Review

Mimics of primary systemic vasculitides

The primary systemic vasculitides are well defined entities, but a number of diseases can imitate their clinical, laboratory, radiographic and histological features. The importance of awareness and recognition of these conditions lies in the initiation of correct therapy for the specific disease process and in the avoidance of unnecessary and potentially harmful immunosuppression. In this review, we have provided a comprehensive, but by no means complete, review of some of the imitators of the primary vasculitides. Every attempt must be made to establish the diagnosis before indicated therapy is commenced. This will help to avoid therapeutic misadventures when managing patients with these complex diseases.

KEYWORDS: differential diagnosis n mimics n vasculitis Atul Khasnis & Eamonn Molloy† †Author for correspondence: Medscape: Continuing Medical Education Online Department of Rheumatology, Orthopedic and Rheumatology This activity has been planned and implemented in accordance with the Essential Areas and policies of Institute, Cleveland Clinic, the Accreditation Council for Continuing Medical Education through the joint sponsorship of 9500 Euclid Avenue A50, MedscapeCME and (Future Medicine Ltd). Cleveland, OH 44195, USA MedscapeCME is accredited by the Accreditation Council for Continuing Medical Education Tel.: +1 216 444 8834; (ACCME) to provide continuing medical education for physicians. Fax: +1 216 445 7569; MedscapeCME designates this educational activity for a maximum of 0.75 AMA PRA Category 1 [email protected] Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at http://cme.medscape.com/ CME/futuremedicine; (4) view/print certificate.

Learning objectives Upon completion of this activity, participants should be able to: n Identify reasons for distinguishing mimics from true primary vasculitides n Describe the difference between vasculitis associated with syphilis and TB n List inherited conditions that can be mimics of primary vasculitides n Identify drugs and toxins associated with mimics of primary vasculitides n Describe clinical features of antiphospholipid syndrome

Financial & competing interests disclosure Editor Elisa Manzotti, Editorial Director, Future Science Group, London, UK. Disclosure: Elisa Manzotti has disclosed no relevant financial relationships. Author & Credentials Atul Khasnis, MD, Department of Rheumatology, Orthopedic and Rheumatology Institute, Cleveland Clinic, OH, USA Disclosure: Atul Khasnis has disclosed no relevant financial relationships. Eamonn Molloy, MD, MPH, Department of Rheumatology, Orthopedic and Rheumatology Institute, Cleveland Clinic, OH, USA Disclosure: Eamonn Molloy has disclosed no relevant financial relationships. CME Author Désirée Lie, MD, MSEd, Clinical Professor, Department of Family Medicine, University of California, Irvine, CA, part of USA; Director, Division of Faculty Development, UCI Medical Center, Irvine, CA, USA Disclosure: Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships.

10.2217/IJR.09.37 © 2009 Future Medicine Ltd Int. J. Clin. Rheumatol. (2009) 4(5), 597–609 ISSN 1758-4280 597 Review Khasnis & Molloy Mimics of primary systemic vasculitides Review

