An inflammatory disorder of blood vessels
- Clinical features result from the destruction of blood vessel walls with subsequent thrombosis, ischemia, bleeding, and/or aneurysm formation.
- Vasculitis is a large, heterogeneous group of diseases classified by the predominant size, type, and location of involved blood vessels (1).
- Small-vessel vasculitis
- Microscopic polyangiitis (MPA)
- Granulomatosis with polyangiitis (GPA; formerly Wegener granulomatosis)
- Eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome)
- Antiglomerular basement membrane disease (anti-GBM)
- Cryoglobulinemic vasculitis
- IgA vasculitis (formerly Henoch-Schönlein purpura)
- Hypocomplementemic urticarial vasculitis
- Medium-vessel vasculitis
- Polyarteritis nodosa (PAN)
- Kawasaki disease (KD)
- Large-vessel vasculitis
- Takayasu arteritis (TAK)
- Giant cell arteritis (GCA)
- Small-vessel vasculitis
- Vasculitis occurs as a primary disorder or secondary to infection, a drug reaction, malignancy, or connective tissue disease.
- Variable vessel vasculitis
- Behçet disease
- Cogan syndrome
- Single-organ vasculitis
- Cutaneous leukocytoclastic angiitis
- Cutaneous arteritis
- Primary CNS vasculitis
- Vasculitis associated with systemic disease
- Lupus vasculitis
- Rheumatoid vasculitis
- Sarcoid vasculitis
- Vasculitis associated with other etiology
- Hepatitis C–associated cryoglobulinemic vasculitis
- Hepatitis B–associated vasculitis
- Syphilis-associated aortitis
- Drug-induced immune complex vasculitis
- Drug-associated antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis
- Cancer-associated vasculitis
- Variable vessel vasculitis
- Protean features often delay definitive diagnosis.
Highly variable, depending on the particular syndrome
- Hypersensitivity vasculitis is most commonly encountered in clinical practice.
- KD, IgA vasculitis, and dermatomyositis are more common in children.
- TAK is most prevalent in young Asian women. GPA, MPA, and EGPA are more common in middle-aged males.
- GCA occurs exclusively in those >50 years of age and is rare in the African American population.
Annual incidence in adults (unless otherwise specified)
- IgA vasculitis: 200 to 700/1 million in children <17 years of age
- GCA: 100 to 170/1 million in Caucasians age >50 years
- KD: depends on race/age; ~200/1 million
- PAN: 2 to 33/1 million
- GPA: 4 to 15/1 million
- MPA: 1 to 24/1 million
- EGPA: 1 to 3/1 million
- TAK: 2/1 million
- Primary CNS vasculitis: 2/1 million in adults
- Hypersensitivity vasculitis: depends on drug exposure
- Viral-/retroviral-associated vasculitis: unknown; >90% of cases of cryoglobulinemic vasculitis are associated with hepatitis C.
- Connective tissue disorder–associated vasculitis: variable
Etiology and Pathophysiology
- Three major immunopathogenic mechanisms
- Immune-complex formation: systemic lupus erythematosus (SLE), IgA vasculitis (HSP), and cryoglobulinemic vasculitis
- ANCAs: GPA, MPA, and EGPA
- Pathogenic T-lymphocyte response: GCA and TAK
- Pathophysiology best understood where known drug triggers have been identified (e.g., antibiotics, sulfonamides, and hydralazine)
- Several vasculitides linked to candidate genes
- No single gene has been found to cause vasculitis.
- Angiotensin-converting enzyme insertion/deletion polymorphism is associated with susceptibility to vasculitis, especially in Behçet disease and IgA vasculitis.
A combination of genetic susceptibility and environmental exposure likely triggers onset.
Early identification is the key to prevent irreversible organ damage in severe forms of systemic vasculitis.
Commonly Associated Conditions
Hepatitis C (cryoglobulinemic vasculitis), hepatitis B (PAN), cytomegalovirus (CMV), Epstein-Barr virus (EBV), HIV (viral-/retroviral-associated vasculitis), SLE, rheumatoid arthritis (RA), Sjögren syndrome, mixed connective tissue disease (MCTD), dermatomyositis, ankylosing spondylitis, Behçet disease, relapsing polychondritis (CTD-associated vasculitis), respiratory tract methicillin-resistant Staphylococcus aureus (MRSA) in GPA, levamisole-adulterated cocaine, medications: propylthiouracil, methimazole, hydralazine, minocycline, levamisole-tainted cocaine
- Consider age, gender, and ethnicity.
- Comprehensive medication history
- Family history of vasculitis
- Constitutional symptoms: fever, weight loss, malaise, fatigue, diminished appetite, sweats
- CNS/PNS: mononeuritis multiplex, polyneuropathy, headaches, visual loss, tinnitus, stroke, seizure, encephalopathy
- Heart/lung: myocardial infarction, cardiomyopathy, pericarditis, cough, chest pain, hemoptysis, dyspnea
- Renal: hematuria
- GI: abdominal pain, hematochezia, perforation
- Musculoskeletal: arthralgia, myalgia
- Miscellaneous: unexplained ischemic or hemorrhagic events, chronic sinusitis, and recurrent epistaxis
- Note the organs affected and estimate the size of blood vessels involved.
