MINI REVIEW

published: 09 May 2019

doi: 10.3389/fped.2019.00149

Vasculitis in Juvenile-Onset Systemic

Lupus Erythematosus
Eve M. D. Smith 1,2*† , Hanna Lythgoe 3† and Christian M. Hedrich 1,2
1
Department of Women and Children’s Health, Institute of Translational Medicine, University of Liverpool, Liverpool,
United Kingdom, 2 Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust, Liverpool,
United Kingdom, 3 St Helen’s and Knowsley Teaching Hospital NHS Trust, St Helens, United Kingdom

Juvenile-onset systemic lupus erythematosus (JSLE) is a rare, heterogeneous

multisystem autoimmune disease that can affect any organ, and present with diverse
clinical and serological manifestations. Vasculitis can be a feature of JSLE. It more
commonly presents as cutaneous vasculitis than visceral vasculitis, which can affect the
central nervous system, peripheral nervous system, lungs, gut, kidneys, heart, and large
vessels. The incidence and prevalence of vasculitis in JSLE has not been well described
to date. Symptoms of vasculitis can be non-specific and overlap with other features
of JSLE, requiring careful consideration for the diagnosis to be achieved and promptly
treated. Biopsies are often required to make a definitive diagnosis and differentiate JSLE
related vasculitis from other manifestations of JSLE, vasculopathies, and JSLE related
Edited by: antiphospholipid syndrome. Visceral vasculitis can be life threatening, and its presence
Claudio Pignata, at the time of JSLE diagnosis is associated with permanent organ damage, which
University of Naples Federico II, Italy
further highlights the importance of prompt recognition and treatment. This review will
Reviewed by:
Micaela Fredi,
focus on the presentation, diagnosis, management and outcomes of vasculitis in JSLE,
Azienda Socio Sanitaria Territoriale of highlighting gaps in the current evidence base.
the Spedali Civili of Brescia, Italy
Klaus Tenbrock, Keywords: childhood lupus, JSLE, vasculitis, cutaneous vasculitis, visceral vasculitis
RWTH Aachen Universität, Germany
*Correspondence:
Eve M. D. Smith INTRODUCTION
[email protected]
Vasculitis is a well-recognized feature of juvenile-onset systemic lupus erythematosus (JSLE).
† Joint first authors Despite this, there is a paucity of literature in this area. Vasculitis is defined by inflammatory
changes to vessel walls, affecting different types (arteries, veins, capillaries) and/or sizes of vessels
Specialty section: (large, medium, small) and a variety of sites (e.g., skin or visceral/internal organs). Symptoms
This article was submitted to of JSLE-related vasculitis can be non-specific (e.g., fatigue, fever, weight loss) and overlap with
Pediatric Immunology,
other features of the disease. Careful consideration is required to detect vasculitis, in particular
a section of the journal
Frontiers in Pediatrics
visceral vasculitis, which is less common but potentially life-threatening and requires prompt
and aggressive treatment. Histopathological assessment of tissue biopsies are the diagnostic gold
Received: 25 December 2018
standard, but patients may be classified with “probable vasculitis” based on clinical features
Accepted: 01 April 2019
Published: 09 May 2019
alone (1). This review will update readers on literature available and highlight gaps in the
current evidence-base.
Citation:
Smith EMD, Lythgoe H and
Vasculitis can be associated with disease flares in SLE (2–4), and is therefore integral part of
Hedrich CM (2019) Vasculitis in disease activity assessment tools, including the Systemic Lupus Activity Index (SLAM), British Isles
Juvenile-Onset Systemic Lupus Lupus Assessment Group (BILAG), and Systemic Lupus Activity Assessment Index 2000 (SLEDAI)
Erythematosus. Front. Pediatr. 7:149. (5). Patients with skin lesions that are not specific to SLE, such as cutaneous vasculitis, experience
doi: 10.3389/fped.2019.00149 significantly more active disease when compared to patients with lupus-specific skin lesions only

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Smith et al. Vasculitis in JSLE

(e.g., malar rash) (3). The presence of major organ vasculitis

at baseline influences the damage trajectory in JSLE patients,
and is associated with greater JSLE related permanent organ
damage (6).

