Management of Primary Small-Vessel Vasculitis

Crystal E. Nwannunu, BS¹; Radhika Shah, BS, MS²; Allison L. Limmer, BS, BA¹; Ravi R. Patel, MD³; Uyen Ngoc Mui, MD³; Stephen K. Tyring, MD^1,3

¹Department of Dermatology, McGovern Medical School, The University of Texas Health Sciences Center, Houston, TX, USA
²Texas A&M University College of Medicine, Dallas, TX, USA
³Center for Clinical Studies, Houston, TX, USA

Conflict of interest:
All of the authors have no conflicts to declare for this work.

Abstract:
Small-vessel vasculitides (SVV) are a group of disorders that occur due to primarily systemic inflammation or as sequelae of an infection, malignancy, or other rheumatic disease. Arising in any organ including the skin, the clinical features of SVV encompass a variety of manifestations. A comprehensive diagnostic assessment should be performed as management protocols widely differ. Although rare, physicians should be familiar with the common types of SVV to ensure prompt management and prevention of severe, life-threatening end-organ damage. Given the variable manifestations and associated etiologies of SVV, the following review aims to discuss the pathogenesis of more prevalent SVVs, highlight distinguishing features to aid in patient evaluation and diagnosis, and examine evidence-based management options for treatment and care.

Key Words:
cryoglobulinemic vasculitis, diagnostic workup, eosinophilic granulomatosis with polyangiitis, granulomatosis with polyangiitis, immunoglobulin A vasculitis, management, microscopic polyangiitis, primary vasculitis, small-vessel vasculitis, SVV, treatment, vasculitides

Introduction

Vasculitis is defined as inflammation of blood vessel walls.¹ Such inflammation manifests as thickening, weakening, narrowing, or scarring of the vessels, leading to restricted blood flow and tissue damage. Vasculitides can occur in any organ, including the skin, and can present with a variety of clinical symptoms.² This broad spectrum of disease is most often classified by the size of the blood vessel involved.^1,2 Small-vessel vasculitis, the focus of our review, is a disease subtype that targets arterioles, venules, and capillaries.² Given this disease’s variable manifestations and associated etiologies, the following review aims to discuss the pathogenesis of common primary small-vessel vasculitides (SVV), highlight distinguishing features to aid in patient evaluation and diagnosis, and define evidence-based management options for patient treatment and care.

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.

Diagnostic Workup

The diagnosis of SVV is based on compatible clinical, histological and laboratory findings. It is recommended to perform an initial screen to exclude infection, as infection can commonly mimic vasculitis. This includes obtaining blood cultures, echocardiogram, hepatitis screen (B and C), HIV test, anti-glomerular basement membrane antibody, antiphospholipid antibodies and antinuclear antibodies. To assess for the extent of vasculitis involvement, examine for internal organ involvement, even in individuals with isolated cutaneous vasculitis. This can be performed with a thorough history, physical examination, urine dipstick, chest radiograph, and nerve conduction studies. To confirm diagnosis, a biopsy is done, with the biopsy site choice dependent on its likelihood of affecting treatment decisions. To identify the specific type of small-vessel vasculitis, it is particularly important to check serum levels of ANCA, cryoglobulin, complement, and eosinophils/IgE. In addition, specific findings on biopsies such as the presence or absence of necrotizing granulomatous inflammation, IgA deposits, and immune complex formation can aid in specific diagnostic identification.¹⁶ Figure 1 provides a summarized workup in diagnosing small-vessel vasculitis.

Current Management

Management of SVV is based on the severity of systemic involvement, skin lesions, and treatment of any underlying comorbidities. A multidisciplinary approach involving rheumatology, pulmonology, nephrology, and others is often beneficial in severe cases. The most common and effective therapies for SVV can be found in Table 1.

Of note, while the majority of IgAV cases require symptomatic treatment only (i.e., managing arthropathy and abdominal pain with rest and analgesia), preventative measures are attempted to manage associated renal disease.¹⁸ Although there are multiple therapeutic agents used for renal disease intervention, their treatment efficacy is still being debated. A meta-analysis of 13 randomized controlled trials was conducted to analyze the benefits and harms of these agents compared to placebo in the prevention and treatment of kidney disease in adults and children. Results revealed no evidence of benefit in the use of prednisone or antiplatelet agents in preventing kidney disease in children with IgAV, and no evidence of benefit has been found for cyclophosphamide treatment in adults or children with severe kidney disease.²³