The vasculitides are defined by histological Syphilis inflammation of blood vessels in various tissues. Syphilis is invoked most commonly in the dif- They are classified as primary or secondary and ferential diagnosis of the aortic and aortic branch have their identifiable causes such as infectious involvement of the large vessel vasculitides. agents, drug reactions, systemic autoimmune dis- Cardiovascular syphilis occurs as part of the eases or malignancy. However, in addition, there tertiary manifestations of syphilis, caused by the are myriad conditions that can mimic true vas- spirochete Treponema pallidum. Cardiovascular culitis clinically, on laboratory testing, on radi- syphilis presents with inflammation of the aorta ography and at histopathology. Distinguishing resulting in aortic wall thickening, aneurysm vascular inflammation from nonvasculitic dis- formation, aortic valvular incompetence and orders has significant therapeutic implications, coronary artery disease. Approximately 11% of since immunosuppressive therapy directed at the untreated patients progress to develop cardio- primary systemic vasculitides may be associated vascular syphilis [1]. Aortic aneurysms occur with significant toxicities, and a failure to recog- most commonly in the ascending aorta where nize a vasculitis mimic may delay the initiation they may be symptomatic (from pressure on the of effective therapy for the disorder in question. surrounding structures) but less commonly they For purposes of this review, the term ‘mimic’ will can affect the descending thoracic and abdomi- include conditions that may or may not result nal aorta where they are often asymptomatic. in true vascular inflammation (‘vasculitis’) but The prevalence of abdominal aortic aneurysms present similarly to the defined primary systemic varies and most commonly involves the supra- vasculitides. We will discuss the key categories renal aorta. Rare reported manifestations of of disease that may mimic the primary systemic cardiovascular syphilis include involvement of vasculitides, focusing on a few important entities the pulmonary arteries and great vessels arising in each category; however, a detailed discussion from the aortic arch, hepatic artery and renal of all potential vasculitis mimics is beyond the artery [2]. Histopathologically, syphilitic aorti- scope of this article. tis is characterized by the collection of lympho­ cytes and plasma cells in the perivascular spaces Infections surrounding the vasa vasorum in the adventitia Diseases caused by infectious agents can mimic of the root of the aorta, a lack of ‘skip lesions’, any of the primary systemic vasculitides and plasma cell microabscesses and the rare occur- may affect vessels of all sizes. Acute bacterial or rence of fibrinoid necrosis and sclerotic lesions viral infections or chronic infections with bac- (sometimes mildly inflammatory) with or teria, viruses, mycobacteria, fungi or parasites without thrombosis [3]. The sensitivity of the may mimic vasculitis. While in many cases the Venereal Disease Research Laboratory (VDRL) infectious agents discussed can cause a true sec- test for cardiovascular syphilis is 73% and for ondary vasculitis rather than being a vasculitis the fluorescent treponemal antibody (FTA-ABS) mimic per se, they remain a critical exclusion in test sensitivity is 96%. Co-existent neuro­syphilis the evaluation of a patient with suspected pri- may provide a clue to the diagnosis. Syphilis can mary systemic vasculitis, not least because of the also rarely confound the diagnosis of a small potential of causing significant harm to patients vessel vasculitic process affecting the lungs. with active infection if they are inappropriately Syphilitic involvement of the lungs resulting in treated with immunosuppressive therapy. For necrotizing vasculitis with gumma in the pul- example, syphilitic affection of the aorta results monary parenchyma presenting as mass lesions in true vascular inflammation but it is still has been reported [4]. considered to ‘mimic’ the primary large vessel vasculitides and is treated differently. The clini- Mycobacterial infections cal, imaging and histopathological appearance TB (caused by Mycobacterium tuberculosis) can of vascular disease caused by infectious agents result in granulomatous arteritis leading to vessel may resemble the primary systemic vasculitides. wall thickening, aneurysm formation and ste- However, infectious agents have been listed here noses that can affect the aorta and its branches, as a ‘mimic’ since they are distinct entities in thereby mimicking large vessel vasculitis [5]. terms of well-defined etiologies, pathogenic Moreover, vasculitis may be seen at histopa- mechanisms and therapeutic approaches. The thology in the region of tuberculous granulo- presence of true vascular inflammation in these mas. Involvement of the descending aorta or conditions has also led to their being classified renal artery may resemble Takayasu’s arteritis as ‘secondary’ vasculitides. (TAK), especially in clinical settings where this

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pattern of aortic involvement from TAK is com- ‘granular’ immune complex deposits (immuno- mon [6]. Four types of TB arterial disease have globulin and complement) on the subepithelial been described: or subendothelial glomerular basement mem- ƒƒMiliary TB of the intima brane seen by electron microscopy and immuno- fluorescence[14] in contrast with GN, occurring ƒƒTB polyps attached to the intima from primary systemic small vessel vasculitides, ƒƒTB involving the vascular wall such as Wegener’s granulomatosis (WG) and microscopic polyangiitis, which are classically ƒƒTB aneurysm [7] associated with few to absent immune deposits Tuberculous aortitis may be differentiated (referred to as pauci-immune GN). from TAK owing to its tendency to cause ero- sion of the vessel wall with the formation of Viral hepatitis true or false aneurysms, particularly affecting Hepatitis A infection is rarely associated with the descending thoracic and abdominal aorta in cutaneous vasculitis and cryoglobulinemia [15]. contrast with arterial stenoses that are more typi- Hepatitis B (HBV), and less commonly, Hepatitis cal of TAK [8]. The diagnosis may be suggested C viruses (HCV), are well known to cause a by the co-existence of extrapulmonary TB. medium vessel vasculitis resembling polyarteritis Atypical mycobacteria (Mycobacterium avium nodosa (PAN). The strict definition of PAN as a intracellulare) have been reported to result in primary vasculitis at this time excludes the PAN- granulomatous and vascular pulmonary disease like diseases caused by viruses [16]. In a study of and positive antineutrophil cytoplasmic anti- 115 patients with HBV-associated PAN [17], renal bodies (ANCA). The ANCA in these patients involvement was always accompanied by vasculi- are often of the perinuclear (P-ANCA) pattern tis in the absence of GN. ANCA was negative in and are reactive to nonmyeloperoxidase (MPO) all cases. Relapses were rare and never occurred antigens [9]; however, MPO-reactive P-ANCA after seroconversion. A combination of antiviral have been reported in this situation [10]. therapy and immunosuppression resulted in the best outcomes. The major cause of death was Infective endocarditis gastrointestinal tract involvement [17]. Orchitis, Infective endocarditis (IE) has the ability to gastrointestinal and renal artery involvement mimic the entire spectrum of vasculitides clini- resulting in hypertension are common in HBV- cally, radiologically and at histopathology. IE associated PAN, whereas cutaneous and pulmo- can cause mycotic (infected) aneurysms affect- nary involvement is rare [18]. HCV can also cause ing the aorta and its branches and pulmonary cryoglobulinemic vasculitis – an immune com- arteries, as well as small vessel inflammation plex-mediated small vessel disease (purpura and in various organs either from direct infection GN) with mixed cryoglobulinemia. In a study (septic vasculitis) or through immune complex- of 1200 patients with chronic HCV infection, mediated (purpura, glomerulonephritis [GN]) cryoglobulins were observed in 40% of patients or embolic mechanisms. The presence of cutane- and vasculitis developed in 1% of patients (all ous findings, such as ‘splinter hemorrhages’, may with cryoglobulins) [19]. The histopathology also be seen in both IE and small vessel vasculi- of cutaneous vasculitis from HCV-associated tis. In one series of patients who underwent sur- cryoglobulinemia shows leukocytoclastic vas- gical repair for aortic aneurysms, the prevalence culitis with inflammatory infiltrates and, in of mycotic aneurysms was 2.3% [11]. Mycotic some cases, fibrinoid necrosis of the arteriolar aneurysms can occur in any arterial location, walls and luminal thrombi. Renal involvement resulting in symptoms related to organ-specific from mixed cryoglobulinemia classically results or multiorgan ischemia and inflammation. The in Type I membranoproliferative GN. Other aneurysms occur at major branches of the aorta, described pathologies include focal and mesan- most frequently the femoral artery and abdomi- gioproliferative GN, membranous GN and nal aorta, followed by the thoraco–abdominal thrombotic microangiopathy [20]. and thoracic aorta [12]. Transesophageal echo- cardiography can provide valuable information Progressive multifocal by visualizing IE affecting the cardiac structures, leukoencephalopathy as well as the root of the aorta and ascending Progressive multifocal leukoencephalopathy aorta [13]. Blood cultures are useful in identifying (PML) presents with progressive cognitive the responsible organism as well. GN observed decline, altered mental status, neurologic deficits in the setting of IE is typically associated with became apparent upon physical examination and

