Key points

Among the most challenging aspects of evaluating and caring for patients with systemic vasculitis is the need to distinguish rigorously between vasculitis and a host of conditions that can mimic vasculitis closely ( Box 1 ). The treatment approaches for vasculitis mimickers are varied and often differ substantially from those required to treat vasculitis. This article reviews 9 challenging vasculitis mimickers: fibromuscular dysplasia (FMD), calciphylaxis, segmental arterial mediolysis, antiphospholipid syndrome (APS), hypereosinophilic syndrome, lymphomatoid granulomatosis (LMPG), malignant atrophic papulosis, livedoid vasculopathy, and immunoglobulin (Ig) G4–related disease (IgG4-RD).

Fibromuscular dysplasia

FMD is a noninflammatory vasculopathy of small and medium-sized arteries that can lead to aneurysm, stenosis, occlusion, and dissection. This disease may occur in any age group, but mainly affects children and individuals more than 50 years of age. The prevalence of FMD in the general population is estimated to be around 2% to 3%. Women comprise up to 90% of cases in adults. Approximately 10% of patients with FMD report a family member carrying the same diagnosis.

The most commonly affected vascular sites are middle and distal portions of the renal, internal carotid, and vertebral arteries (∼65% of the cases). Lesions are detected less frequently in the intracranial, common carotid, external carotid, subclavian, coronary, mesenteric, iliac, and limb arteries. Aortic disease has rarely been reported. More than half of the patients have 2 or more vascular territories involved, and bilateral distributions of disease are common. The etiopathogenesis of FMD is poorly understood, but genetic, biomechanical, and hormonal factors have been implicated.

FMD is classified in 5 main types, based on the histologic characteristics and the location of the process within the arterial wall. These types are: (1) medial fibroplasia (∼90%), (2) intimal fibroplasia (∼10%), (3) perimedial fibroplasia (<1%), (4) medial hyperplasia (<1%), and (5) adventitial (periarterial) hyperplasia (<1%). The specific FMD type correlates well with the radiologic findings in a given case (discussed later).

The presentation of FMD is determined primarily by the distribution of the arteries that are involved. The presentations vary from incidental findings in asymptomatic individuals to a diverse array of clinical manifestations such as renovascular hypertension (the most common presentation), headache, lightheadedness, pulsatile tinnitus, neck pain, limb claudication, postprandial angina, and acute coronary syndrome. The physical examination may reveal pulse deficits, asymmetric blood pressure readings, and vascular bruits. At times, patients present with rupture of an aneurysm (eg, subarachnoid hemorrhage). Embolization of intravascular thrombi from aneurysmal segments can also occur, leading to amaurosis fugax, transient ischemic attack, stroke, and cyanotic toes. Spontaneous arterial dissections, most frequently of the carotid arteries, occur in up to 20% of the patients. Arterial aneurysms are seen in approximately 20% of the cases as well. Both dissections and aneurysms seem to be more prevalent in men.

The diagnosis of FMD is typically made with vascular imaging. Duplex ultrasonography is a reasonable first-line screening technique, followed by noninvasive studies such as computed tomography angiography (CTA) or magnetic resonance angiography (MRA) as confirmatory tests. However, conventional angiography remains the gold standard for diagnosis. The classic string-of-beads appearance on angiography generally corresponds with the medial fibroplasia FMD type ( Fig. 1 ). In contrast, unifocal lesions described as focal concentric narrowing and diffuse tubular stenosis correlate more closely with the intimal and periadventitial fibroplasia FMD types.

Fibromuscular dysplasia. Conventional angiography in a patient with FMD showing a classic string-of-beads lesion affecting the distal portion of a right renal artery.

( Courtesy of Dr George Oliveira, Massachusetts General Hospital.)

The differential diagnoses of FMD from a rheumatologic perspective are Takayasu arteritis (TAK), giant cell arteritis (GCA), and polyarteritis nodosa (PAN). Clues that may help to differentiate FMD from vasculitides include the presence of normal inflammatory markers (unless severe ischemia leads to tissue infarction); the absence of arthralgias, fever or constitutional symptoms; and the absence of arterial wall thickening, edema, or contrast uptake on cross-sectional vascular imaging. On diagnosis, patients with FMD should undergo screening of the cervical, intracranial, and renal vasculature to identify potential synchronous lesions.

