The major pathogenetic mechanism in CSVV is the Gell and Coombs type III immune complex-mediated reaction (5) (Figure 1A). The latent period between the trigger and manifestation of CSVV can range from seven days to more than 2 weeks, depending on the time required to produce sufficient quantities of antibodies and antigen-antibody complexes upon encountering a stimulus (14). Immune complexes (ICs) circulating in the patients can activate the complement system, generating C3a and C5a anaphylatoxins, which initiate neutrophil chemotaxis and release of vasoactive amines causing endothelial cell retraction (5). Pro-inflammatory cytokines and chemokines, such as IL-1, TNF-α, IFN-γ, IL-8, MCP-1, and RANTES produced by macrophages increase the expression of endothelial selectins, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), which promotes neutrophil diapedesis. After the neutrophils exit the blood vessel, neutrophil degranulation releases collagenases and elastases, and generates reactive oxygen species (ROS), resulting in sustained inflammation and fibrinoid necrosis of neighboring vessel walls (5). ICs can also deposit directly on endothelial cells and trigger localized inflammation, such as the deposition of IgA-ICs in glomerular capillaries as seen in cases of Henoch-Schonlein purpura with glomerulonephritis (5). As the disease progresses, lymphocytes gradually become more abundant over time and may also be involved in the pathogenesis and disease progression, eventually becoming the most abundant cell type in lesion histopathology (4). CD4⁺ helper T cells secrete cytokines, notably IL-1, IFN-γ, and TNF-α, and recruit CD8⁺ cytotoxic T cells, B cells and natural killer cells to the affected site, further promoting inflammation (5). Unlike in systemic vasculitides such as GPA, CSVV is not associated with abnormal circulating Treg counts, indicating that CSVV usually does not have systemic involvement (4).

Previous studies have identified various stimuli that can trigger the production of pathogenic antibodies in CSVV patients, which subsequently lead to immunopathology. Hepatitis C virus infection can induce the production of cryoglobulins (immunoglobulins that precipitate at temperature below 37°C), leading to cryoglobulinemic vasculitis where cryoglobulin immune complexes precipitate and deposit on affected small vessels. This subsequently activates the classical complement pathway and causes endothelial damage (15). Besides infection, several drugs have also been known to trigger cutaneous hypersensitivity vasculitis, often presenting as superficial neutrophil or lymphocytic small vessel vasculitis. Drug-induced CSVV accounts for ~20% of all CSVV cases (16). Examples of drugs that may induce CSVV include TNF-α inhibitors and levamisole (17, 18). CSVV may also be triggered directly by endothelial damage due to infections by vasculotropic viruses such as the COVID-19 causative agent, SARS-CoV-2 (14); or indirectly by antibodies generated against exposed autoantigens, such as antiphospholipid antibodies and anti-neutrophil cytoplasm antibodies (ANCA) (5). Although possible, ANCA are rarely found in patients with CSVV, with cases being defined in a distinct subgroup as ANCA-associated vasculitides (AAV).

Although the pathogenesis of AAV is multifaceted and multifactorial, it shares many aspects of that in CSVV, involving the activation of both cytokine-primed neutrophils and alternative complement pathways (11) (Figure 1B). ANCAs are autoantibodies generated by the immune recognition of autoantigens, such as neutrophil myeloperoxidase (MPO), proteinase-3 (PR3) and neutrophil elastase (NE) (19). While most MPO and PR3 are localized in the cytoplasm of unstimulated neutrophils, small amounts of these antigens can be found on the cell surface, even in healthy individuals. However, healthy individuals have only low levels of circulating natural autoantibodies against these auto-antigens, and the epitope specificity of their MPO-ANCA differs from that of pathogenic MPO-ANCA (2). In AAV patients, several mechanisms such as apoptosis and NETosis (release of neutrophil extracellular traps) can further promote the release of cytoplasmic antigens into the extracellular space or increase cell surface expression of cytoplasmic antigens by neutrophils. It was shown in vivo that neutrophils from AAV patients with active disease were more likely to undergo apoptosis and their cells had higher expression of surface PR3 and MPO (20). In kidney biopsies from AAV patients, NETs comprising DNA, histones, granule proteins MPO, PR3, LL37, and NE were found in the glomeruli (20). In addition, levels of inflammatory mediators such as tumor necrosis factor-alpha (TNF-α) and C5a were increased in AAV patients and these can also promote the migration of intracellular MPO and PR3 from the cytoplasm to the cell membrane or into the extracellular space (21, 22).