CUTANEOUS VASCULITIS
Epidemiology
The exact prevalence of cutaneous vasculitis in JSLE is not
known. A study involving 179 patients with JSLE in the UK
found that 12% experienced cutaneous vasculitis (7). A Brazilian
study of 414 patients with SLE including 60 patients with JSLE
found that 21.6% of JSLE patients developed cutaneous vasculitis
compared with 15.4% of those with adult-onset disease (aSLE,
difference was not statistically significant) (8). A study involving
50 aSLE patients found individuals with cutaneous vasculitis to
be significantly younger when compared to patients who did not
develop vasculitis (26.5 vs. 30.3 years; p = 0.018) (9).

Associations With Other Organ

Manifestations of SLE
In aSLE cutaneous vasculitis has been shown to be associated
with lupus nephritis, hyopocomplementaemia (9, 10),
musculoskeletal, constitutional, cardiovascular manifestations
and Sjogren’s syndrome (9). In a further study involving 170
aSLE patients, patients with lupus nephritis were shown to be
at increased risk of cutaneous vasculitis (10). Lastly, cutaneous
FIGURE 1 | Skin manifestations in SLE and SLE-like disease. Small vessel
vasculitis may also be associated with neuropsychiatric lupus in vasculitis is a “common” feature in SLE-associated skin vasculitis. (A) Petechia
aSLE (11, 12). and ecchymosis are the result of capillary inflammation and red blood cell
extravasation; (B) palpable purpura are caused by inflammatory damage to
Clinical Presentation and Pathophysiology venules and/or arterioles; (C) ulcerations and tissue necrosis are the result of
In JSLE, skin manifestations can be divided into lupus- reduced perfusion; (D,E) chilblain lesions can manifest as chilblains (cold
induced sores) that may ulcerate, or painful and/or itchy bluish-reddish
specific (e.g., malar rash, discoid lupus, panniculitis) and lupus discoloration with swelling; (F) vasculopathy and finger atrophy in a patient
non-specific, including cutaneous vasculitis. SLE-associated with complement deficiency and secondary type I interferon upregulation.
cutaneous vasculitis affects small or medium-sized vessels in
the skin and subcutaneous tissues. It has a wide variety of
presentations that depend on the size of vessels involved and the medium-sized vessels (15). Cutaneous ulcers, nodules, digital
the extent of the vasculature affected. Cutaneous vasculitis most gangrene, livedo racemosa, and pyoderma-gangrenosum-like
frequently affects the lower and upper limbs (13). lesions are indicative of arterial involvement. Individuals affected
Vasculitis affecting the small vessels of the skin (arterioles, have higher probability of associated visceral vasculitis (16).
capillaries, post-capillary venules in the superficial, and mid- Lesions mimicking vasculitis can be caused by haemorrhagic and
dermis) usually presents with petechiae, purpura, and/or vaso-occlusive disease (17).
punctate vasculitis lesions. Petechiae are pinprick macules which Cutaneous vasculitis in JSLE is most commonly an immune-
do not blanch and are not palpable, resulting from capillary complex mediated small-vessel vasculitis (18) (Figure 2).
inflammation and red blood cell extravasation (Figure 1A) (14). Histological examination of lesions allows determination
Purpura are caused by inflammation of venules and/or arterioles of the size of vessel affected and immune cells driving
and consist of larger papules and plaques which do not blanch inflammation. Typical findings in lupus-related cutaneous
and become palpable as damage progresses (Figure 1B) (14). vasculitis are small (predominantly) and medium vessel (less
Punctate vasculitic lesions, ulcerations and tissue necrosis are commonly) neutrophilic vasculitis with IgG, IgM and/or
caused by reduced perfusion; shallow ulcers are caused when complement deposition at the basement membrane zone on
this affects the small vessels and deeper ulcers are caused when direct immunofluorescence examination (14).
medium-sized vessels are affected (Figure 1C).
Vasculitis of medium sized vessels in the dermis or Urticarial Vasculitis
subcutaneous layers may cause livedo reticularis, nodules, and/or Urticarial vasculitis is a recognized rare presentation of SLE
the aforementioned deep ulcers (15). Livedo reticularis is a presenting with hives lasting more than 24 h which may
small or widespread area of mottled, reticulated, reddish-purplish be entirely asymptomatic, pruritic, or painful. It usually
discoloration of the skin caused by compromised blood flow in resolves with hyperpigmentation or purpura (18, 20, 21).