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subcortical white matter changes on MRI of the and rupture have been reported [24]. Again, in brain, which can mimic the presentation of CNS this disease, arterial wall thickening or steno- vasculitis. It is a rapidly progressive, generally ses were not observed. The histopathology of fatal, neurological disease owing to reactivation the arterial wall in both Marfan’s syndrome of the John Cunningham (JC) virus polyoma and Ehlers–Danlos syndrome type IV is cys- virus. It has been observed in patients with tic medial necrosis, which clearly differs from malignances on immunosuppressive therapy, but the granulomatous inflammation seen with the systemic lupus erythematosus (SLE) may bear primary large vessel vasculitides. However, this an independent predisposition to PML, even in distinction may be difficult to make as evidence patients on minimal immunosuppression owing of active inflammation is generally only found to immune dysregulation [21]. PML must be con- in approximately half of surgical specimens from sidered in the differential diagnosis of immuno- patients with large vessel vasculitides [25,26] since suppressed patients presenting with progressive surgery is usually performed in these patients neurological deficits, regardless of the intensity when the disease is considered quiescent. of immunosuppression, and especially if worsen- ing occurs after increasing immunosuppression. Loeys–Dietz syndrome The diagnosis can be confirmed by testing the Loeys–Dietz syndrome is characterized by cerebrospinal fluid for JC virus by PCR; how- a triad of arterial tortuosity and aneurysms, ever, brain biopsy may be needed if clinically hypertelorism and bifid uvula or cleft palate indicated and PCR testing is negative. owing to mutations in the TGF-b receptors (TGFBR 1 and 2). Thoracic and abdominal aor- Inherited disorders tic dissections are the leading causes of death in „ „Disorders of the connective Loeys–Dietz syndrome. The reported mean age tissue matrix of dissection is 26 years and the mean age for sur- Marfan’s syndrome gical intervention for ascending aortic aneurysm Vascular involvement in Marfan’s syndrome, or dissection is 20 years. Other arteries that can an autosomal dominant disorder of connective be affected by aneurysms include the thoracic, tissue caused by mutations in the gene for fibril- head and neck and abdominal vessels [27]. The lin-1 (FBN1), is characterized by abnormalities bicuspid aortic valve has also been associated with in the wall of the thoracic aorta leading to aortic aortic dissection from the possible overactivity of aneurysms and dissection. Aortic regurgitation matrix metalloproteinases [28]. occurs in 15–44% of patients [22]. Thoracic aor- Genetic testing is available for mutations in tic involvement from Marfan’s syndrome can FBN1, COL3A1 and TGFBR1/2 and helps to mimic other etiologies of aneurysm including establish the diagnosis in suspected cases. giant cell arteritis and Takayasu’s arteritis. The large vessel vasculitides can be differentiated „„Other inherited disorders from Marfan’s syndrome based on their ten- Neurofibromatosis type I dency to cause arterial stenoses, their pattern Neurofibromatosis type I is also an autosomal of vascular involvement, a lesser likelihood of dominant disorder that may affect large- or causing arterial dissection and a lack of other medium-sized vessels. Large vessel involvement accompanying features of Marfan’s syndrome can lead to aortic dissection and rupture [29]. (i.e., ocular, skeletal and cutaneous). FBN1 The most common vascular involvement in mutations have also been described in patients neurofibromatosis type I is renal artery stenosis with thoracic aortic aneurysms and dissection resulting in hypertension. Other lesions include without the typical marfanoid body habitus [23]. cerebrovascular involvement, pulmonary artery stenosis and intra-abdominal vessel involve- Ehlers–Danlos syndrome type IV ment [30]. Vascular involvement has been clas- Ehlers–Danlos syndrome type IV is another sified as pure intimal, advanced intimal, intimal autosomal dominant arterial wall matrix disor- aneurysmal and nodular. Histopathology of the der that results from mutations in the type III intimal subtype shows marked, concentric inti- procollagen gene (COL3A1) and may be com- mal proliferation of spindle cells with or without plicated by arterial dissection or rupture, bowel fibrosis and a thinned media. The aneurysmal perforation or organ rupture. Arterial involve- subtype demonstrates marked fibrous intimal ment is most commonly seen in the thoracic thickening, irregular loss of media smooth or abdominal arteries, but carotico-cavernous muscle and elastic fragmentation in small-sized fistulas, carotid artery dissection, aneurysm arteries [31].

