¹University of Edinburgh Medical School, Edinburgh, United Kingdom
²Faculty of Medicine, University of Toronto, Toronto, ON, Canada
³SKiN Centre for Dermatology, Peterborough, ON, Canada
⁴Queen’s University, Kingston, ON, Canada
⁵Probity Medical Research, Waterloo, ON, Canada

Conflict of interest:
Julian McDonald and Khalad Maliyar have no conflicts of interest. Melinda Gooderham has been an investigator, speaker, advisor or consultant for AbbVie, Amgen, Akros, Arcutis, BMS, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Galderma, GSK, Janssen, Kyowa Kirin, Medimmune, Merck, Novartis, Pfizer, Roche, Regeneron, Sanofi Genzyme, Sun Pharma, UCB, and Valeant/Bausch Health.

Abstract:
Psoriasis is a common, chronic, immune-mediated, inflammatory disorder with significant skin manifestations and substantial burden on quality of life. Interleukin-23 is a key regulator of different effector cytokines and plays a cardinal role in the pathogenesis of psoriasis. The monoclonal antibody, risankizumab, inhibits this key cytokine and thus prevents the downstream inflammatory cascade. This article aims to review our current understanding of risankizumab through the analysis of the various clinical trials.

Key Words:
biologic, interleukin-23, IL-23, psoriasis, risankizumab, systemic therapy

Role of Immune Dysfunction in Psoriasis

Studies have linked the immunological basis for psoriasis susceptibility to variants in genes for the interleukin-23 (IL-23) receptor and p19 subunit of IL-23.¹ IL-23 is produced primarily by antigen-presenting cells and induces T helper 17 (TH17) and TH22 cell differentiation,^2,3 which are sources of proinflammatory cytokines, including IL-17 (from TH17 cells) and IL-22 (from TH22 cells) that mediate tissue inflammation and epidermal hyperplasia.⁴ Risankizumab (BI 655066/ABBV-066) is a human immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds to the unique p19 subunit of IL-23 with high affinity, thus blocking the activity of IL-23 and its signalling cascade.⁵

Risankizumab Clinical Trials

Phase I

First phase testing of risankizumab was through a randomized, placebo-controlled, double-blinded, single-rising-dose, multicenter, within-dose cohort trial.⁵ Its primary objective was to evaluate the safety and tolerability of risankizumab based on the results of clinical examination and the presence of adverse events (AEs). Secondary efficacy endpoints included changes from baseline Psoriasis Area and Severity Index (PASI) and Static Physician Global Assessment (sPGA) scores over time. Patients aged 18 to 75 years with moderate-to-severe plaque psoriasis for ≥6 months were included. Thirty-nine eligible patients received a single dose of intravenous (IV) risankizumab (n=18), subcutaneous (SC) risankizumab (n=13), or matched placebo (n=8), with follow-up over the subsequent 24 weeks.

Risankizumab was well tolerated. AEs were reported with similar frequency in risankizumab and placebo groups, with 65% (20/31) of patients receiving IV or SC risankizumab experiencing an AE compared with 88% (7/8) on placebo. Mild-to-moderate upper respiratory tract infections, mild nasopharyngitis and mild-tomoderate headache were the most frequently reported AEs.

Assessment of secondary endpoints were also positive with rapid, substantial, and enduring clinical improvement.⁵ At week 12, 75%, 90% and 100% decreases in PASI (PASI75, PASI90 and PASI100) were achieved by 87%, 58% and 16% of risankizumabtreated patients, respectively, vs. none receiving placebo. PASI100 responses were maintained in some patients for up to 66 weeks after treatment, as observed in patients who entered an optional follow-up extension study. These marked clinical improvements, represented by significant PASI score reductions, supported the idea of the IL-23 pathway playing a central role in the pathogenesis of psoriasis and further studies were completed.

Phase II

The Phase II trial compared the efficacy of risankizumab to that of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with moderate-to-severe plaque psoriasis.⁶ Ustekinumab targets the p40 subunit, common to both IL-12 and IL-23, thus blocking the activity of both cytokines. While ustekinumab has demonstrated significant efficacy and safety in the treatment of psoriasis, it is now understood that inhibition of IL-23 to be primarily responsible for its efficacy. This Phase II trial was the first direct comparison between ustekinumab and a drug that specifically targets IL-23, risankizumab, via selective p19 inhibition.⁶ The primary endpoint was reaching PASI90 at week 12.

The 48-week, multicenter, randomized, dose-ranging trial enrolled patients aged 18 to 74 years with >6-month history of moderate-to-severe plaque psoriasis, ≥10% body surface area (BSA) involvement, a PASI score of ≥12, and a sPGA score of ≥3. A total of 166 patients were randomly assigned to receive either risankizumab or ustekinumab at weeks 0, 4, and 16. Those allocated to risankizumab received either a single 18 mg dose at week 0 only (n=43), 3 doses of 90 mg (n=41) or 3 doses of 180 mg (n=42), while ustekinumab was administered according to label in 3 doses of 45 mg or 90 mg, depending on body weight (if less than or greater than 100 kg) (n=40). The study was doubleblinded and 139 patients (84%) finished the trial, including 107 patients (77%) who completed follow-up through week 48.