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Smith et al. Vasculitis in JSLE

FIGURE 2 | Pro-inflammatory mechanisms in immune complex vasculitis. Immune complex vasculitis is not disease specific and can be a feature or leading symptom
of various disorders, including infections and autoimmune/inflammatory conditions. Immune complex deposition result in complement activation, which in turn
mediates local inflammation and oedema. This results in the recruitment of immune cells, including macrophages, neutrophils, and NK cells, which further contribute
to inflammation and tissue damage through inflammatory cytokine expression. Mast cell and basophil degranulation further amplifying tissue edema and mediates
vasodilation. Reproduced with permission from (19).

The incidence of JSLE-associated urticarial vasculitis is severe disease may require high-dose steroids, intravenous
unknown but there are several case reports (22–25). Urticarial immunoglobulins (IVIG), plasmapheresis, and/or cytotoxic
vasculitis is an immune-complex mediated small-vessel process treatments (18). Rituximab can be effective in some SLE patients
with leukocytoplastic changes on histology (14). The term with otherwise treatment refractory cutaneous vasculitis (15).
“hypocomplementemic urticarial vasculitis” describes the
coexistence of hypocomplementemia. Affected individuals
frequently exhibit anti-C1q antibodies, which may contribute to
VISCERAL VASCULITIS
altered immune complex processing and removal, and associated Visceral vasculitis is present in approximately 6% of aSLE patients
systemic involvement (21, 26, 27). (30). Reliable data on the prevalence in JSLE does not exist. It can
affect a number of organs including the central nervous system
Cryoglobulinaemic Vasculitis
(CNS), peripheral nervous system (PNS), lungs, gut, and more
Cutaneous vasculitis can present with cryoglobulinaemic
rarely the kidneys, heart, and large abdominal and/or thoracic
vasculitis, manifesting as purpuric lesions. IgM and C3
vessels (1). Visceral vasculitis usually manifests in the context of
containing immune complexes are present on direct
disease flares, and can coexist with cutaneous vasculitis (1).
immunofluorescence (Figure 2). Reports on cryoglobulinaemia
and vasculitis in children are limited (13, 28).
CNS Vasculitis
Diagnosis In patients developing neuropsychiatric manifestations
The diagnosis of SLE-associated cutaneous vasculitis is based on of SLE, CNS vasculitis should be considered. However,
clinical assessment. However, where practical and in cases of the contribution of CNS vasculitis in CNS lupus may be
uncertainty, biopsies should be taken to confirm the diagnosis limited (1). Indeed, other mechanisms including T-cell and
(15). This is of particular importance because cutaneous autoantibody-mediated damage to neuronal tissue underlie
vasculitis can be a sign of high disease activity, and may trigger the majority of neuropsychiatric manifestations (31, 32).
escalation of treatment (3). A study in aSLE patients found Historic postmortem studies estimated the incidence of CNS
that while 36% of patients with digital lesions were clinically vasculitis in SLE to be around 7–10% (33). In the context of
diagnosed with vasculitis, following dermatological/histological neuropsychiatric SLE it is particularly important to consider
review only 4% actually had confirmed vasculitis (29). Timing, the contribution of antiphospholipid syndrome (APS) (34). SLE
location, and appropriate depth of biopsy are important for vasculitis and APS are the result of very different underlying
diagnostic accuracy. Ideally, biopsies should be taken within 48 h pathologies that may require differential treatment. APS leads
of the lesions appearing, to avoid false negative results (14). to thrombo-occlusive vasculopathy, warranting treatment with
anticoagulation (e.g., heparin) and/or anti-aggregation (e.g.,
Treatment apsirin, clopidogrel) and/or intensive immunosuppressive
Topical and low-dose systemic corticosteroids, and/or therapy (e.g., corticosteroids, IVIG, rituximab or other
antimalarial agents (usually Hydroxychloroquine) are usually immunosuppressive therapy, plasma exchange) in the context
considered first-line treatment for cutaneous vasculitis. More of catastrophic APS (35). Case management is informed by the

