Small Vessel Vasculitides

Small vessel vasculitides include conditions like MPA, GPA, Churg-Strauss, IgA nephropathy, and Goodpasture syndrome. A hallmark feature is palpable purpura, characterized by raised, non-blanching, diffuse erythematous papules and plaques. Patients frequently present with glomerulonephritis that can range from mild hematuria and proteinuria to severe conditions like AKI. Many of these syndromes are also linked to rapidly progressive glomerulonephritis (RPGN), featuring crescent formation within the glomerulus.

Another common manifestation is pneumonitis, which can vary in presentation, from infiltrates and asthma to interstitial fibrosis and alveolar hemorrhage. The underlying mechanism often involves antibodies known as ANCAs. These antibodies, c-ANCA or anti-proteinase-3, and p-ANCA or anti-myeloperoxidase, target proteinase-3 in cytoplasmic neutrophil granules and perinuclear myeloperoxidase, respectively. Sensitized neutrophils in predisposed individuals express these enzymes on their surfaces, leading to autoantibody binding and activation. Upon activation, these neutrophils release cytokines and reactive oxygen species, resulting in endothelial damage and ultimately, vasculitis.

Granulomatosis with polyangiitis (GPA) is often seen in older men and is c-ANCA positive. Its development is likely triggered by airborne environmental antigens in predisposed individuals. GPA presents a triad of symptoms affecting the upper respiratory tract, lungs, & kidneys. Upper respiratory involvement commonly manifests as chronic rhinosinusitis leading to congestion and purulent nasal discharge. Moreover, GPA causes granuloma formation with multinucleated giant cells on histology, often accompanied by central necrosis. Pulmonary manifestations include recurrent pneumonia, interstitial fibrosis, cavitary lesions, and hemorrhagic nodules.

In contrast, microscopic polyangiitis (MPA) is usually p-ANCA associated and has a particular affinity for pulmonary vessels. This leads to recurrent pneumonia, pneumonitis, & interstitial fibrosis. Damage to pulmonary vessels may result in alveolar hemorrhage, manifesting as dyspnea and hemoptysis. MPA, like other ANCA-positive vasculitides, commonly features glomerulonephritis but lacks immune complex deposition in the glomeruli, often described as ’pauci-immune' on microscopy.

Churg-Strauss syndrome, also known as eosinophilic granulomatosis with polyangiitis, is usually p-ANCA positive and is often related to exposure to an unknown allergen, infection, or drug, leading to atopy and development of p-ANCA antibodies. Almost all patients have asthma and often present with pulmonary infiltrates, nodules, and effusions due to eosinophilic infiltration. This syndrome causes granulomatous inflammation, marked by eosinophilia, tissue necrosis, and the formation of multinucleated giant cells. Up to 50% of patients may experience myocardial involvement leading to fibrosis and congestive heart failure.

Inflammation in ANCA-associated vasculitides can extend to peripheral nerves, causing symptoms like pain, paresthesias, or paresis affected two or more nerves, termed mononeuritis multiplex.

Henoch-Schonlein purpura (HSP) often occurs in young children and frequently follows an upper respiratory infection. It is a type III hypersensitivity reaction that involves IgA immune complex deposition in various tissues, activating the complement system and leading to inflammation. Clinically, this manifests as palpable purpura, non-deforming arthritis affecting the lower extremities, and GI symptoms like intermittent, colicky abdominal pain and mild GI bleeding. Renal involvement is also common, presenting as glomerulonephritis with hematuria and sometimes proteinuria. Adults with HSP are at higher risk for severe renal complications, including hypertension and renal failure.

On the other hand, Goodpasture syndrome is usually encountered in older populations and is a type II hypersensitivity condition triggered by anti-glomerular basement membrane (GBM) autoantibodies directed against type IV collagen. These autoantibodies cause damage to both the renal and pulmonary systems, resulting in glomerulonephritis and symptoms like alveolar necrosis, shortness of breath, and hemoptysis. Immunohistochemistry often shows linear IgG and extensive C3 deposition along the GBM, which is unique to anti-GBM disease. While HSP is associated with defective mucosal immunity, Goodpasture syndrome involves a more autoimmunity-driven pathogenesis.

Cryoglobulinemia, more common in older women, is also a type III hypersensitivity reaction that involves the formation of immune complexes. These complexes, called cryoglobulins (usually IgM), bind via the Fc regions of IgG and precipitate in cold temperatures. Immune complex deposition activates the complement system and induces inflammation and tissue damage. Cryoglobulinemia has a strong association with hepatitis C infection, as well as other conditions like multiple myeloma, myeloproliferative diseases, and lupus.