ANCAs play various roles in the pathogenesis of AAV, contributing to disease development and progression. They are able to induce NETosis by binding to FcγRIIA on neutrophils and their ability to induce NETosis correlated with disease activity (20, 23). ANCAs can also bind to cytoplasmic antigens exposed on neutrophil surface leading to respiratory burst, neutrophil degranulation and release of inflammatory mediators such as pro-inflammatory cytokines, ROS and lytic enzymes, which can damage the vascular endothelium (11, 24). ANCA-activated neutrophils can induce injury in nearby microvascular beds, with NETosis leading to the release of neutrophil autoantigens for presentation by antigen-presenting cells. In individuals with active disease, increased numbers of defective Tregs and Bregs may be found (25, 26). Functional Bregs are potent immunosuppressors and inducers of Tregs, where Breg deficiency has been demonstrated in various autoimmune diseases such as SLE and MS, and most likely in AAV (26). The loss of an exon-2-deficient FOXP3 in Tregs due to aberrant splicing results in the loss of downstream protein sequestration involved in immunosuppressive pathways disrupts adaptive immune tolerance, leading to activation of neutrophils and subsequent inflammation of the vessel walls (1, 2, 11, 25, 27). Defective Treg function is thought to be associated with exaggerated neutrophil activity, although the underlying mechanisms are not fully understood (28).

In a mouse model of MPO-ANCA vasculitis, neutrophil depletion prevented disease progression, highlighting the pivotal role of neutrophils in the development of AAV (11). In AAV patients, there is a higher proportion of autoantigen-presenting neutrophils, which can trigger the production of ANCAs through effect T cell recruitment and subsequent B cell activation, resulting in disease (1). Circulating neutrophils isolated from patients with active disease have been shown to generate more basal superoxide, suggesting that they have been primed in vivo (24). In addition, surface expression of PR3 on apoptotic cells acts as a signal to initiate efferocytosis by macrophages. PR3-expressing apoptotic neutrophils increase production of pro-inflammatory cytokines, chemokines and nitric oxide (NO) via the IL-1R1/MyD88 signal pathway (11). The internalization of PR3 results in diminished anti-inflammatory macrophage reprogramming, leading to sustained inflammation in a positive feedback loop (29).

Activation of the complement system through the alternative pathway also has a central role in the development of AAV, bridging the inflammatory and coagulation processes found in active disease (30). C5a induces expression of tissue factor (TF) on neutrophils and endothelial cells, triggering the extrinsic coagulation pathway. Increased expression of TF, which may result in hypercoagulability, has been reported in AAV patients with active disease (31). Various components of the coagulation and fibrinolytic cascades can cleave C3 and C5 to generate C3a and C5a, respectively. Activated platelets express receptors for C3a and C5a, while C5b-9 induce the release of alpha-granules and microparticles which further activate the complement system. Platelet counts are often elevated in patients with active AAV and these correspond to disease severity, though the actual crosstalk and interactions are not fully understood (30). In a mouse model of MPO-ANCA vasculitis, C5-deficient mice were completely protected from developing the disease (32), suggesting that C5a can be a potential therapeutic target.

