What is primary systemic vasculitis, including its history, physical exam, etiology, diagnosis approach, differential diagnosis, management, complications, and prognosis?

Primary Systemic Vasculitis: A Comprehensive Overview

Primary systemic vasculitis (PSV) is characterized by inflammation of blood vessel walls without identifiable cause, classified by vessel size (large, medium, small), with treatment tailored to specific type and severity to reduce morbidity and mortality. 1

Classification and Types

• PSV is classified according to vessel size as per the 2012 Chapel Hill Consensus Conference nomenclature: large vessel (aorta and major branches), medium vessel (main visceral arteries), and small vessel (intraparenchymal vessels) 1
• Small vessel vasculitis is further divided into two major categories: ANCA-associated vasculitis (AAV) and immune complex vasculitis 2
• AAV includes three main subtypes: Granulomatosis with polyangiitis (GPA, formerly Wegener's), Microscopic polyangiitis (MPA), and Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss) 2
• Immune complex small vessel vasculitis includes conditions such as cryoglobulinemic vasculitis and IgA vasculitis (Henoch-Schönlein purpura) 1

Pathophysiology

• About 90% of patients with small-vessel vasculitis affecting the kidneys have ANCA, directed primarily against myeloperoxidase (MPO) or proteinase 3 (PR3) neutrophil proteins 3
• In EGPA, immunofluorescent patterns with ELISA detecting antibodies to myeloperoxidase (MPO) is the most common finding, with p-ANCA positivity varying between 26-48%, increasing to 75% with renal involvement 4
• ANCA-positive patients are more likely to have peripheral neuropathy, glomerulonephritis and purpura (due to small vessel vasculitis) compared to those with myocardial, respiratory and gastrointestinal involvement who are more often ANCA negative 4

Clinical Manifestations

General Features

• Clinical presentation varies widely depending on the vessels involved and organs affected 2
• Constitutional symptoms include fever, weight loss, fatigue, and myalgia 1

Organ-Specific Manifestations

• Kidney involvement manifests as glomerulonephritis with hematuria, proteinuria, and declining renal function 3
• Pulmonary-renal syndrome, characterized by simultaneous lung and kidney injury, is a serious manifestation of small vessel vasculitis 2
• In EGPA, asthma and marked blood eosinophilia are distinguishing features 4
• ENT involvement is common in GPA with sinusitis, otitis media, hearing loss, and nasal crusting 1

Diagnosis Approach

Laboratory Evaluation

• Laboratory evaluation should include ANCA testing, complement levels, renal function tests, and urinalysis 2
• High-quality antigen-specific immunoassays are the preferred screening method for MPO- and PR3-ANCA 3
• Other tests include complete blood count, inflammatory markers (ESR, CRP), and specific tests based on clinical presentation 1

Imaging

• Sinus CT in EGPA shows pan-opacification similar to diffuse polypoid rhinosinusitis, with mean Lund-Mackay scores of 9-17 reported in large cohorts 4
• Chest imaging may reveal pulmonary infiltrates, nodules, or cavities depending on the type of vasculitis 1

Histopathology

• Histopathologic examination typically shows leukocytoclastic vasculitis with fibrinoid necrosis of vessel walls 2
• Kidney biopsy remains the gold standard for diagnosis with a diagnostic yield as high as 91.5% in GPA 3
• The presence or absence of immune deposits can distinguish between immune complex and pauci-immune vasculitis 2

Differential Diagnosis

• The differential diagnosis for EGPA includes other eosinophilic pneumonias, idiopathic hypereosinophilic syndrome, c-ANCA positive granulomatosis, microscopic polyangiitis, sarcoid, allergic bronchopulmonary aspergillosis, and parasitic infections 4
• For other vasculitides, consider infections, malignancies, drug reactions, and other autoimmune conditions 1
• EGPA can usually be distinguished from other primary systemic vasculitides by the presence of asthma and a marked blood eosinophilia 4

Management

Treatment Goals

• Treatment goals include inducing remission, preventing relapse, and minimizing treatment toxicity 1
• Treatment intensity should be determined by disease severity and extent of organ involvement 1

Induction Therapy

• For ANCA-associated vasculitis, induction therapy includes high-dose corticosteroids combined with either cyclophosphamide or rituximab 2
• Rituximab has been shown to be non-inferior to cyclophosphamide for achieving complete remission at 6 months (64% vs 53%) 5
• In cases of diffuse alveolar bleeding with hypoxemia, plasma exchange may be considered in addition to standard therapy 3

Maintenance Therapy

• Maintenance therapy typically uses less toxic agents such as azathioprine, methotrexate, or rituximab 2
• Azathioprine maintenance therapy should be started at 1.5-2 mg/kg/day for 18-24 months, then decreased to 1 mg/kg/day until 4 years after diagnosis 3
• Glucocorticoids should be continued at 5-7.5 mg/day for 2 years and then slowly reduced by 1 mg every 2 months 3

Management of Relapse

• Patients with relapsing disease should be reinduced, preferably with rituximab 3
• Based on investigator judgment, retreatment with rituximab has been used for disease relapse occurring between 8 and 17 months after the induction treatment 5
• Refractory disease can be treated by increasing glucocorticoids, adding rituximab, or considering plasma exchange 3

Complications and Prognosis

Mortality

• Without treatment, severe small vessel vasculitis can lead to significant morbidity and mortality, particularly with kidney and lung involvement 2
• Mortality in randomized controlled trials of AAV ranged from 0 to 27.4% at 1 year, reflecting different disease severity at inclusion 4
• Prospective and retrospective outcome studies reported a 1-year survival between 77.5% and 99%, and a 5-year survival between 45% (for MPA) and 81% 4

Prognostic Factors

• The strongest predictive factors of mortality are advanced renal involvement, cardiomyopathy, lung hemorrhage, gut involvement requiring surgery, and male sex 4
• In EGPA, factors predicting poor outcome are cardiomyopathy or features of the Five-Factor Score (creatininemia >140umoles/litre; proteinuria >1g/day; involvement of central nervous system, gastrointestinal or heart) 4
• The initial Birmingham Vasculitis Activity Score (BVAS) and the Five Factor Score are predictive of mortality 4

Long-term Outcomes

• With appropriate treatment, survival rates for EGPA are comparable to GPA, with overall remission rates of 81-92%, though over a quarter do relapse 4
• After one year of treatment with rituximab, 44% of patients achieved complete remission at 6 and 12 months, and 38% achieved complete remission at 6,12, and 18 months 5
• Regular monitoring of disease activity, treatment toxicity, and infection is essential for optimal outcomes 2

Special Considerations

Pregnancy

• Pregnancy requires modification of treatment regimens to avoid teratogenic medications 1
• A multidisciplinary approach involving specialists based on organ involvement is recommended for optimal management 1

Disease Activity Monitoring

• Regular assessment of disease activity using validated tools helps guide treatment decisions 1
• The Vasculitis Damage Index (VDI) at 2 years is predictive of future mortality 4

Infection Risk

• Infection prophylaxis with trimethoprim-sulfamethoxazole is recommended during immunosuppressive therapy 1
• Careful monitoring of cardiovascular risk factors, osteoporosis prevention, and infection risk is essential 2