Management of Primary Small-Vessel Vasculitis

Crystal E. Nwannunu, BS; Radhika Shah, BS, MS; Allison L. Limmer, BS, BA; Ravi R. Patel, MD; Uyen Ngoc Mui, MD; Stephen K. Tyring, MD


Skin Therapy Letter. 2020;25(3):5-8. 

In This Article

Pathogenesis/Distinguishing Clinical Features

Vasculitides are primarily defined by the size of blood vessels affected, typically small, medium, large, or variable, but are more recently defined using the Chapel Hill nomenclature system, which is based on clinical and histopathological features.[3,4] Small vessels include arterioles, capillaries, and venules; medium vessels include main visceral arteries and veins; and large vessels include the aorta and its major branches.[3] Using the Chapel Hill system, the systemic vasculitides are categorized into two groups – large-vessel vasculitis and necrotizing vasculitis.

Primary Vasculitis

Eosinophilic Granulomatosis With Polyangiitis. (EGPA, formerly Churg-Strauss syndrome) is a rare, anti-neutrophil cytoplasmic antibody (ANCA)-associated subtype of the necrotizing vasculitides, affecting small- to medium-sized vessels. Patients afflicted with this condition can be ANCA-positive or -negative, which reflects the disease's inherent heterogeneity.[5] The mechanism underlying ANCA-negative disease involves T helper cell type 2 (TH-2)-mediated immune response in which cytokines released by the TH-2 lymphocytes, most notably interleukin (IL)-5, activate epithelial and endothelial cells. Not only is IL-5 key in the regulation of eosinophil maturation and release, but its role in EGPA is important, as serum levels of IL-5 correlate with disease activity and have been seen to decrease with immunosuppressive therapy.[5,6] Once activated, epithelial and endothelial cells release eosinophil-specific chemokines, which facilitate recruitment of eosinophils and effector TH-2 cells via C-C chemokine receptor type 4 (CCR4) interaction. Eosinophils then secrete peroxidases, neurotoxins, and eosinophil granule major basic protein, leading to tissue damage.[6] Distinguishing features from other necrotizing vasculitides include the presence of asthma, rhinosinusitis, and peripheral eosinophilia.[5,6] Skin findings are seen in half to two-thirds of EGPA patients and include granulomas, nonthrombocytopenic palpable purpura, urticarial rashes, skin infarcts, and livedo reticularis.[6]

Granulomatosis With Polyangiitis. (GPA, formerly Wegener's granulomatosis) is another ANCA-associated, small-vessel, necrotizing vasculitis. Patients with GPA have a high frequency of self-reactive B lymphocytes, which mature into plasma cells that secrete ANCA. ANCA is able to target cytoplasmic (c)-ANCA and p-ANCA on neutrophils and monocytes, which then generates reactive oxygen species, cytokines, proteases, and neutrophil extracellular trap (NET-derived) products. The subsequent inflammatory response involving complement activation and formation of membrane attack complexes (MACs) leads to necrotizing systemic vasculitis, necrotizing glomerulonephritis, and granulomatous inflammation of the airways.[7] GPA can be characterized, much like EGPA, by a combination of vague generalized symptoms (malaise, myalgia, arthralgia, weight loss, and fevers) and multi-organ damage. Cutaneous manifestations of GPA range from leukocytoclastic vasculitis to purpura to skin infarcts, ulcers, and gangrene.[7] Ear, nose, respiratory tract, cardiovascular, gastrointestinal, renal, and central nervous system findings have been noted in GPA patients.[7]

Microscopic Polyangiitis. (MPA) is yet another small-vessel, ANCA-associated vasculitis (AAV). However, its underlying mechanism is poorly understood beyond the evidence suggesting an autoimmune etiology. The presence of p-ANCA in patients with MPA is most common, but c-ANCA can be present as well. Interestingly, it has been found that titers of p-ANCA do not correlate well with disease activity in MPA, suggesting a multifactorial pathophysiology.[8] MPA does not typically present until the fifth or sixth decade of life, with renal involvement being its most prominent feature. Pulmonary hemorrhage or findings mirroring idiopathic pulmonary fibrosis; myalgias, arthralgias, and arthritis; ocular, ear, nose, and throat symptoms; gastrointestinal pain or bleeding; and neuropathy are also common. Dermatologic manifestations include purpura and splinter hemorrhages.[9]

Immunoglobulin a Vasculitis. (IgAV, formerly Henoch- Schönlein purpura) is a small-vessel, immune-complex vasculitis. Antigen exposure via bacteria, viruses, and parasites in genetically predisposed individuals can lead to increased IgA type 1 (IgA1) production. Abnormal glycosylation of IgA1 results in decreased clearance and subsequent increased serum levels of the immunoglobulin (Ig). Additionally, identification of human leukocyte antigen DR beta 4 (HLA-DRB4) supports the role of a genetic component to this disease's pathogenesis.[10] It is characterized clinically by purpura or petechiae greatest in the lower extremities, abdominal pain (classically secondary to intussusception), arthritis or arthralgia, and renal symptoms.[11,12]

Cryoglobulinemic Vasculitis. (CV) is a small-vessel vasculitis that involves the skin, joints, peripheral nervous system (PNS), and kidneys. Mainly produced as a consequence of chronic hepatitis C (HCV) infection, cryoglobulins are immune complexes that deposit in small vessels, leading to systemic vasculitis in affected patients. It often presents with a triad of purpura, arthralgia, and asthenia in hepatitis C-positive patients. Other skin findings include acrocyanosis, livedo reticularis, nonhealing ulcers, and Raynaud's phenomenon. Renal, neurologic, and hyperviscosity symptoms are also common in CV, with respiratory and gastrointestinal manifestations more rare. Thyroid disease, type-2 diabetes mellitus, and B-cell non- Hodgkin lymphoma have also been reported in CV patients.[13] CV can be detected by precipitation of proteins in patients' serum and is then categorized by immunochemical analysis into types I, II, and III. Type I involves the presence of single monoclonal Igs due to an underlying B-cell lymphoproliferative disorder. Type II is categorized as a mixed cryoglobulinemia and involves polyclonal IgG and monoclonal IgM with rheumatoid factor activity. Type III is also a mixed cryoglobulinemia with polyclonal IgG, polyclonal IgM, and rheumatoid factor activity.[14] In patients with chronic HCV infection, intrahepatic and circulating B-cells are persistently stimulated, resulting in an expanded B-cell population. This population includes VH1–69 clones that can produce Igs with rheumatoid factor activity, eventually leading to the formation of cryoglobulins. Lesion development in CV is dependent on physical and chemical properties of the Igs involved, such as heavy-chain glycosylation and differences in solubility and rigidity. These properties influence the Igs' ability to form immune complexes and induce inflammation.[15]

Secondary Vasculitis

The general pathogenesis driving these blood vessel disorders involves cell-mediated inflammation, immune complex (IC)- mediated inflammation, and ANCA-mediated inflammation. These pathways of inflammation can result in vessel occlusion and tissue destruction due to endothelial cell activation, leading to long-standing disease.[4] Common secondary causes include autoimmune diseases, infection, drugs and malignancy. It is important to note these common causes for a thorough differential diagnostic evaluation. In this manuscript, the common secondary causes of small-vessel vasculitis will not be further discussed. We aim to focus solely on the clinical approaches to primary small-vessel vasculitis.