Although small numbers and short duration limits drawing conclusions about safety, 81%, 80%, 69% and 72% of the 18 mg risankizumab, 90 mg risankizumab, 180 mg risankizumab and ustekinumab groups, respectively, experienced AEs with nasopharyngitis the most commonly reported. Additionally, 5 patients (12%), 6 patients (15%), 0 and 3 patients (8%) had serious AEs in the 18 mg, 90 mg and 180 mg risankizumab groups and ustekinumab group, respectively. Basal cell carcinoma was diagnosed in 2 patients and a major adverse cardiac event occurred in 1 patient who had received risankizumab treatment.

SustaIMM⁷ was a Phase II/III, double-blinded, placebo-controlled study of Japanese patients with moderate-to-severe plaque psoriasis (n=171) that was conducted to evaluate the efficacy and safety of two different dose regimens of risankizumab. Patients were randomized 2:2:1:1 to 75 mg risankizumab, 150 mg risankizumab, placebo with cross-over to 75 mg risankizumab and placebo with cross-over to 150 mg risankizumab. The primary endpoint was PASI90 at week 16 for risankizumab vs. placebo. At week 16, the PASI90 response was significantly higher in patients who received 75 mg (76%) or 150 mg (75%) risankizumab compared to placebo (2%). The study concluded that both doses of risankizumab were superior to placebo in the treatment of Japanese patients with moderate-to-severe plaque psoriasis. Moreover, the safety profile was similar to other previous risankizumab trials, with no new AEs reported.

These preliminary findings support the use of selective IL-23 blockade through p19 subunit inhibition to provide more complete suppression of IL-23 activity vs. that offered by p40 inhibition.

Phase III

Risankizumab has been investigated in four Phase III clinical trials. Refer to Table 1 for a brief overview of each of the trials and Figure 1 for a summary of efficacy results. Two Phase III studies, UltIMMa-1 and UltIMMa-2, were the first of four Phase III studies to report findings on the efficacy and safety of risankizumab compared with placebo or ustekinumab in patients with moderate-to-severe chronic plaque psoriasis.⁸ UltIMMa-1 and UltIMMa-2 are replicate randomized, double-blinded, placebo-controlled and active compactor-controlled trials. Adult patients (aged ≥18 years) were included in the study if they had stable (≥6 months) moderate-to-severe chronic plaque psoriasis (with or without psoriatic arthritis), with a BSA involvement 10% or greater, PASI score of 12 or more and sPGA score of 3 or greater.

Part A of the study was a 16-week double-blinded treatment period. In Part A of UltIMMa-1, 506 patients were randomly assigned (3:1:1) to receive either risankizumab 150 mg (n=304), ustekinumab dosed per label (45 mg for body weight ≤100 kg or 90 mg for body weight >100 kg) (n=100), or placebo (n=102). In Part A of UltIMMa-2, 491 patients were assigned to receive either risankizumab 150 mg (n=294), ustekinumab dosed per label (45 mg or 90 mg) (n=99), or placebo (n=98). After the 16 week-period, in Part B (double-blinded, weeks 16- 52), patients who were initially assigned to placebo switched to 150 mg risankizumab at week 16; while other patients continued their originally randomized treatment. The study drug was administered subcutaneously at weeks 0 and 4 during Part A and at weeks 16, 28, and 40 during Part B. Safety was measured throughout the study. Co-primary endpoints were PASI90 and sPGA 0 or 1 at week 16. At week 16 of UltIMMa-1, PASI90 was achieved by 75.3% of patients on risankizumab compared to 4.9% on placebo and 42% on ustekinumab. At week 16 of UltIMMa-2, PASI90 was achieved by 74.8% patients on risankizumab compared to 2% on placebo and 47.5% on ustekinumab. At week 16 of UltMMa-1, sPGA 0 or 1 was achieved by 87.8%, 7.8% and 63.0% in patients receiving risankizumab, placebo and ustekinumab, respectively. At week 16 of UltMMa-2, sPGA 0 or 1 was achieved by 83.7%, 5.1% and 61.6% in patients receiving risankizumab, placebo and ustekinumab, respectively. The authors concluded that risankizumab demonstrates superior efficacy when compared with both placebo and ustekinumab in the treatment of moderate-to-severe plaque psoriasis.

IMMvent was the next Phase III study to investigate the efficacy and safety of risankizumab compared with adalimumab for moderate-to-severe chronic plaque psoriasis.⁹ IMMvent is a randomized, double-blinded, active-comparator-controlled trial in a patient population similar to the UltIMMa trials.