- Demographics, clinical features, and the predominant vessel size/organ involvement help identify specific type of vasculitis.
- Vital signs: blood pressure (hypertension) and pulse (regularity and rate)
- Skin: palpable purpura, livedo reticularis, nodules, ulcers, gangrene, nail bed capillary changes
- Neurologic: cranial nerve exam, sensorimotor exam
- Ocular exam: visual fields, scleritis, episcleritis
- Cardiopulmonary exam: rubs, murmurs, arrhythmias
- Abdominal exam: tenderness, organomegaly
- Fibromuscular dysplasia
- Embolic disease (atheroma, cholesterol emboli, atrial myxoma, mycotic aneurysm with embolization)
- Drug-induced vasospasm (cocaine, amphetamines, ergots)
- Thrombotic thrombocytopenic disorders (disseminated intravascular coagulation [DIC], thrombotic thrombocytopenic purpura [TTP], antiphospholipid syndrome, heparin- or warfarin-induced thrombosis), thromboangiitis obliterans
- Systemic infection (infective endocarditis, fungal infections, disseminated gonococcal infection, Lyme disease, syphilis, Rocky Mountain spotted fever [RMSF], bacteremia, ehrlichiosis, babesiosis)
- Malignancy (lymphomatoid granulomatosis, angioimmunoblastic T-cell lymphoma, intravascular lymphoma)
- Miscellaneous (Goodpasture syndrome, sarcoidosis, amyloidosis, Whipple disease, congenital coarctation of aorta)
Diagnostic Tests & Interpretation
Renal involvement is often clinically silent. Routine serum creatinine and urinalysis with microscopy are needed to identify underlying glomerulonephritis.
- Initial tests exclude alternate diagnoses and guide therapy.
- Routine tests
- Liver enzymes
- Serum creatinine
- Urinalysis with microscopy
- Specific serology
- Antinuclear antibodies (ANA)
- Rheumatoid factor (RF)
- Rapid plasma reagin/venereal disease reaction level (RPR/VDRL)
- RMSF titers; Lyme titers
- Complement levels C3, C4
- Antiproteinase 3 (anti-PR3) antibodies
- Antimyeloperoxidase (anti-MPO) antibodies
- Hepatitis screen for B and C
- Anti-GBM titer
- Serum and urine protein electrophoresis
- Drug screen
- C-reactive protein
- Creatine kinase (CK)
- Blood culture
- CXR, CT scan, MRI, and arteriography may be required to delineate extent of organs involved.
- Electromyography with nerve conduction can document neuropathy and target nerve for biopsy.
- Biopsy of affected site confirms diagnosis (e.g., temporal artery, sural nerve, renal biopsy).
- If biopsy is not practical, angiography may be diagnostic for large- and medium-vessel vasculitides.
- Bronchoscopy may be required to differentiate pulmonary infection from potentially life-threatening hemorrhagic vasculitis in patients with hemoptysis.
Blood vessel biopsy shows immune cell infiltration into vessel wall layers with varying degrees of necrosis and granuloma formation, depending on the type.
- Discontinue offending drug (hypersensitivity vasculitis).
- Simple observation for mild cases of IgA vasculitis
- ANCA-associated vasculitis has two-phase treatment: initial induction followed by maintenance (steady tapering of corticosteroids with immunosuppressants or immunomodulators).
Corticosteroids are initial anti-inflammatory of choice.
Cytotoxic medications, immunomodulatory, or biologic agents (e.g., cyclophosphamide (2)[B],(3)[A], methotrexate (4)[A], azathioprine (4)[A], leflunomide (4)[A], mycophenolate mofetil (2)[B], and rituximab (3)[A]) are often required in combination with corticosteroids for rapidly progressive vasculitis with significant organ involvement or inadequate response to corticosteroids. Rituximab (3)[A] is the first FDA-approved treatment for GPA and MPA. Tocilizumab (5)[A] is the first FDA-approved treatment for GCA. Mepolizumab (6)[A] is the first FDA-approved treatment for EGPA.
Issues For Referral
- Rheumatology referral for complicated cases where newer or more toxic treatments are required
- Nephrology referral for persistent hematuria or proteinuria, rising creatinine, or a positive ANCA titer
- Pulmonary referral for persistent pulmonary infiltrate unresponsive to antibiotic therapy or if gross hemoptysis
Rarely, corrective surgery is required to repair tissue damage as a result of aggressive vasculitis.
- Hemoptysis, acute renal failure, intestinal ischemia, any organ-threatening symptoms or signs, and/or need for biopsy
- Initial therapy is guided by the organ system involved.