The treatment of FMD may include medical therapy and surveillance, endovascular procedures, and surgery. However, disease-modifying agents have not been identified. Patients with renovascular hypertension require antihypertensive therapy. Hypertension in this setting is secondary to upregulation of the renin-angiotensin-aldosterone system, therefore the drugs of choice are angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs). Close monitoring of kidney function is required during the initiation of ARBs or ACEIs because a subset of patients with FMD develop abrupt decline in the glomerular filtration rate, requiring drug discontinuation. More than 1 pharmacologic agent is frequently needed for adequate blood pressure control.

For patients with hypertension who respond poorly to medical therapy or for those with hemodynamically significant lesions in the renal arteries or in other vascular territories, revascularization is indicated. Endovascular treatment options include percutaneous transluminal balloon angioplasty (PTA) with or without stenting (eg, stenoses, dissections, and aneurysms) or coiling (eg, aneurysms). Surgical interventions are reserved for restenosis after PTA, complex lesions, or lesions that are difficult to reach by PTA (eg, renal artery branches). Unlike atherosclerotic disease, resolution of hypertension is common after revascularization of FMD-related renal artery stenosis.

Monitoring via imaging is required after PTA or surgery to assess the short-term and long-term patency of revascularized arterial segments. If no revascularization is indicated, longitudinal imaging surveillance is also advisable to monitor the progression of disease and determine the indication and timing of revascularization. Experts recommend heparin therapy acutely followed by 3 to 6 months of anticoagulation with warfarin for patients who develop arterial dissection. However, high-quality evidence supporting this practice is still not available. In addition, identification and correction of concomitant cardiovascular risk factors (eg, smoking, dyslipidemia, and diabetes) is strongly recommended.

Fibromuscular dysplasia

FMD is a noninflammatory vasculopathy of small and medium-sized arteries that can lead to aneurysm, stenosis, occlusion, and dissection. This disease may occur in any age group, but mainly affects children and individuals more than 50 years of age. The prevalence of FMD in the general population is estimated to be around 2% to 3%. Women comprise up to 90% of cases in adults. Approximately 10% of patients with FMD report a family member carrying the same diagnosis.

The most commonly affected vascular sites are middle and distal portions of the renal, internal carotid, and vertebral arteries (∼65% of the cases). Lesions are detected less frequently in the intracranial, common carotid, external carotid, subclavian, coronary, mesenteric, iliac, and limb arteries. Aortic disease has rarely been reported. More than half of the patients have 2 or more vascular territories involved, and bilateral distributions of disease are common. The etiopathogenesis of FMD is poorly understood, but genetic, biomechanical, and hormonal factors have been implicated.

FMD is classified in 5 main types, based on the histologic characteristics and the location of the process within the arterial wall. These types are: (1) medial fibroplasia (∼90%), (2) intimal fibroplasia (∼10%), (3) perimedial fibroplasia (<1%), (4) medial hyperplasia (<1%), and (5) adventitial (periarterial) hyperplasia (<1%). The specific FMD type correlates well with the radiologic findings in a given case (discussed later).

The presentation of FMD is determined primarily by the distribution of the arteries that are involved. The presentations vary from incidental findings in asymptomatic individuals to a diverse array of clinical manifestations such as renovascular hypertension (the most common presentation), headache, lightheadedness, pulsatile tinnitus, neck pain, limb claudication, postprandial angina, and acute coronary syndrome. The physical examination may reveal pulse deficits, asymmetric blood pressure readings, and vascular bruits. At times, patients present with rupture of an aneurysm (eg, subarachnoid hemorrhage). Embolization of intravascular thrombi from aneurysmal segments can also occur, leading to amaurosis fugax, transient ischemic attack, stroke, and cyanotic toes. Spontaneous arterial dissections, most frequently of the carotid arteries, occur in up to 20% of the patients. Arterial aneurysms are seen in approximately 20% of the cases as well. Both dissections and aneurysms seem to be more prevalent in men.