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Fibromuscular dysplasia 3p24.2-p26, 17q25, 8q23, 6) and occurrence Fibromuscular dysplasia (FMD) is a non­ of certain haplotypes (HLA-B35 in the Korean inflammatory vascular disease characterized by population) [35]. stenoses and aneurysm formation in multiple vascular territories, usually from medium-sized Cerebral autosomal dominant vessel involvement. Histopathologically, FMD arteriopathy with subcortical infarcts is classified as intimal, medial or perimedial and leukoencephalopathy based on the predominant, but not exclusive, Cerebral autosomal dominant arteriopathy with arterial wall layer involvement. Renal and subcortical infarcts and leukoencephalopathy carotid arteries are most commonly involved, (CADASIL) is considered a typical monogenic but other arteries may be involved in 10% of inherited cause of stroke resulting from mutations cases. Angiographically, FMD has been classi- in the Notch3 gene [36]. Recurrent strokes may fied as multifocal (‘string-of-beads’ appearance), eventually cause multi-infarct dementia. Other tubular, focal and mixed [32]. Depending on the presentations include migraine and psychiatric vascular territory and vessel size involved, FMD disturbances. MRI reveals white matter and a can mimic polyarteritis nodosa or TAK. An diffuse small vessel ischemia pattern within the autosomal dominant inheritance has been sug- periventricular white matter, basal ganglia, thala- gested for renal artery involvement from FMD mus, internal capsule and pons. This widespread in a French study [33]. vascular involvement and stroke/dementia-like presentation mimics the presentation of primary Grange syndrome CNS vasculitis. The angiographic picture can Grange syndrome is a recently described also be similar due to the appearance of arterial hereditary disorder characterized by a vari- stenoses. Histopathology reveals degeneration able combination of multiple arterial stenoses and loss of smooth muscle in middle- and small- and aneurysms, brachysyndactyly, bone fragil- sized arteries, basophilic granular degeneration ity, learning disability and cardiac defects [34]. of the media, vessel fibrosis, hyalinization and Arterial involvement can mimic FMD, manifest- enlargement of perivascular spaces. The presence ing with hypertension and angiographic ‘bead- of granular osmophilic material in the medial ing’. No clear genetic defect has yet been dis- layer on electron microscopy is pathognomonic covered in Grange syndrome, but an autosomal and corresponds to the extra­cellular domain recessive inheritance pattern has been observed. of the protein coded by the Notch3 gene on immunohistochemistry [37]. CADASIL should Moyamoya disease/syndrome be suspected in the right clinical context and if a Moyamoya disease is a vasculopathy of family history is suggestive of this condition [38]. unknown etiology that most commonly affects the cerebrovascular circulation predisposing Cerebral amyloid angiopathy a stroke. The classical involvement results in Cerebral amyloid angiopathy (CAA) is a hereditary bilateral internal carotid artery stenosis result- or sporadic disorder characterized by deposition of ing in a florid collateral circulation that, given extracellular eosinophilic material (amyloid) in the the appearance of ‘a puff of smoke’ on the cerebral vessels. Hereditary forms of CAA result angiogram, the Japanese term for this appear- from mutations in various amyloid proteins (such ance is ‘Moyamoya’. However, the arteries com- as cystatin C, presenilin, prion protein, transthyre- prising the circle of Willis may also be com- tin and gelsolin). Clinical presentations of CAA monly involved with ‘spontaneous occlusion’. include stroke (both ischemic and hemorrhagic), Moyamoya disease occurs most commonly in subarachnoid hemorrhage, transient neurologic the Asian–American population in children and phenomena, cognitive impairment and dementia middle aged adults with a female predominance. [39]. Histopathology demonstrates thickening of The symptoms typically arise as a consequence the small- and medium-sized arterial and arte- of vascular ischemia or hemorrhage from the riolar walls (and less often veins), resulting from collaterals. Vascular smooth muscle cell hyper- deposition of an amorphous, intensely eosinophilic plasia and thrombosis are described at histopa- material on light microscopy with a characteristic thology, with no evidence of vascular inflam- ‘apple-green’ birefringence on polarized micros- mation. Renal artery stenosis has been reported copy after Congo red staining [40]. The incidence in Moyamoya syndrome. A genetic basis has of CAA increases with age and even in the heredi- been suggested based in family studies reveal- tary forms of the disease, a large variation in the ing increased linkage ana­lysis (chromosomes age of presentation is reported.