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Smith et al. Vasculitis in JSLE

overall clinical picture and laboratory parameters. While APS is [pneumonitis: 0–14% (44), DAH: 2–5.4% of aSLE patients
characterized by the presence of persistent moderate-high titers (45, 46)]. Reports on the prevalence in JSLE currently do
of antiphospholipid antibodies associated with APS, SLE flares not exist. Both conditions may present with sudden-onset
with vasculitis are associated with leukopenia, anti-ds-DNA dyspnea, cough, fever, and hypoxia. Main clinical differences
antibodies and hypocomplementaemia (1). are pleuritic chest pain in acute lupus pneumonitis, and
Diagnosing CNS vasculitis requires a high index of suspicion, blood stained sputum or haemoptysis in DAH (47). However,
a systematic multi-disciplinary approach to diagnostic evaluation none of these necessarily have to be present. Radiological
with MRI imaging playing a central role, and thorough exclusion features of acute lupus pneumonitis on computed tomography
of the differential diagnoses. Investigations should be directed (CT) scan include an often bilateral diffuse acinar filling
at the exclusion of underlying conditions, including infections pattern in the lower lobes, and frequently coexists with
(the most common causes of secondary CNS vasculitis), pleural effusion in ∼50% of patients (48). In DAH, diffuse
drug-induced vasculitis, malignancy-associated vasculitis, alveolar opacities are characteristically seen on CT (Figure 3).
non-vasculitic inflammatory brain diseases, demyelinating Diffusion capacity for carbon monoxide (DLCO) is usually
disorders, and antibody-mediated inflammatory brain diseases increased due to the increased availability of hemoglobin
(36). The recent European evidence-based recommendations for within the alveoli (47). In both conditions, bronchoscopy and
diagnosis and treatment of JSLE (the SHARE initiative) imply bronchial alveolar lavage (BAL) are required (where the patient’s
that the initial diagnostic work-up of patients with suspected condition allows it) to exclude infectious differential diagnoses
neuropsychiatric JSLE should be performed as in patients or confirm the diagnosis. In DAH, aspirated fluid is bloody
without SLE, and lumbar puncture/cerebrospinal fluid analysis, and microscopically red blood cells and haemosiderin-laden
electroencephalogram, neuropsychological assessment of macrophages are present (45). Occasionally, an open lung
cognitive function, ophthalmologist review, nerve conductional biopsy may be needed to reach a diagnosis of acute lupus
studies, and MRI scanning should be considered. However, pneumonitis, with pathological findings including capillaritis,
SHARE did not provide specific recommendations for suspected diffuse alveolar damage and necrosis, cellular infiltrates, hyaline
SLE CNS vasculitis, but highlighted that a MRI scan cannot membranes, and sometimes alveolar hemorrhage (47). The
exclude neuropsychiatric lupus (37). Even with angiography, pathogenesis of both acute pulmonary pneumonitis and
false negative results are possible if the small vessels are DAH is incompletely understood, but thought to involve
predominantly involved (38), and brain biopsy may be required deposition of immune complexes in the alveolar septae
(1, 36, 39). Treatment usually involves high-dose glucocorticoids and blood vessels, and activation of complement leading
and cyclophosphamide, and may include plasmapheresis and to capillaritis, with immunohistological studies demonstrating
IVIG (40). immune complexes which include anti-ds-DNA antibodies and
C3 (49) (Figure 2).
Peripheral Nervous System Treatment of both acute lupus pneumonitis and DAH is based
(PNS) Involvement upon case reports and small case series. Early detection and
Peripheral neuropathies including mononeuritis multiplex treatment initiation are crucial. Patients are usually treated with
can be the result of vasculitis and ischemic damage in JSLE. broad-spectrum antibiotics, high-dose corticosteroids and/or
Mononeuritis multiplex is substantially more common in cyclophosphamide, and may need mechanical ventilation, IVIG
aSLE, when compared to JSLE patients. It is characterized and potentially plasma exchange (46, 47, 50). Both conditions are
clinically by symmetric, mild-to-moderately severe sensorimotor characterized by poor prognosis with associated mortality rates of
polyneuropathy (39). Nerve biopsies usually unveil axonal ∼50%. In those who survive, persistent interstitial infiltrates and
degeneration and/or depletion, which can be associated
with nonspecific vascular changes or chronic perivascular
inflammation. Occasionally, biopsies may show necrotising
vasculitis (41). As few as two cases of mononeuritis multiplex
have been described in JSLE patients to date (42, 43).
Other causes of mononeuritis multiplex in children include
Eosinophilic Granulomatosis with Polyangiitis (EGPA;
formerly known as Churg-Strauss syndrome), polyarteritis
nodosa, hypersensitivity/toxic vasculitides, diabetes mellitus,
and Tangier’s disease (an inborn error of metabolism) (43).
Treatment of PNS vasculitis in JSLE may involve high-dose
corticosteroids and cyclophosphamide, but is based upon aSLE
case series (43).

