8/7/2020 Management of Primary Small-Vessel Vasculitis

Management of Primary Small-Vessel Vasculitis

By STL Volume 25 Number 3 - June 1, 2020

Crystal E. Nwannunu, BS 1, Radhika Shah, BS, MS 2; Allison L. Limmer, BS, BA1; Ravi R. Patel,
MD;3; Uyen Ngoc Mui, MD;3; Stephen K. Tyring, MD;1,3

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

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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

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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.1 0 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.1 1 ,1 2

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.1 3 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.1 4 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.1 5

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

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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.1 6 Figure 1 provides a summarized workup in diagnosing small-
vessel vasculitis.

Fi gure 1: Workup of a s mall-ves s el vas culitis

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.1 8 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.2 3

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

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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

Mepolizumab

Source
Treatment Indication Monitoring Notes
(Referenc
CBC,
Methotrexate Non-severe GPA creatinine, 17
transaminases
Non-severe GPA 17
Non-severe
6
EGPA
Abdominal and
joint pain in 18
Glucocorticoids IgAV
To halt end-
organ damage
in 19
cryoglobulinemic
vasculitis
Cyclophosphamide should be
Combination
Periodic CBCs, switched to MTX or
glucocorticoids + Severe GPA 1, 17
LFTs azathioprine after 3-6
cyclophosphamide
months
Combination Immunosuppressive or
glucocorticoids + Severe EGPA 6
cytotoxic agent
immunosuppressive
or cytotoxic agents MPA Cytotoxic agent 20

Severe GPA 17
Rituximab Alternative for
MPA 20
cyclophosphamide
Humanized
monoclonal
EGPA 21
antibody
against IL-5
Plasma exchange MPA with anti- In addition to conventional
20
GBM antibodies immunosuppression
Severe, life- 22
threatening
HCV-related

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mixed
cryoglobulinemic
vasculitis
Refractory
cutaneous
noninfectious 22
mixed
cryoglobulinemia
Combination HCV-related
pegylated mixed
22
interferon alpha cryoglobulinemic
and ribavirin vasculitis
HCV-related
mixed Since patients have
Low-dose IL-2 22
cryoglobulinemic decreased regulatory T-cells
vasculitis
Example: bortezomib for
Treatments
Type I Waldenstrom
directed against 19
cryoglobulinemia macroglobulinemiaassociated
underlying disorder
cryoglobulinemia
Table 1: Therapies in small-vessel vasculitides.
CBC = complete blood count, EGPA = eosinophilic granulomatosis with polyangiitis, GBM = glomerula
basement membrane , GPA =
granulomatosis with polyangiitis, IgAV = IgA vasculitis, LFT = liver function test, MPA = microscopic
polyangiitis, MTX = methotrexate

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.2 5

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

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receiving a combination of cyclophosphamide or rituximab and CCX168 versus placebo. Although

the data is promising, further research is needed.2 5

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.2 5 ,2 6

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.

References

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