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Miscellaneous Box 1. Vasculitis mimics. noninherited disorders Infection „ „Segmental arterial mediopathy ƒƒ Treponema pallidum Segmental arterial mediopathy (SAM), origi- ƒƒ HIV nally called segmental mediolytic arteritis, was ƒƒ Hepatitis B virus first described by Slavin in 1976 in three patients ƒƒ Hepatitis C virus at autopsy who were found to have large abdom- ƒƒ Hepatitis A virus ƒƒ Mycobacteria inal muscular arteries affected by dissecting ƒƒ Herpes viruses aneurysms, partial or total mediolysis accompa- ƒƒ Infective endocarditis nied by linear fibrin deposits between the media ƒƒ Mycotic aneurysms and adventitia and a variable inflammatory infil- ƒƒ John Cunningham virus trate [41]. SAM commonly affects medium-sized ƒƒ Protozoa vessels in various territories (most commonly in Inherited disorders the abdomen) and presents as arterial dilatation, ƒƒ Disorders of connective tissue matrix solitary aneurysm, multiple aneurysms, arterial – Marfan’s syndrome dissections with hematomas, and arterial steno- – Ehlers Danlos syndrome type IV ses and occlusions. Most patients with SAM are – Pseudoxanthoma elasticum middle aged to elderly individuals with an equal – Loeys–Dietz syndrome male/female distribution. Patients typically ƒƒ Other inherited disorders present with abdominal pain or retroperitoneal – Neurofibromatosis type I hemorrhage owing to rupture of a visceral artery – Fibromuscular dysplasia aneurysm. SAM is hypothesized to be a part – Grange syndrome of the pathological continuum from an initial – Moyamoya disease vasospastic process that may eventually evolve – Cerebral autosomal dominant arteriopathy with subcortical infarcts and into a PAN-like disease [42,43]. Radiographic leukoencephalopathy [44] and clinical [43] long-term follow up studies – Cerebral amyloid angiopathy indicate that SAM is most likely to be an acute Drugs/toxins disorder with resolution or unchanged arterial ƒƒ Cocaine involvement over time. ƒƒ Sympathomimetics Atherosclerosis & arteriolosclerosis Drugs/toxins ƒƒ Hypercoagulable states A wide variety of drugs may result in mimics – Thrombotic thrombocytopenic purpura of vasculitis or indeed cause a true vasculitis. – Antiphospholipid syndrome A number of drugs, such as minocycline and Vasospastic disorders hydralazine, may be associated with positive ƒƒ Reversible cerebral vasoconstriction syndrome ANCA testing, and in some cases may be asso- ƒƒ Reversible posterior leukoencephalopathy syndrome ciated with a vasculitic syndrome [45]. However, Immunodeficiency disorders cocaine use may be a particularly elusive mimic ƒƒ Common variable immunodeficiency ƒƒ HLA class I deficiency of WG. Cocaine use may result in nasal mucosal Malignancies irritation and necrosis, intense vasoconstriction ƒƒ Leukemia leading to nasal septal perforation and collapse ƒƒ Lymphoma with a saddle-nose deformity. These patients can ƒƒ Glioma present with facial pain, epistaxis and constitu- ƒƒ Angiocentric lymphoma tional symptoms. In addition, they can have a Multisystem inflammatory disease classical-ANCA pattern on immunofluorescence ƒƒ Sarcoidosis and positive antiproteinase 3 (PR3) testing ƒƒ Susac’s syndrome by immunoassay, compounding the diagnos- Miscellaneous tic confusion with WG. PR3-ANCA has been ƒƒ Degos disease reported in up to 50% of patients with cocaine- ƒƒ Segmental arterial mediolysis induced midline destructive lesions [46]. However, ƒƒ Cardiac myxoma the epitope on the PR3 molecule for ANCA in ƒ ƒ Calciphylaxis patients with cocaine-induced lesions is different ƒƒ Cholesterol emboli syndrome from that of patients with WG. The antigen for ƒƒ Postradiation therapy ƒƒ Paraneoplastic ANCA in patients with cocaine-induced lesions is human neutrophil elastase (HNE); antibodies