The diagnosis of FMD is typically made with vascular imaging. Duplex ultrasonography is a reasonable first-line screening technique, followed by noninvasive studies such as computed tomography angiography (CTA) or magnetic resonance angiography (MRA) as confirmatory tests. However, conventional angiography remains the gold standard for diagnosis. The classic string-of-beads appearance on angiography generally corresponds with the medial fibroplasia FMD type ( Fig. 1 ). In contrast, unifocal lesions described as focal concentric narrowing and diffuse tubular stenosis correlate more closely with the intimal and periadventitial fibroplasia FMD types.

Fibromuscular dysplasia. Conventional angiography in a patient with FMD showing a classic string-of-beads lesion affecting the distal portion of a right renal artery.

( Courtesy of Dr George Oliveira, Massachusetts General Hospital.)

The differential diagnoses of FMD from a rheumatologic perspective are Takayasu arteritis (TAK), giant cell arteritis (GCA), and polyarteritis nodosa (PAN). Clues that may help to differentiate FMD from vasculitides include the presence of normal inflammatory markers (unless severe ischemia leads to tissue infarction); the absence of arthralgias, fever or constitutional symptoms; and the absence of arterial wall thickening, edema, or contrast uptake on cross-sectional vascular imaging. On diagnosis, patients with FMD should undergo screening of the cervical, intracranial, and renal vasculature to identify potential synchronous lesions.

The treatment of FMD may include medical therapy and surveillance, endovascular procedures, and surgery. However, disease-modifying agents have not been identified. Patients with renovascular hypertension require antihypertensive therapy. Hypertension in this setting is secondary to upregulation of the renin-angiotensin-aldosterone system, therefore the drugs of choice are angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs). Close monitoring of kidney function is required during the initiation of ARBs or ACEIs because a subset of patients with FMD develop abrupt decline in the glomerular filtration rate, requiring drug discontinuation. More than 1 pharmacologic agent is frequently needed for adequate blood pressure control.

For patients with hypertension who respond poorly to medical therapy or for those with hemodynamically significant lesions in the renal arteries or in other vascular territories, revascularization is indicated. Endovascular treatment options include percutaneous transluminal balloon angioplasty (PTA) with or without stenting (eg, stenoses, dissections, and aneurysms) or coiling (eg, aneurysms). Surgical interventions are reserved for restenosis after PTA, complex lesions, or lesions that are difficult to reach by PTA (eg, renal artery branches). Unlike atherosclerotic disease, resolution of hypertension is common after revascularization of FMD-related renal artery stenosis.

Monitoring via imaging is required after PTA or surgery to assess the short-term and long-term patency of revascularized arterial segments. If no revascularization is indicated, longitudinal imaging surveillance is also advisable to monitor the progression of disease and determine the indication and timing of revascularization. Experts recommend heparin therapy acutely followed by 3 to 6 months of anticoagulation with warfarin for patients who develop arterial dissection. However, high-quality evidence supporting this practice is still not available. In addition, identification and correction of concomitant cardiovascular risk factors (eg, smoking, dyslipidemia, and diabetes) is strongly recommended.

Calciphylaxis

Calciphylaxis is a noninflammatory vasculopathy characterized by ectopic calcification within the wall of small and medium-sized arteries. This potentially serious process can lead to vascular occlusion, ischemia, and necrosis of the skin and subcutaneous tissues. Calciphylaxis is observed in up to 4% of patients undergoing hemodialysis and is therefore sometimes termed calcific uremic arteriolopathy. However, the disease can also occur in nonuremic patients.

Calciphylaxis has been described in the context of primary hyperparathyroidism, malignancy, chronic liver disease, acute kidney injury, inflammatory bowel disease, warfarin anticoagulation, and systemic autoimmune disorders (eg, systemic lupus erythematosus, Sjögren syndrome, polymyositis, rheumatoid arthritis, APS, sarcoidosis, and GCA). The disease is usually seen in the fifth or sixth decade of life, and is most frequent in women. Some studies indicate that obesity, hypoalbuminemia, and the use of corticosteroids are also risk factors.

