Mimics of Vasculitis

Ernest Maningding; Tanaz A. Kermani

Disclosures

Rheumatology. 2021;60(1):34-47. 

In This Article

Vasculopathies

Vasculopathies are an important mimic of large and medium vessel vasculitis (Table 1). They can present with stroke, infarction, arterial occlusions and arterial dissections (Figure 2). Unlike systemic vasculitis, vasculopathies do not usually present with systemic features or elevated inflammatory markers. There are hereditary and non-hereditary causes. Immunosuppression is not thought to alter the underlying clinical course of these conditions.

Figure 2.

Vasculopathies. Vascular abnormalities in patients with vasculopathies including (A) beading of the right renal artery on conventional angiography in a patient with fibromuscular dysplasia, and, computed tomography angiography showing dissection of (B) the distal abdominal aorta and (C) the right common iliac artery.

Hereditary Conditions

Several genetic causes, which primarily affect the connective tissue matrix (except neurofibromatosis type 1), can cause non-inflammatory vascular abnormalities and are important to consider in the differential diagnosis of large and medium vessel vasculitis.[60–65]

Marfan's syndrome is an autosomal dominant condition characterized by mutations in the fibrillin-1 (FBN1) gene that encodes the connective tissue protein fibrillin-1.[61] It can cause large vessel manifestations, including aortic root dilatation or dissection.[61] Diagnosis is based on the 2010 revised Ghent nosology criteria, which includes aortic root dilation or dissection, mutations in the FBN1 gene and lens displacement (i.e. ectopia lentis) as principal features.[61] Other criteria include typical Marfanoid body features.[61]

Vascular Ehlers–Danlos syndrome (VEDS; previously EDS type IV) is an autosomal dominant disorder characterized by mutations in the type III procollagen gene (COL3A1) resulting in abnormal procollagen production.[63,65] In contrast to other EDS types, VEDS is characterized by the absence of large joint hypermobility, although smaller joints may be involved.[63,65] Perforation of visceral organs such as the sigmoid colon or uterus is a feature.[63,65,66] VEDS can affect the descending thoracic aorta, abdominal aorta and renal, mesenteric, iliac and femoral arteries, with life threatening manifestations including dissections and rupture.[63,65,66] Dissections of vertebral arteries and carotid arteries (intra- and extracranial) have also been described.[63,65,66] Another feature, carotid-cavernous sinus fistula, is a major criteria for this diagnosis.[63,65] A family history of arterial rupture/dissection in individuals <40 years of age or unexplained intestinal spontaneous pneumothorax should raise concern for this diagnosis.[63]

Loeys–Dietz syndrome is an autosomal dominant connective tissue disorder that results from mutations in the TGF-β receptor genes (TGFBR1, TGFBR2), although mutations in SMAD3 and TGFB2 in association with Loeys–Dietz syndrome phenotypes have also been reported.[67] Loeys-Dietz syndrome is characterized by the triad of arterial tortuosity and aneurysms (particularly of the aorta), hypertelorism (i.e. widely spaced eyes) and bifid uvula or cleft palate, each occurring in >80% of patients in a previously described cohort.[60,67] Vascular manifestations include aortic dilatation and dissection, aneurysms of the branches of the aorta and arterial tortuosity (most commonly of the head and neck vessels).[60,62,67]

Neurofibromatosis type 1 (NF-1; von Recklinghausen disease) is an autosomal dominant disorder characterized by mutations in the neurofibromatosis type 1 (NF1) gene that encodes the protein neurofibromin. Updated 1997 National Institutes of Health diagnostic criteria include the presence of at least two clinical features, including café-au-lait macules, neurofibromas, axillary or inguinal freckling and a first-degree relative with NF-1, among others.[68] Vasculopathy in NF-1 includes stenosis, aneurysms and arteriovenous malformations, particularly in the aortic, renal, carotid/vertebral and mesenteric circulations, but also in other vascular beds.[64,69]

Fibromuscular Dysplasia (FMD)

FMD is an idiopathic, segmental, non-atherosclerotic arterial disease characterized by abnormal growth of predominantly medium-sized arteries, particularly in the kidneys and brain.[70] It most commonly affects the renal and extracranial carotid and vertebral arteries. The resulting strokes, transient ischaemic attacks, dissections and/or renal infarctions, especially in younger individuals, may raise concern for vasculitis.

A recent collaborative effort between the European Society of Hypertension and the Society for Vascular Medicine included data from large registries of patients with FMD from the USA (1885 patients) and Europe/international (609 patients).[70] In both registries, the majority of patients are females (95% USA, 83% European/international) with a mean age at diagnosis of 46–53 years.[70] The most common presenting symptoms were hypertension (67% USA, 74% European/international), headache (69%, data only analysed for the US registry), pulsatile tinnitus (23%, data only analysed for the US registry), stroke (10% USA, 8% European/international) and transient ischaemic attack (12% USA, 4% European/international).[70]

Imaging findings (Table 3) included multifocal lesions in >70% and multivessel involvement (55% in the US registry, 31% European/international registry).[70] In the US registry, cerebrovascular involvement was most common (80%) followed by renal (66%), whereas in the European/international registry renal artery involvement was most common (92%) followed by cerebrovascular (59%) (Table 3).[70] Aortic aneurysms were noted in 11% (data only analysed for the US registry).[70] Arterial dissections were noted in 28% of the US cohort and 3% of the European/international cohort.[70]

FMD should be considered in patients (especially women) with early-onset (<35 years of age) or resistant hypertension, epigastric bruits, severe and recurrent headaches, pulsatile tinnitus or a history of ischaemic disease, including transient ischaemic attack or stroke.[70] While aortic dissections can occur in large vessel vasculitis, dissections of primary/secondary branches of the aorta should raise concern for vasculopathy over vasculitis.