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directed against HNE were found in patients Hypercoagulable states with cocaine-induced midline destructive lesions „ „Thrombotic thrombocytopenic by one assay in 84%, by two assays in 68%, and purpura by all three assays in 36% (indirect immunofluo- Thrombotic thrombocytopenic purpura (TTP) is rescence, direct and indirect capture ELISA) but a microvascular angiopathy that may be familial, were not observed in patients with WG [46]. The idiopathic or secondary to medications, infections ANCA reacting with both HNE and PR3 dem- or organ transplantation. It is clinically character- onstrate a P-ANCA pattern on indirect immun- ized by microangiopathic hemolytic anemia, con- ofluorescence [46]. Evidence for multisystem sumptive thrombocytopenia, renal failure, fever disease should be carefully sought and clearly and altered mental status or other neurological favors a diagnosis of WG. However, the absence deficits[50] . All features do not need to be present of the antibodies does not preclude a diagnosis to make the diagnosis. Microvascular thromboses of WG. Sustained use of other vasoconstrictor in multiple vascular territories are associated with medications, such as oxymetazoline and pheny- tissue infarction and hence, invoke the differential lypropanolamine, can also result in similar injury diagnosis of vasculitis. The pathogenesis of TTP to the nasal mucosa through ischemia and also involves deficient activity of a metalloproteinase mimic chronic sinusitis owing to the occurrence (ADAMTS13) resulting in von Willebrand fac- of rebound phenomena such as rhinitis medica- tor multimers with resultant platelet aggrega- mentosa, but will not typically be associated with tion [51,52]. Histopathology of tissues in patients positive ANCA testing. with TTP typically demonstrates thrombi com- posed predominantly of platelets, with little fibrin Atherosclerosis & arteriolosclerosis deposited in the myocardial microcirculation Atherosclerosis is a well-defined inflammatory and variable involvement of the circulation in the vascular disease [47], distinct from vasculitis. kidney, pancreas, brain and adrenal glands [53]. It is influenced by genetic factors modified by Microangiopathic hemolytic anemia (evidenced metabolic risk factors such as diabetes melli- by schistocytes on the peripheral blood smear), tus, hypertension, hyperlipidemia and smok- thrombocytopenia and histological findings ing. Atherosclerosis results in aortic aneurysms (platelet thrombi) help differentiate TTP from (most commonly in the infrarenal aortic seg- primary systemic vasculitis. ment), aortic valve sclerosis and stenoses in the aortic branches and medium-sized arteries. It „„Antiphospholipid syndrome can mimic vasculitis clinically (symptoms from Antiphospholipid syndrome is an autoimmune tissue ischemia and infarction, absent or weak hypercoagulable disorder, clinically characterized pulses and bruits) and angiographically (focal, by recurrent arterial and venous thrombotic events, short segmental or diffuse arterial narrowing pregnancy loss, thrombocytopenia and persistently and aneurysms). At histopathology, atheroscle- positive anticardiolipin or lupus anticoagulant rosis is characterized by ‘plaques’ consisting of antibodies. Pathogenetic mechanisms underlying lipids, inflammatory cells and platelets with or the thrombotic manifestations include activation without thrombus. The clinical suspicion for of endothelial cells, monocytes or platelets, com- atherosclerosis should be heightened in the rel- plement activation and inhibition of protein C [54]. evant clinical setting in a patient with a typi- Multifocal thrombotic events with angiographic cal clinical risk factor profile and presentation. appearances of arterial narrowing secondary to Arteriolosclerosis is a systemic noninflammatory luminal thrombi can mimic the clinical and angio- small vessel (arteriolar) disease characterized by graphic appearance of vasculitis. Antiphospholipid hyalinization of the intima (hyalinosis) with syndrome can occur as a primary disorder or in proliferation and hypertrophy of the media. It association with diseases such as SLE. Other is usually silent, associated with ageing, diabe- manifestations include hematologic (hemolytic tes mellitus and hypertension and is most com- anemia), neurologic (transverse myelopathy or monly described in the renal [48] and cerebral myelitis, multiple sclerosis-like involvement, cho- microvasculature [49]. Histopathology of arte- rea and migraine), cutaneous (livedo reticularis/ riolosclerosis consists of subendothelial protein racemosa, atrophie blanche), cardiac (thrombotic deposits staining bright magenta with peri- endocarditis and valvular disease) and hyperten- odic acid-Schiff stains and has a glassy texture sion from renal involvement. The diagnosis can (hyaline). Inflammatory changes do not occur be confirmed by serial testing for antiphospholipid ­distinguishing it from true vasculitis. antibodies in the right clinical context.