- If pulmonary hemorrhage is present, life-saving measures may include mechanical ventilation, plasmapheresis, and immunosuppression.
- If acute renal failure is present, attend to electrolyte and fluid balance and consider plasma exchange and immunosuppression.
- If signs of intestinal ischemia are present, make NPO and consider plasmapheresis, immunosuppression, and parenteral nutrition.
- Discharge criteria: stabilization or resolution of potential life-threatening symptoms
If significant coronary artery disease is involved in KD, moderate activity restriction may be of benefit.
Frequent clinical follow-up supported by patient self-monitoring to identify disease relapse
Alter diets for patients with renal involvement or hyperglycemia/dyslipidemia.
Prognosis is good for patients with vasculitis and limited organ involvement. Relapsing courses, renal, intestinal, or extensive lung involvement have a poorer prognosis.
- Persistent organ dysfunction may be the result of the disease, medications, or inflammation/scarring in the more serious forms of vasculitis.
- Early morbidity/mortality is due to active vasculitic disease; delayed morbidity/mortality may also be secondary to complications of chronic therapy with cytotoxic medications.
- Gatto M, Iaccarino L, Canova M, et al. Pregnancy and vasculitis: a systematic review of the literature. Autoimmun Rev. 2012;11(6–7):A447–A459. [PMID:22155197]
- Lee YH, Choi SJ, Ji JD, et al. Associations between the angiotensin-converting enzyme insertion/deletion polymorphism and susceptibility to vasculitis: a meta-analysis. J Renin Angiotensin Aldosterone Syst. 2012;13(1):196–201. [PMID:22277255]
- National Heart, Lung, and Blood Institute. What is vasculitis? http://www.nhlbi.nih.gov/health/health-topics/topics/vas/. Accessed October 24, 2018.
- Vasculitis Foundation: https://www.vasculitisfoundation.org
- D69.0 Allergic purpura
- D89.1 Cryoglobulinemia
- I77.6 Arteritis, unspecified
- M30.0 Polyarteritis nodosa
- M30.1 Polyarteritis with lung involvement [Churg-Strauss]
- M30.3 Mucocutaneous lymph node syndrome [Kawasaki]
- M31.0 Hypersensitivity angiitis
- M31.30 Wegener’s granulomatosis without renal involvement
- M31.31 Wegener’s granulomatosis with renal involvement
- M31.4 Aortic arch syndrome [Takayasu]
- M31.5 Giant cell arteritis with polymyalgia rheumatica
- M31.6 Other giant cell arteritis
- 273.2 Other paraproteinemias
- 287.0 Allergic purpura
- 446.0 Polyarteritis nodosa
- 446.1 Acute febrile mucocutaneous lymph node syndrome [MCLS]
- 446.20 Hypersensitivity angiitis, unspecified
- 446.4 Wegener’s granulomatosis
- 446.5 Giant cell arteritis
- 446.7 Takayasu’s disease
- 447.6 Arteritis, unspecified
- 155441006 Polyarteritis nodosa (disorder)
- 190815001 Cryoglobulinemic vasculitis
- 191306005 Henoch-Schonlein purpura (disorder)
- 195353004 Wegener’s granulomatosis (disorder)
- 31996006 Vasculitis (disorder)
- 359789008 Takayasu’s disease (disorder)
- 414341000 giant cell arteritis (disorder)
- 60555002 Hypersensitivity angiitis (disorder)
- 75053002 Acute febrile mucocutaneous lymph node syndrome (disorder)
- 82275008 Allergic granulomatosis angiitis (disorder)
- Suspect vasculitis in patients with a petechial rash, palpable purpura, glomerulonephritis, pulmonary-renal syndrome, intestinal ischemia, or mononeuritis multiplex.
- Exclude silent renal involvement by routinely obtaining serum creatinine and urinalysis with microscopy.
- Vasculitis has “skip” lesions, which may complicate diagnostic biopsy.
- In patients with vasculitis, look for an underlying inciting process such as medication, infection, thrombosis, or malignancy.
Irene J. Tan, MD, FACR
- Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum. 2013;65(1):1–11. [PMID:23045170]
- Appel GB, Contreras G, Dooley MA, et al; for Aspreva Lupus Management Study Group. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009;20(5):1103–1112. [PMID:19369404]
- Stone JH, Merkel PA, Spiera R, et al; for RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221–232. [PMID:20647199]
- Walters GD, Willis NS, Craig JC. Interventions for renal vasculitis in adults. A systematic review. BMC Nephrol. 2010;11:12. [PMID:20573267]
- Villiger PM, Adler S, Kuchen S, et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387(10031):1921–1927. [PMID:26952547]
- Wechsler ME, Akuthota P, Jayne D, et al; for EGPA Mepolizumab Study Team. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017;376(20):1921–1932. [PMID:28514601]
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