Pulmonary Vasculitis
Acute lupus pneumonitis and diffuse alveolar hemorrhage
(DAH) are the two most common pulmonary presentations FIGURE 3 | Diffuse alveolar hemorrhage in a 16-year-old SLE patient.
of vasculitis in SLE. Fortunately, both are relatively rare

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Smith et al. Vasculitis in JSLE

lung function abnormalities are frequently seen, with potential any vasculitis, but “only” 2/76 (3%) experienced renal vasculitis
for progression on to chronic interstitial pneumonitis (48). (13). Treatment of renal vasculitis in JSLE usually involves high-
dose corticosteroid and cyclophosphamide (39).
Gastrointestinal Vasculitis
Gastrointestinal symptoms are not uncommon in JSLE patients Cardiac Vasculitis
and may relate to either treatment-related side effects, infections Cardiac involvement in JSLE typically comprises pericarditis,
or JSLE disease activity. Lupus mesenteric vasculitis (LMV), cardiomegaly, valvulitis, and conduction abnormalities. SLE
characteristically presents with the clinical picture of an “acute is associated with an increase in coronary heart disease risk,
abdomen” with sudden onset, diffuse and severe abdominal and a 50-fold increased risk of myocardial infarction (62).
pain which can be associated with nausea, rectal bleeding, Coronary artery vasculitis occurs in both JSLE and adult SLE,
and vomiting (51). Of note, corticosteroids and/or other but is rare across all age groups (63–66). Clinical differentiation
immunosuppressive treatments may mask symptoms and result of “classical” coronary artery disease from coronary arteritis is
in diagnostic and therapeutic delay. The estimated prevalence difficult and requires angiography. Coronary vasculitis usually
of LMV ranges between 0.2 and 9.7% among aSLE patients, results in segments of tapered narrowing, coronary ectasia,
making up for ∼29–65% of aSLE patients presenting with an and/or aneurysms. Histopathological examination reveals
acute abdomen (51). In a Taiwanese study comparing aSLE and thrombosis, deposition of immune complexes, infiltration of
JSLE patients presenting with acute abdominal pain, LMV was lymphocytes/neutrophils, and associated fibrinoid necrosis (64).
the most common cause of admission in the JSLE patients. A retrospective study assessed findings and outcomes in JSLE
Furthermore, LMV was significantly more prevalent in JSLE patients who were referred for echocardiography during their
patients when compared to the aSLE group [12/38 (31.6%) vs. initial presentation for either tachycardia or a new murmur. Four
15/1081 (3.9%); p = 0.016], occurring in JSLE patients with patients demonstrated coronary artery dilatation (suggestive
high disease activity (SLE disease activity index, SLEDAI scores of coronary arteritis) which resolved once JSLE was treated,
>8). Children were also found to be more likely to experience leading the authors to conclude that coronary arteritis may be
recurrent episodes of LMV (39.1% vs. 14.8%; p = 0.009) (52). In more common in JSLE than previously appreciated (63). In
contrast to this study, other studies have reported LMV in JSLE a retrospective Taiwanese study looking at cardiopulmonary
patients with low SLEDAI scores (53, 54). involvement in JSLE over a 20-year period, 6/157 patients
Bowel ischemia secondary to LMV can result in perforation, exhibited coronary artery abnormalities, including vascular