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Vasospastic disorders infection/sepsis and organ transplantation [57]. „ „Reversible cerebral Three imaging patterns of reversible posterior vasoconstriction syndromes leukoencephalopathy syndrome on computed Reversible cerebral vasoconstriction syndromes tomography/MRI have been reported: holo­ (RCVS) are vasospastic disorders of unknown hemispheric watershed, superior frontal sulcal etiology affecting the cerebral vasculature that and dominant parieto-occipital [58]. Angiography are usually associated with acute onset and demonstrates irregular vascular abnormalities severe, recurrent headaches, with or without of constriction and dilatation, but these are additional neurological signs and symptoms. reported to reverse at future follow-up imaging. RCVS may be idiopathic or triggered by preg- Histopathology on brain biopsy demonstrated nancy, medications, illicit drug use, metabolic edema of the white matter consistent with that disorders, trauma, postneurosurgery or cath- observed on MRI [59]. eter-based vascular intervention. The typical presentation is with recurrent episodes of acute Immunodeficiency disorders onset of severe (thunder-clap) headache, with „ „Common variable immunodeficiency or without associated nausea, vomiting, photo- Common variable immunodeficiency [60] may sensitivity and transient or permanent visual or mimic WG, as it can manifest with pansinusitis, neuro­logical deficits as a result of intense vaso- recurrent pneumonia, multisystem and pulmo- constriction in that particular cerebral vascular nary granulomatous involvement and inflam- territory. The vasoconstriction can be severe matory polyarthritis. However, it can be differ- enough to result in stroke (either ischemic or entiated from WG by its features of qualitative hemorrhagic) and even death. The diagnosis is and quantitative defects in cellular and humoral made based on the clinical history, normal or immune function, which include cytopenias, near normal cerebrospinal fluid findings and evi- impaired lymphocyte proliferation with mito- dence of multifocal segmental arterial narrowing genic stimulation, decreased immunoglobulin (‘beading’) with reversal within 12 weeks (on levels, specific antibody nonresponsiveness to magnetic resonance angiography or conven- protein and/or polysaccharide antigens, auto- tional dye angiography) [55]. In patients with immune phenomena (such as thrombocytopenia suspected RCVS without the typical clinical and hemolytic anemia) and absence of ANCA. presentation of headache and with neurologic Diagnosis can be established with laboratory deficits and diffuse parenchymal abnormali- evaluation of immune function although genetic ties on MRI, and/or absence of reversibility on testing may be necessary to identify the exact follow-up angiography, a brain biopsy to exclude responsible defect in an individual patient. true CNS vasculitis may be indicated. There is limited data regarding brain biopsy findings in „„HLA class I deficiency patients with true RCVS, but the available data Manifestations of HLA Class I/transporter-­ reports demonstrate no evidence of vasculitis. associated protein deficiency can mimic signs Observational data regarding treatment includes and symptoms of WG. These patients present calcium channel blockers and short courses of with granulomatous skin lesions, cutaneous glucocorticoids, with subsequent reversal of the vasculitis and recurrent bacterial sinus and pul- vascular abnormalities at serial imaging, pro- monary infections [61,62]. The diagnosis may be viding the greatest retrospective confirmation suspected based on the presence of recurrent of RCVS is apparent. infections or may sometimes be made retro- spectively-based on the response to immuno- „„Reversible posterior suppression. The diagnosis can be confirmed by leukoencephalopathy syndrome reverse transcriptase PCR and DNA sequence Reversible posterior leukoencephalopathy syn- ana­lysis [63]. drome, first described in 1996, is a vasoconstric- tive disorder associated with headache, seizures, Miscellaneous conditions confusion, visual disturbances and a pattern „ „Calciphylaxis of predominantly posterior cerebral edema on Calciphylaxis is a noninflammatory vasculopa- imaging. It can occur in isolation or in the con- thy resulting from calcification of the small- text of other diseases such as SLE, WG and sys- sized arterial vessels with consequent tissue temic sclerosis [56], pre-eclampsia, severe hyper- ischemia and infarction. Calciphylaxis is seen tension, when taking medications (ciclosporin, most commonly, but not exclusively, in patients tacrolimus and methotrexate), and as a result of with advanced chronic kidney disease (‘calcific