Part A of the study was a 16-week double-blinded treatment period in which 605 patients were randomly assigned (1:1) to receive either 150 mg risankizumab SC (n=301, 50%) at weeks 0 and 4, or 80 mg adalimumab SC (n=304, 50%) at week 0, then 40 mg at weeks 1, 3, 5, and every other week for the duration of the 16-week period. For weeks 16-44, Part B of the study, patients who achieved a PASI90 on adalimumab (n=144, 47%) remained on adalimumab; individuals who achieved a PASI50 or higher to less than PASI90 (adalimumab intermediate responders) (n=109 patients, 36%) were re-randomized to continue 40 mg adalimumab (n=51/56, 91%) or switch to 150 mg risankizumab (n=51/53, 96%); and individuals who achieved less than PASI50 (n=38, 13%) switched to 150 mg risankizumab. Participants who were initially randomized to risankizumab in Part A remained on risankizumab in Part B. Co-primary endpoints in Part A were PASI90 and sPGA score of 0 or 1 at week 16, and for Part B was PASI90 at week 44 (non-responder imputation). At week 16, PASI90 was achieved in 72% of patients receiving risankizumab and 47% receiving adalimumab, and sPGA scores of 0 or 1 were achieved in 84% and 60% of patients given risankizumab and adalimumab, respectively.

In Part B, among adalimumab intermediate responders, PASI90 at week 44 was achieved by 66% of patients who switched from adalimumab to risankizumab and 21% of patients that continued on adalimumab through to week 44.9 Risankizumab showed significantly greater efficacy than adalimumab in the treatment of moderate-to-severe plaque psoriasis.

The IMMhance trial was the fourth Phase III study conducted to assess safety and maintenance of efficacy for continuous risankizumab treatment compared to withdrawal of therapy (receiving placebo) in patients with moderate-to-severe plaque psoriasis.¹⁰ This was a multinational, multicenter, randomized, double-blinded, placebo-controlled study.

In Part A1 of the study, 507 participants were randomized at baseline, at a ratio of 4:1, to receive either 150 mg risankizumab (n=407) at weeks 0 and 4 or placebo (n=100). In Part A2 of the study, all patients who were randomized at baseline to placebo, received a 150 mg dose of risankizumab at week 16, week 28, and every 12 weeks thereafter up to 88 weeks. In Part B, patients who were originally on risankizumab and achieved a sPGA of 0/1 (n=336) were re-randomized at a ratio of 1:2 to receive risankizumab 150 mg (n=111) or placebo (n=225), and every 12 weeks thereafter up to 88 weeks. The participants who received risankizumab in Part A and were nonresponders (sPGA ≥2) at week 28 (n=63) received risankizumab 150 mg at week 28 and every 12 weeks up to 88 weeks. Starting at week 32, re-randomized participants who relapsed (defined as sPGA ≥3) (n=153) were switched to risankizumab 150 mg every 12 weeks. In Part A, the co-primary endpoints were the percentage of patients with an sPGA of 0/1 at week 16, and the percentage of patients achieving a PASI90 from baseline to week 16. At week 16, it was found that an sPGA 0/1 and PASI90 was achieved by 340 (83.5%) and 298 (73.2%) patients being treated with risankizumab, respectively, compared with 7 (7.0%) and 2 (2.0%) patients receiving placebo.¹¹

In Part B, the primary endpoint was the percentage of patients with a sPGA of 0/1 at week 52. Of the patients who were rerandomized to continue risankizumab, 97 (87.4%) achieved a sPGA of 0/1, whereas those who were re-randomized to placebo 138 (61.3%) maintained a sPGA of 0/1. Among patients who were re-randomized to withdrawal and achieved a loss of response (defined as a sPGA ≥3 on or after Week 32), 83.7% (128/153) regained sPGA 0/1 after 16 weeks of re-treatment (i.e., 2 doses) with 150 mg of risankizumab. The IMMhance trial demonstrated risankizumab’s significant efficacy and durability vs. placebo.

In terms of safety, the most commonly reported AEs with risankizumab treatment include upper respiratory tract infections, nasopharyngitis, and headaches. No dose-dependent associations with AEs have been detected to date. In regard to major adverse cardiac events (MACE), there were few reports of cerebrovascular AEs in all phases of development, but these were unlikely treatment related and the rates would be expected in the population studied. There were also no reports of active tuberculosis or reactivation of latent tuberculosis, hepatitis or other opportunistic infections in risankizumab treated patients. The trials revealed that risankizumab is generally very well tolerated and can provide significant clinical improvements in patients with moderate-to-severe plaque psoriasis.

Moving forward, risankizumab is further being investigated in two studies for psoriasis. The LIMMitless study (NCT03047395), a Phase III, single-arm, multicenter open-label extension study is designed to evaluate the long-term safety and efficacy of 150 mg risankizumab in approximately 2200 patients who had previously been enrolled in risankizumab trials.¹² Risankizumab is also currently being evaluated in a 52-week head-to-head comparator study against the IL-17A inhibitor, secukinumab (NCT03478787) for the treatment of adult subjects with moderate-to-severe plaque psoriasis.¹³

Conclusion

The addition of biologics that target IL-23p19 to our therapeutic armamentarium has succeeded in improving outcomes in patients with moderate-to-severe plaque psoriasis. The Phase I, II, and III clinical trials of risankizumab have clearly demonstrated that the use of risankizumab provides substantial and durable skin clearance with an excellent safety profile. The data presented from these trials further supports the therapeutic value of risankizumab in patients with moderate-to-severe plaque psoriasis.

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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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