hemorrhage and high mortality rates of up to 50%. The dilation, aneurysms, vasculitis, and stenosis (67). With SLE itself
importance of early laparotomy was emphasized by a study being a risk factor for cardiovascular disease, further studies are
demonstrating significantly higher survival in patients who required longitudinally evaluating the impact of echocardiogram
underwent early intervention (0/33 deaths when laparotomy surveillance and treatment of coronary vasculitis on long-term
was undertaken within 24–48 h vs. 10/11 when laparotomy was cardiovascular risk.
performed after 48 h) (55). LMV most frequently affects the
superior mesenteric artery that supplies the ileum and jejunum Aortic Vasculitis
(80–85%), with the rectum less frequently affected (14%), and Vasculitis in SLE predominantly affects medium and small
gastric involvement being very uncommon (56). Abdominal CT vessels. Aortic (large vessel) involvement has been reported in
is a useful investigation for diagnosing LMV. It is characterized small case series and collated within a meta-analysis of 35 cases,
by the presence of dilated bowels, target lesions (abnormal bowel of which 5/35 patients developed SLE in childhood, with aortic
wall enhancement), comb signs (engorgement of mesenteric involvement manifesting between the ages of 23 and 38 years
vessels), bowel wall thickening, and ascites (57). Histology old. Thoracic aneurysms correlated with dissection and cystic
may demonstrate arteritis, venulitis, immune complex, C3, and medial degeneration, while abdominal lesions correlated with
fibrinogen deposition, inflammatory cell infiltration, necrosis, atherosclerosis. A total of 21/35 (60%) cases required surgery
and thrombosis of vessels affected (58). No randomized trials and death was observed in 11/35 (31.4%) patients. Thoracic
are available investigating treatment and associated outcomes lesions resulted in higher mortality rates than abdominal lesions
in LMV. Currently, treatment involves “bowel rest,” intravenous (68). Treatment of aortic vasculitis includes corticosteroids,
corticosteroids, and cyclophosphamide in severe cases (39, 53, 58, cyclophosphamide and blood pressure control. Surgery may be
59). Successful use of Rituximab has also been described in case required in some cases (39, 69). See Table 1 for a summary of
series (58). the prevalence of different vasculitic manifestations and the main
treatments used.
Renal Vasculitis
The prevalence of renal vasculitis in JSLE has not been SLE VASCULITIS vs.
investigated. In aSLE, vasculitic changes affecting the larger ANTI-PHOSPHOLIPID SYNDROME
arterioles and small kidney arteries may (rarely) accompany
proliferative lupus nephritis (60). Focal segmental necrotizing In aSLE patients, APS is associated with cutaneous vasculitis
glomerulonephritis with fibrinoid necrosis can be seen, and may (30, 70). Differentiating between vasculopathy/thrombosis and
lead to rapidly progressive renal failure (61). In a Spanish study vasculitis in SLE-associated APS can be difficult. However, it
evaluating the prevalence and clinical characteristics of vasculitis is of utmost importance as treatment approaches are different
in a cohort of 670 aSLE patients, 76/670 (11%) patients exhibited (anti-inflammatory treatment for vasculitis vs. anti-thrombotic

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Smith et al. Vasculitis in JSLE

TABLE 1 | Prevalence and treatment of different vasculitc manifestations in JSLE.