Although less common, eosinophilia has also been identified in cases of AAV, most commonly in EGPA (33). EGPA is characterized by three phases: (1) asthma and allergy symptoms, (2) tissue and blood eosinophilia, and (3) necrotising vasculitis (33). The presence of ANCAs have been reported in 30–40% of EGPA patients (33). While the direct pathogenic mechanisms of eosinophils in EGPA are unclear due to a lack of a suitable animal model, it has been considered to be a T_H2-mediated disease. CCL17 (a chemokine that recruits T_H2 cells) and IL-25 (a cytokine that induces and enhances T_H2 responses) are amongst the mediators that have been implicated in EGPA pathogenesis (33).

Currently, there is not much literature on the genetic factors that contribute to CSVV pathogenesis. However, some have suggested that the gene ARPC1B may play a role in predisposition to this disease (36, 37). The ARPC1B gene encodes ARPC1B, which is an isoform of ARPC1 (actin-related protein complex-1) and one of the regulatory subunits of the Arp2/3 complex involved in actin polymerization and cellular motility (35). Genetic defects in the proteins regulating cytoskeletal rearrangements often cause syndromes involving the blood and immune systems (50). Arp2/3, in particular, is believed to have a critical role in immune cell synapses formation and T-regulatory cell function (51). A homozygous complex frameshift mutation in ARPC1B was identified in a 7-year-old Moroccan boy who presented with a novel combined immunodeficiency involving recurrent infections, mild bleeding tendency, vasculitis (including leukocytoclastic vasculitis), and allergic reactions (52). This mutation had resulted in a complete lack of the ARPC1B protein in the boy's neutrophils. Kahr et al. also described three patients suffering from CSVV who showed homozygous mutations in the ARPC1B gene (51). As a result of this mutation, complete loss of or minimal ARPC1B protein in their platelets led to defects in Arp2/3 actin filament branching associated with a range of diseases including inflammatory diseases and cutaneous vasculitis. Thus, the ARPC1B gene may be identified as a possible susceptibility locus contributing to CSVV pathogenesis.

Treatment of CSVV is clinically driven, perhaps due to the lack of understanding of the genetic background of this disease. Approach to therapy depends on the etiology and severity of the disease (63, 64). If the underlying etiology can be identified, such as due to an infection or a known drug, eliminating the cause would be the best course of action (64). If the CSVV is a result of a systemic vasculitis (e.g., AAV), treatment will be determined by the severity of internal organ involvement, and will usually require a combination of steroids and an immunosuppressive drug, for example rituximab for the treatment of AAV (64, 65). Idiopathic CSVV, on the other hand, has an excellent prognosis, with 90% of cases resolving within weeks to months of onset (66). Therefore, conservative treatment like bed rest, elevation of lower extremities, warming, analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) and antihistamines can be used to alleviate symptoms such as burning or pruritus (63). If the condition extends to an ulcerative, nodular, or vesicobullous form or it becomes recurrent, additional aggressive systemic medications are necessary (63).

Diet, especially those involving a specific food allergen, is commonly cited as an inciting agent of CSVV, and adjusting to bland, low-antigenic diets is usually recommended to prevent recurrences of the condition (63). With regards to medication, the corticosteroid prednisone is the most widely used treatment for idiopathic CSVV (63, 64). The anti-gout agent colchicine (0.6–1.8 mg per day) has been shown to resolve CSVV within 1–2 weeks (63, 67–69). If colchicine proves ineffective, dapsone, an anti-inflammatory and antineutrophilic agent, can be substituted or added (64). If CSVV is persistent, daily azathioprine, a steroid-sparing agent, may be prescribed (63, 70).

In 2017, a case was reported whereby a woman in her 40s suffering from CSVV, with a history of intermittent purpuric lesions for 20 years, was successfully treated with leflunomide (71). Leflunomide is a pyrimidine synthesis inhibitor and is an inexpensive, effective treatment for psoriatic and rheumatoid arthritis and several types of vasculitis. The patient was reported to remain free of new skin lesions and other cutaneous symptoms following 4 months of leflunomide therapy. Further investigation through prospective clinical trials is needed to assess the efficacy of leflunomide for CSVV treatment.