Segmental Arterial Mediolysis (SAM)

SAM is a rare but serious vasculopathy of unknown aetiology that can present with acute intra-abdominal manifestations like haemorrhage and ischaemia, mimicking the medium vessel vasculitis polyarteritis nodosa (PAN).[71–78] The condition is characterized by lysis of the arterial medial layer from the adventitia, which results in dissection, aneurysm, stenosis and occlusion.[71,72,75–77] Unlike FMD, which predominantly affects women, there is no sex predominance in SAM.[71–79] It typically affects older individuals in the 40–60 year age group.[71–79]

Patients present with abdominal and flank pain, but life-threatening presentations including abdominal haemorrhage and haemorrhagic shock can occur in up to 50% of individuals.[71,72,74–76] Headache, aphasia and other neurologic manifestations have been reported in ~12% of individuals.[74–76] Patients with SAM often lack the constitutional symptoms, cutaneous manifestations and arthralgias that are present in patients with PAN.[73,74] In a literature review of 143 cases of SAM, ESR was elevated in 23% of 33 patients and CRP was elevated in 67% of 51 patients, but values used to define these were not provided.[71] As opposed to PAN, which is a necrotizing panarteritis, the histopathologic findings of SAM are of vacuolar degeneration of smooth muscle cells in the media, with fibrin deposition at the adventitial medial junction without inflammatory infiltrates.[77,78]

While any vessel may be affected, abdominal visceral arteries are most frequently involved (Table 3).[71,72] In a retrospective single-centre cohort of 111 patients with SAM, the coeliac (46%), superior mesenteric (46%) and renal arteries (47%) were most frequently affected (Table 3).[72] The most common abnormalities at the arterial beds were dissection (86%), followed by aneurysm (57%), beading (28%) or occlusion (19%) (Table 3).[72] As in FMD, multivessel involvement was common (Table 3).[72] In a literature review of 143 cases of SAM, superior mesenteric artery involvement was most frequently noted (53%), followed by hepatic (45%), coeliac (36%), renal (26%), splenic (25%) and inferior mesenteric artery (11%) (Table 3).[71] Cerebrovascular involvement was also present (13%).[71] Multiple arterial involvement was present in 62% of patients. Aneurysm formation was most commonly reported (76%), followed by dissection (61%), rupture (46%), stenosis (19%) and occlusion (17%) (Table 3).[71]

The overall clinical picture, including acute presentation in the absence of other systemic manifestations, markers of inflammation (if normal), imaging findings (especially predominantly dissections rather than micro-aneurysms and stenosis) and histopathology, if available, can be useful in distinguishing SAM from PAN.

Reversible Cerebral Vasoconstrictive Syndrome (RCVS)

RCVS is an important mimic of PACNS. RCVS is characterized by thunderclap headaches (TCHs) with or without neurologic deficits and by diffuse, segmental vasoconstrictions of the cerebral arteries, which resolve spontaneously.[80–82] Manifestations may include stroke, cerebral oedema or seizure.[80–82] Risk factors for RCVS include vasoconstrictive triggers, including vasoactive medications, illicit drugs, post-partum state, sexual intercourse, exertion or emotional states.[80–82] There are several useful distinguishing clinical, laboratory and imaging findings that can distinguish RCVS from PACNS.[81,82] The presence of a TCH is the most useful, being reported in 81–94% of patients with RCVS compared with only 3–6% with PACNS.[81,82] Furthermore, recurrent TCHs is very consistent with RCVS (85–87% patients) compared with PACNS (0–2%).[81,82] In one study, 88% with RCVS had a normal cerebrospinal fluid (CSF; <5 cells/mm3 and protein <80 mg/dl) compared with 26% with PACNS.[82] In another study where a lower cut-off value of 45 mg/dl for CSF protein was used, normal CSF was noted in 49% with RCVS compared with 30% with PACNS.[82] A normal brain MRI is uncommon in patients with PACNS (0%) but has been reported in 30–62% with RCVS.[81,82] Other imaging findings seen in RCVS are posterior reversible encephalopathy syndrome (8–28% vs 0–1% for PACNS) and subarachnoid haemorrhage (27–33% vs 2–16% for PACNS).[81,82] Abnormal cerebral angiography was noted in all patients with RCVS compared with 56–77% patients with PACNS, with smooth, tapered narrowing followed by abnormal dilated segments (beading) being most common.[81,82] Angiographic vasoconstriction in RCVS may be delayed by up to 3 weeks.

A diagnostic prediction score has been developed using the following variables: recurrent/single TCH (5 points), intracranial carotid artery involvement (−2 points), vasoconstrictive trigger (1 point), female sex (1 point) and subarachnoid haemorrhage (1 point). A score ≥5 yielded 90% sensitivity and 99% specificity for RCVS, while a score ≤2 excluded RCVS with 85% sensitivity and 100% specificity.[83]

Summary

Vasculopathies are important to consider in the evaluation of suspected large and medium vessel vasculitis. A combination of clinical history and laboratory and imaging studies are often needed to distinguish vasculopathies from vasculitis. Where possible, histopathology can establish the diagnosis. It is also recommended that the diagnostic studies, including imaging studies and histopathology, be reviewed by a radiologist or pathologist with expertise in vasculitis, including outside review when necessary to establish the diagnosis.

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