Vasculitic manifestation Prevalence in JSLE Usual treatments

Cutaneous vasculitis 12–21.6% (7, 8) • Mild—moderate disease/first line treatments—topical and low-dose systemic corticosteroids,
and/or antimalarial agents.
• More severe disease/second line treatment—high-dose steroids, IVIG, plasmapheresis and/or
cytotoxic treatments (18). Rituximab is an option with otherwise treatment refractory cutaneous
vasculitis (15).
CNS vasculitis NA High-dose glucocorticoids and cyclophosphamide, and may require plasmapheresis and IVIG (40).
PNS vasculitis NA High-dose corticosteroids and cyclophosphamide (43).
Pulmonary vasculitis NA Broad-spectrum antibiotics, high-dose corticosteroids, and/or cyclophosphamide. May need
mechanical ventilation, IVIG, and potentially plasma exchange (46, 47, 50).
Gastrointestinal vasculitis 31.6%* (52) Bowel rest, intravenous corticosteroids, and cyclophosphamide in severe cases (39, 53, 58, 59).
Use of Rituximab has also been described in case series (58).
Aortic vasculitis NA Corticosteroids, cyclophosphamide, and blood pressure control. Surgery may be required in some
cases (39, 69).

*31.6% of all JSLE patients presenting with an acute abdomen (52). JSLE, juvenile systemic lupus erythematosus; NA, not available; IVIG, intravenous immunoglobulin.

therapy for vasculopathy) (71). As mentioned above, histological upregulation (Figures 1D,E). Aicardi-Goutières syndrome,
assessment of cutaneous lesions can differentiate vasculitis from familial chilblain Lupus and other type I interferonopathies
cutaneous manifestations of APS. This is particularly relevant in demonstrate vasculopathy, immune complex deposition, and
the context of ischaemic lesions which are difficult to differentiate lymphocytic vasculitis on skin biopsy (73, 77). Indeed, in severe
clinically. Where biopsy is not practical, it is important to cases peripheral vasculopathy can result in atrophy and even
consider the overall context of the presentation and potential digital auto-amputation in some patients (Figure 1F) (72). This
evidence of other APS-related manifestations such as thrombosis. has particularly been reported in spondyloenchondrodysplasia
In cases with extra-cutaneous evidence of SLE disease flare with immune dysregulation (SPENCDI), a rare immuno-osseous
or systemic vasculitis, immunosuppressive treatment should be dysplasia caused by biallelic mutations in the ACP5 gene (72) and
favored (13). Stimulator of interferon genes (STING)-associated vasculopathy
with onset in infancy (SAVI) that includes heterozygous
VASCULITIS IN THE CONTEXT OF mutations in TMEM173 (78). Both disorders, in addition
to increased activation of type I interferon responses, share
“SLE-LIKE” DISEASE clinical features with “classical” SLE including neurological and
Primary type-I interferonopathies are a group of Mendelian immune manifestations in SPENCDI, and pyrexia, vasculitis,
disorders that share the upregulation of type-I interferon microthrombotic angiopathy, and interstitial lung disease in
signaling as key pathophysiological feature. These monogenic SAVI (78).
diseases include (but are not limited to) Aicardi-Goutières
syndrome and syndromic forms of SLE-like disease (72, 73). A CONCLUSIONS
common clinical feature across type I interferonopathies is skin
involvement with chilblain lesions and/or vasculitis as well as JSLE is a rare, heterogeneous and complex condition. This
systemic vasculopathy and/or vasculitis, all of which can also translates to difficulty in the recognition and management of
been seen in patients with “classical” JSLE. Though very rare and disease, particularly when less common manifestations, such
not fully reflecting the molecular and clinical phenotype of JSLE, as vasculitis are involved. Cutaneous is more common than
primary type I interferonopathies and their pathophysiology are visceral vasculitis, and more prevalent in JSLE when compared
useful “models” for “classical” JSLE, which is also frequently to adult-onset disease. Reports on visceral vasculitis in JSLE
characterized by type I interferon activation. Furthermore, a are limited, which may be a reflection of difficulty in achieving
number of other SLE-like conditions, including complement the diagnosis and differentiating vasculitis from other JSLE-
deficiencies, are characterized by type I interferon responses that related complications. Early recognition and treatment of SLE-
are not primarily caused by mutations in positive or negative associated vasculitis are paramount to optimizing outcomes and
regulators of interferons, but the result of immune complex preventing tissue and organ damage. Collaborative approaches
accumulation, another key contributor to the pathophysiology of are required to improve our knowledge on the demographics,
SLE (74, 75). clinical presentations, disease courses, and treatment options in
Aicardi-Goutières syndrome manifests with progressive JSLE-associated vasculitis.
encephalopathy that is associated with calcification of the
basal ganglia, mimicking congenital viral infections (76). AUTHOR CONTRIBUTIONS
Clinical skin manifestations include chilblain lesions, which
are the name giving feature of familial chilblain Lupus, another ES, HL, and CH all participated in review and
monogenic SLE-like disorder characterized by type I interferon interpretation of the literature. All authors were involved