A recent study explored the role of oxidative stress in CSVV pathogenesis, suggesting that damage to blood vessels so often seen in CSVV could be caused by an imbalance in redox homeostasis (72). Recruitment of neutrophils to the affected tissues triggers ROS production, leading to lipid peroxidation in skin tissues and forming acrolein, a type of reactive aldehyde (73). The study showed that the concentration of acrolein-protein adducts in the skin of small-vessel vasculitis patients is proportional to disease severity (72). Therefore, CSVV might be treated through the mitigation of oxidative stress using antioxidative pharmacologic agents, while disease activity could be assessed using immunohistochemical assessments of acrolein content in the patient's skin, thus allowing for more targeted treatments (72). One such promising antioxidative therapeutic agent is peoniflorin, the main component of total glucosides of peony derived from the root of Paeonia lactiflora Pall. (74–76). The results from a study revealed that peoniflorin reversed the oxidative damage in human umbilical vein endothelial cells caused by hydrogen peroxide, hence suggesting that peoniflorin may be a candidate therapeutic strategy for oxidative stress-related vascular diseases (76).

Based on findings derived from genetic studies, it has been elucidated that ANCA-mediated neutrophil activation and B cells are crucial to AAV pathogenesis, and therefore potential treatments can include B cell-depleting drugs (36, 77). In terms of the induction of AAV remission, rituximab represents a very promising contender (65). Rituximab is a murine / human chimeric monoclonal antibody against CD20, a B cell marker, and was licensed in 2011 for remission induction of AAV (65, 77, 78). During the first phase of an international randomized controlled trial known as RITAZAREM, rituximab was shown to be very effective in reinducing remission in relapsed AAV patients when taken in combination with relatively low doses of glucocorticoids (77).

One of the classical features of AAV is represented by granulomatous inflammatory lesions, which are initiated by macrophages and CD4+ T cells (79). T cell activation requires a costimulatory receptor (CD28) and CTLA-4 acts as a negative regulator of CD28, preventing the binding of CD28 with its ligand, thus blocking T cell activation (80). Abatacept, a disease-modifying anti-rheumatic drug (DMARD), is made up of the CTLA-4 ligand-binding domain and a modified Fc domain derived from IgG1, hence can be a possible therapeutic option for AAV treatment (80). An open label clinical trial involving patients with relapsing GPA showed that abatacept resulted in remission in 80% of patients (81). There is also an ongoing phase III clinical trial (NCT02108860) that aims to assess the efficacy of abatacept in achieving sustained remission in patients suffering from a non-severe relapse of GPA.

Despite the promise of these biological agents as therapeutics for AAV, they are still limited by adverse effects such as infections (81, 82). One study found that severe pulmonary infections were the major infectious complication observed in AAV patients treated with a low dose of rituximab (82). They attributed the B cell-depleting role of rituximab as a cause of these infections and identified renal dysfunction and old age as risk factors of such adverse effects. Given that both rituximab and abatacept are immunosuppressants, it is not surprising that patients treated with these drugs are more vulnerable to infections, and therefore this adverse event should be assessed accordingly during follow-up appointments with the clinicians (81, 82).

Plasma exchange, an effective treatment against thrombocytopenic purpura, a disorder which causes low platelet count, is also considered as a course of treatment for AAV patients (83–85). Plasma exchange may benefit patients by removing pathogenic ANCAs in the plasma, as well as clotting factors involved in the coagulation cascade (85, 86). However, the PEXIVAS trial, the largest study of plasma exchange in AAV, did not show that adjunctive plasma exchange benefits patients with severe AAV (87, 88). Nevertheless, it was suggested that patients with both ANCA and anti-glomerular basement membrane (GBM) antibodies should still be treated with adjunctive plasma exchange. Treatments for patients with anti-GBM disease involve immunosuppression and adjunctive plasma exchange (87). Since both patients with single anti-GBM positivity and double positivity for anti-GBM antibodies and ANCA experience aggressive pulmonary and renal disease, plasma exchange seems appropriate for treating double positivity patients (87).