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uremic arteriopathy’). Other risk factors include with a livedo reticularis-like rash and normal female gender, elevated phosphate levels, ele- pulses. Other cutaneous findings include pur- vated alkaline phosphatase, hypoalbuminemia, pura, ulcers, nodules, cyanosis and frank gan- obesity, liver disease, systemic glucocorticoid grene [69]. Renal involvement can result in acute use and calcium phosphate product greater renal failure, sometimes necessitating dialysis. 2 2 than 70 mg /dl [64,65]. Patients usually develop Treatment is largely supportive and renal func- severe pain in the muscles or skin breakdown, tion may be irrecoverably lost [70]. Other sites of but other presentations such as rhabdomyoly- embolization include the gastrointestinal tract sis, or involvement of the cardiac, penile, pul- and CNS. Bedsides, ophthalmoscopy may reveal monary, pancreatic and ocular vasculature have retinal cholesterol emboli. A deep skin biopsy been described [66]. The proposed pathogenesis shows cholesterol crystals (identified by ‘cho- of calciphylaxis involves a switch of the vascu- lesterol clefts’) in the cutaneous microvessels. lar smooth muscle phenotype to an osteoblastic The skin biopsy can be diagnostic in as many phenotype. Histopathology shows small vessel as 92% of cases [71]. Elderly male patients with calcification, intimal proliferation, endovascular pre-existing renal disease have a worse prognosis fibrosis and intravascular thrombosis. Vascular and this condition is associated with significant inflammation is not seen. mortality [72].

„„Cardiac myxoma Future perspective Cardiac myxomas are the most common primary Greater awareness of vasculitis mimics will cardiac tumors that are benign, occur most com- facilitate diagnosis and additional study of these monly in the left atrium and can produce symp- entities. Future development of more reliable toms due to valvular obstruction, embolization or biomarkers, novel genetic markers and advances paraneoplastic effects. They are most commonly in diagnostic imaging modalities may provide observed in middle-aged females. Paraneoplastic better tools to characterize known vasculitis manifestations of myxomas include fever, arthral- mimics and to distinguish them from the pri- gias and weight loss that can mimic the consti- mary systemic vasculitides. With advances in tutional symptoms seen with systemic vasculitis. the understanding of the pathophysiology of Recurrent embolic phenomena can lead to tis- known infectious agents and the future discov- sue infarction with digital ischemia, cutaneous ery of novel infectious agents, it is likely that infarcts, limb claudication, hemoptysis (pulmo- additional infectious agents with the ability to nary infarction), hematuria (renal infarction) mimic vasculitis will be identified. However, and stroke (cerebral infarction). Elevated MPO- the most important consideration will always ANCA that normalized after surgery has been be to separate these entities from the primary reported in a patient with cardiac myxoma [67]. systemic vasculitides due to the consequent Transesophageal echocardiography or computed therapeutic and prognostic implications. tomography/MRI can be used to diagnose myxo- mas, and surgical resection with reconstruction Financial & competing interests disclosure improves prognosis [68]. The authors have no relevant affiliations or financial involvement with any organization or entity with a finan- „„Cholesterol emboli syndrome cial interest in or financial conflict with the subject matter Cholesterol embolization (atheroembolism) can or materials discussed in the manuscript. This includes occur from the arterial wall as a result of trauma employment, consultancies, honoraria, stock ownership or from catheter manipulation, direct trauma, options, expert testimony, grants or patents received or surgery, anticoagulation or thrombolysis. It pending, or royalties. most commonly affects the extremities where No writing assistance was utilized in the production of it manifests with symptoms of limb ischemia this manuscript.

Executive summary ƒƒ The primary systemic vasculitides are rare diseases and are generally less common than secondary forms of vasculitis and the vasculitic mimics. ƒƒ Many of the vasculitic mimics are noninflammatory and treating with immunosuppressive therapy is not only unnecessary, but is also potentially hazardous. ƒƒ An attempt must always be made to establish a diagnosis using the best risk–benefit strategy and therapy is then instituted accordingly. ƒƒ The diagnosis of primary systemic vasculitis should always be re-appraised in the event of failure to respond to immunosuppressive therapy.

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Mimics of primary systemic vasculitides

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1. Which of the following best describes reasons for distinguishing mimics from true primary vasculitides? £ A Avoid adverse effects of immunosuppressive drugs £ B Avoid missing treatable conditions £ C Identify causes of vasculitis £ D All of the above

2. A patient presents with secondary vasculitis that is thought to be associated with syphilis or TB. Which of the following clinical features would most likely distinguish the two conditions? £ A Effect on ascending versus descending aorta £ B Presence of aneurysms £ C Involvement of vessels of the lung £ D Presence of large-vessel vasculitis

608 Int. J. Clin. Rheumatol. (2009) 4(5) future science group Review Khasnis & Molloy Mimics of primary systemic vasculitides Review

3. Which of the following vasculitis mimic conditions is least likely to have an autosomal dominant inheritance? £ A Fibromuscular dysplasia £ B Ehlers–Danlos syndrome £ C Grange’s syndrome £ D Marfan’s syndrome

4. Which of the following toxins or drugs is most likely to be associated with pathology that mimics Wegener’s granulomatosis? £ A Minocycline £ B Cocaine £ C Oxymetazoline £ D Hydralazine

5. A 36-year-old woman presents with recurrent pregnancy losses, hypertension and hemolytic anemia, and a vasculitis is suspected. Which of the following features is least likely to be associated with a diagnosis of antiphospholipid syndrome? £ A Transverse myelopathy £ B Migraine £ C Livedo reticularis £ D Thrombocythemia

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