Management of cutaneous lesions consists of providing supportive care, avoiding triggers, assessing skin lesion severity, and treating the underlying systemic disease. For mild and non-ulcerative skin lesions, supportive measures including leg elevation, gradient support hose, and avoidance of tight clothing, sun exposure, and cold temperatures are recommended. Medications such as antihistamines, topical steroids and topical calcineurin inhibitors can be helpful to alleviate skin symptoms. Antibiotics should also be employed when there is an associated infection. High-dose steroids can be used to treat patients with symptoms of ulcerative cutaneous lesions and signs of minimal systemic disease. It is recommended that high-dose prednisone of up to 1 mg/kg/day be given along with a slow 4-6 week taper to limit some of the severe side effects of long-term systemic corticosteroid use. If recurrent vasculitis occurs during tapering, the addition of a steroid-sparing agent may reduce a patient’s exposure to high-dose steroid therapy. Helpful agents include methotrexate (MTX) at <25 mg weekly after proper evaluation of the patient’s creatinine clearance or azathioprine at 2 mg/kg/day. For patients displaying a more severe cutaneous/ systemic presentation, pulse doses of prednisone can be given intermittently instead of a long taper.²

Lastly, since comorbid conditions such as hypertension, diabetes, hypercholesterolemia, and smoking can accelerate vascular damage, appropriate management of these diseases and cessation of smoking should be highly recommended.¹

Future Aims in Management

In the setting of small-vessel vasculitis, future management through a biological approach would potentially be the most beneficial, since pathology of the systemic vasculitides, especially ANCA-associated, is better understood.²⁴ The success of nonselective B-cell depletion using rituximab has paved the way for the next generation of targeted therapies focusing on innate and adaptive immunity. Researchers have noted that B-cellactivating factor (BAFF) is highly involved in stimulating B-cell proliferation and promoting immature B-cell survival. Increased BAFF levels lead to increased production of autoantibodies and is seen in patients with GPA. The ANCA-stimulated neutrophils observed in this disease release BAFF to promote B-cell survival, and because studies have shown increased BAFF after B-cell depletion with rituximab in ANCA-associated vasculitis models, it has been proposed that BAFF may have a key role in promoting autoreactive B-cell survival, facilitating relapse and chronicity of disease. Belimumab, a monoclonal antibody against BAFF in the treatment of systemic lupus erythematosus, has been investigated in a phase III trial to evaluate its efficacy and safety in combination with azathioprine for GPA and MPA maintenance of remission.²⁵

In addition, abnormal T-cell activation may also have a role in the pathogenicity of AAV. A study evaluating abatacept, a fusion protein that blocks the T-cell activation co-stimulatory signal, demonstrated disease improvement in 90% of the study population. A phase III trial (NCT02108860) evaluating abatacept in the setting of relapsing, non-severe AAV is ongoing. Component C5a of the complement system has also been implicated in the pathogenesis of AAV. C5a serves as a priming agent for neutrophils, resulting in an increased surface expression of PR3 and MPO. Their interaction with ANCA leads to an amplification loop of ANCA-mediated neutrophil activation, further propagating disease. CCX168 (avacopan) is an orally administered inhibitor of the C5a receptor with phase II data reporting complete remission in a majority of patients receiving a combination of cyclophosphamide or rituximab and CCX168 versus placebo. Although the data is promising, further research is needed.²⁵

Finally, it has been shown that inflammatory cytokines may also play an important role in AAV pathogenicity. In patients with active AAV, serum and histopathologic sample levels of IL-6 are increased and appear to be associated with patients who frequently relapse and suffer more severe organ damage. A few case reports have shown that an IL-6 blockade with tocilizumab is successful but requires further evaluation. Along with IL-6, IL-17 and IL-23 may also be involved in more active disease. For this reason, additional research regarding targeted antiinflammatory cytokine therapies is key.^25,26

Conclusion

The SVV are a heterogenous group of diseases that include eosinophilic granulomatosis with polyangiitis, granulomatosis with polyangiitis, microscopic polyangiitis, IgA vasculitis, and cryoglobulinemic vasculitis. These disorders can arise without obvious cause or in the setting of autoimmune disease or infection. Clinical manifestations are broad, but often involve cutaneous findings such as purpura and petechiae that can distress affected patients. Effective therapy is founded upon adequate management of the vasculitis primarily via immunomodulation as well as identification and control of modifiable risk factors such as diabetes, hypercholesterolemia, and tobacco use. SVV have the potential to be impacted by emerging immunotherapeutic interventions, especially biologic agents targeting B- and T-cells; however, additional research is needed in this area.

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