scarring painful genital ulcers
    • Skin: erythema nodosum-like nodules, papulopustular lesions, acne, pyoderma gangrenosum, pathergy reaction
    • Ocular: uveitis (anterior, posterior, or pan-uveitis) and retinal vasculitis
    • Arthritis: non-erosive, oligoarticular; often migratory
    • Vascular: pulmonary artery aneurysm, DVT/PE, dural venous thrombosis, Budd-Chiari syndrome, retinal vasculitis
    • CNS: brainstem or hemispheric lesions, aseptic meningitis, meningoencephalitis
    • Gastrointestinal: ileocecal ulceration, abdominal pain, bleeding
  • Subsequent undulating course: most patients manifest symptoms within 5 years of diagnosis, then improve slowly over time

Evaluation

  • Diagnosis is clinical; no diagnostic criteria
  • 2014 IBCD International Criteria for Behçet’s Disease (classification criteria) can help guide (score ≥4 supports diagnosis): recurrent oral ulcers (2), genital ulcers (2), ocular lesions (2), skin lesions (1), vascular lesions (1), positive pathergy test (1)

Management

  • Highly individualized based on specific organ involvement and severity
    • Mucocutaneous and/or arthritis: colchicine +/- topical steroids (1st line), apremilast, azathioprine, biologics (adalimumab, etanercept, etc.)
    • Thrombotic: anticoagulation is controversial. Very important to exclude pulmonary artery aneurysms prior to initiating anticoagulation due to risk of bleeding.
    • Moderate/severe disease (uveitis, major organ involvement, vascular, CNS): systemic steroids, azathioprine, cyclosporine; if refractory, consider biologics (TNFi and IL-1/Il-6 inhibitors) or cyclophosphamide

Polymyalgia Rheumatica (PMR)

Tina Arkee

Background

  • PMR is a disorder of inflammatory pain and stiffness predominantly affecting shoulders and pelvic girdle (hips, sacrum, and coccyx)
  • Incidence: typically >50 years, peak ages 70-80; more common in women (2:1)
  • PMR is often seen in patients with GCA; occurs in up to 50% of GCA, while 15-30% of PMR patients develop GCA. Either condition may present initially, or may occur concomitantly
  • Etiology: poorly understood but likely genetic predisposition (HLA DR4 allele, Caucasian background) and environmental factors (including infections) contribute to IL-6-mediated inflammatory response

Presentation

  • Acute or subacute onset of:
    • bilateral, symmetric pain and stiffness of shoulders (in almost all cases), neck, and/or pelvic girdle that is worse in the morning and with inactivity
    • +/- Difficulty with ADLs such as brushing their hair or teeth, lifting their arms to put clothing on, and rising from a seated position
    • +/- Non-specific constitutional symptoms (fatigue, low-grade fever, weight loss)
  • Physical exam: normal muscle strength. Objective muscle weakness should raise suspicion for another disease process.
  • Screen for GCA red flag symptoms; headache, jaw claudication, visual changes, scalp tenderness)

Evaluation

  • Diagnosis: clinical diagnosis; can use ACR/EULAR 2012 classification criteria for patients ≥50 with new shoulder pain and elevated ESR/CRP (≥4 if not using ultrasound; ≥5 if using ultrasound): morning stiffness lasting >45 min (2 points), hip pain or limited range of motion (1 point), negative RF and CCP titers (2 points), presence of pain in other joints (1 point), shoulder/hip ultrasound findings of inflammation (1 point)
  • Labs: elevated ESR and CRP (almost always); consider TSH, CK, RF, anti-CCP to rule out mimics
  • Imaging: MSK ultrasound may demonstrate bursitis, tenosynovitis, or non-PMR etiologies; similarly, MRI may confirm inflammation or demonstrate structural pathology

Management

  • 1st line: steroids, initially 12.5-25mg prednisone daily à assess response with expected improvement within 2-4 weeks. Lack of improvement strongly suggests an alternative diagnosis unless the patient has GCA.
  • Taper: decrease slowly to the minimum effective dose (often 5mg/day for up to 1-2 years). CRP/ESR can help provide additional insight into disease remission/ guide taper
  • Refractory disease or high risk of steroid side effect: consider steroid-sparing agent (MTX, tocilizumab, sarilumab)

Adult-Onset Still’s Disease (AOSD)

Meridith Balbach

Background

  • Rare autoinflammatory syndrome characterized by systemic inflammation, spiking fevers, arthralgia/arthritis, and a salmon-colored rash
  • Autoinflammatory diseases involve dysregulation of innate immune system (rather than dysregulation of the adaptive immune system, as in autoimmune disease)
    • Includes both inherited (e.g. monogenic syndromes like Familial Mediterranean Fever (FMF), cryopyrin-associated periodic syndromes (CAPS), and TNF receptor–associated periodic syndrome (TRAPS)) and acquired syndromes (e.g. AOSD and VEXAS)
  • Incidence: generally sporadic (no clear genetic predisposition) at 16-35y but can occur at any age. Slight female predominance (51-60%). Rare (~0.16–0.4 cases per 100,000 persons annually)
    • AOSD is the adult counterpart to systemic juvenile idiopathic arthritis

Presentation

  • Classic triad: quotidian fevers (often late afternoon/evening), arthralgias/arthritis (often polyarticular and migratory), evanescent salmon-colored rash (maculopapular, often nonpruritic) RHEUMATOLOGY 602
  • Additional features: sore throat, lymphadenopathy, hepatosplenomegaly, serositis, elevated LFTs, hyperferritinemia

Evaluation

  • Diagnosis of exclusion: must rule out infection, malignancy, other inflammatory etiologies
  • Serologic workup: elevated ESR/CRP, very high ferritin, CBC (mild leukocytosis, thrombocytosis, anemia), elevated LFTs, ANA and RF (should be negative),
  • Imaging workup: consider to identify serositis or lymphadenopathy (nonspecific)
  • 2023 ACR/EULAR classification criteria may help with diagnosis (requires ≥5 points total, including ≥2 clinical criteria; sensitivity: ~85% and specificity: ~99%)
  • Clinical criteria: fever ≥39°C for ≥3 days (2), arthralgia or arthritis (2), evanescent rash (2), pharyngitis (1), lymphadenopathy and/or hepatosplenomegaly (1), serositis (pleuritis or pericarditis) (1)
  • Laboratory criteria: neutrophils ≥80% (1), ferritin >1000 ng/mL (1), negative ANA and RF (1)

Management

  • Treatment is based on severity:
    • Mild/moderate: NSAIDs and/or steroids
    • Moderate/severe or steroid-refractory: steroids (prednisone 0.5–1 mg/kg/day) + MTX
    • Severe systemic or refractory: steroids + IL-1 or IL-6 inhibitor
  • Monitor for progression to secondary macrophage activation syndrome (progressive cytopenias, hyperferritinemia, coagulopathy, liver dysfunction, multiorgan failure)
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