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Smith et al. Vasculitis in JSLE

in drafting the manuscript and revising it critically ACKNOWLEDGMENTS

for important intellectual content. They have also
all read and given final approval of the version to We thank the patients who have consented for use of their clinical
be published. images for publication.

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73. Hedrich CM, Fiebig B, Hauck FH, Sallmann S, Hahn G, Pfeiffer C, et al. Conflict of Interest Statement: CH’s work is supported by
Chilblain lupus erythematosus–a review of literature. Clin Rheumatol. (2008) the Fritz-Thyssen Foundation (research grant: SLE), Novartis
27:949–54. doi: 10.1007/s10067-008-0942-9 Pharmaceuticals (research grant: psoriasis), LUPUS UK (research grant: SLE),
74. Hedrich CM. Shaping the spectrum - From autoinflammation the Hugh Greenwood Legacy Fund (research grant: bronchial inflammation), the
to autoimmunity. Clin Immunol. (2016) 165:21–8. Michael Davie Research Foundation (research grant: CNO/CRMO), and the FAIR
doi: 10.1016/j.clim.2016.03.002 charity (research grants: bronchial inflammation and SLE). CH received honoraria
75. Tsokos GC, Lo MS, Costa Reis P, Sullivan KE. New insights into the for advisory board activities and presentations from Novartis pharmaceuticals and
immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol. Roche (systemic autoinflammatory disease).
(2016) 12:716–30. doi: 10.1038/nrrheum.2016.186
76. Goutieres F, Aicardi J, Barth PG, Lebon P. Aicardi-Goutieres syndrome: an The remaining authors declare that the research was conducted in the absence of
update and results of interferon-alpha studies. Ann Neurol. (1998) 44:900–7. any commercial or financial relationships that could be construed as a potential
doi: 10.1002/ana.410440608 conflict of interest.
77. Kolivras A, Aeby A, Crow YJ, Rice GI, Sass U, Andre J.
Cutaneous histopathological findings of Aicardi-Goutieres syndrome, Copyright © 2019 Smith, Lythgoe and Hedrich. This is an open-access article
overlap with chilblain lupus. J Cutan Pathol. (2008) 35:774–8. distributed under the terms of the Creative Commons Attribution License (CC BY).
doi: 10.1111/j.1600-0560.2007.00900.x The use, distribution or reproduction in other forums is permitted, provided the
78. Omoyinmi E, Melo Gomes S, Nanthapisal S, Woo P, Standing original author(s) and the copyright owner(s) are credited and that the original
A, Eleftheriou D, et al. Stimulator of interferon genes-associated publication in this journal is cited, in accordance with accepted academic practice.
vasculitis of infancy. Arthritis Rheumatol. (2015) 67:808. doi: 10.1002/ No use, distribution or reproduction is permitted which does not comply with these
art.38998 terms.

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