The etiopathogenesis of calciphylaxis is poorly understood. Disturbances of calcium-phosphate homeostasis are clearly central to the disease process, as shown by the increased prevalence in patients with end-stage renal disease (ESRD) and parathyroid dysfunction. Moreover, parathyroid hormone (PTH) or vitamin D administration is known to induce soft tissue calcification and skin necrosis in experimental models. Additional research suggests that deficiency of circulatory and tissue calcium and phosphate binding proteins (eg, fetuin-A, matrix Gla protein), inflammation, and alteration of the coagulation (eg, protein C and S deficiency) and the RANK (receptor activator of nuclear factor kappa-B)/osteoprotegerin systems might also be involved in the pathogenesis of the disease.

Calciphylaxis typically involves adipose tissues (eg, the thighs, buttocks, abdomen, flanks). A variety of cutaneous lesions can be evident: violaceous, indurated plaques and nodules; ulcerations; necrotic eschars; and lesions that mimic the purpura of vasculitis ( Fig. 2 ). Skin lesions are extremely painful and easily become infected. Skin contractures, penile involvement, myopathy, or cardiopulmonary calcification may rarely develop. The diagnosis is usually made by skin biopsy, which shows medial calcification, intimal hyperplasia, intimal fibrosis, and superimposed thrombosis affecting dermohypodermic arterioles and venules ( Fig. 3 ). Vascular obstruction leads to ischemia, necrosis, and secondary inflammation (calcifying septal panniculitis).

Calciphylaxis. An eschar over the lateral thigh of a woman who self-administered excessive doses of vitamin D and calcium in the belief that she needed such doses for enhanced health. She developed deep ulcerative lesions over her thighs and buttocks, and some of the lesions evolved eschars such as this one. She died of infection because of compromise of her integument.

Calciphylaxis. Calcium deposits within blood vessels of the subcutaneous fat. Irregular purple spicules of calcium are shown within vessel walls.

In patients with ESRD, the serum levels of PTH, calcium, and/or phosphate tend to be increased. However, most nonuremic calciphylaxis cases have no obvious abnormalities of those parameters. Radiography and computed tomography of the affected areas may reveal vascular and extravascular calcium deposits. In addition, 3-phase technetium methylene diphosphate bone scans can help to define the extension of the disease and also monitor response to therapy. The differential diagnosis of calciphylaxis not only includes systemic necrotizing vasculitides (eg, PAN, cryoglobulinemia, and antineutrophil cytoplasmic antibody (ANCA) associated vasculitis), but also warfarin-induced skin necrosis, primary skin and soft tissue infections, cholesterol atheroembolism, APS, neutrophilic dermatosis, and nephrogenic systemic fibrosis.

Treatment of calciphylaxis remains largely empiric because of its rarity, the incomplete knowledge with regard to its etiopathogenesis, and the absence of therapies showing clear-cut efficacy. Stopping possible offending agents (eg, calcium and vitamin D supplements) and adequate pain control are essential measures. When identified, hypercalcemia and hyperphosphatemia should be corrected to a target calcium × phosphate product less than 55 mg ² /dL ² . The use of corticosteroids in calciphylaxis remains controversial. Agents such as bisphosphonates, cinacalcet, and tissue plasminogen activator have been tried with mixed results. Nonpharmacologic interventions like hemodialysis intensification with low-calcium dialysates, parathyroidectomy, and hyperbaric oxygen have also been used with variable outcomes. Unless otherwise indicated, anticoagulation is not generally indicated. More recently, encouraging preliminary results have been obtained with intravenous administration of sodium thiosulfate (STS). Although good response to STS is typically heralded by rapid improvement of the cutaneous pain, complete resolution of the skin lesions can take up to several months. Possible complications of this therapy include the development of metabolic acidosis. However, the mortality of calciphylaxis commonly exceeds 50% and is usually caused by sepsis. Therefore, aggressive wound care such as surgical debridement when necessary, and prompt antibiotic therapy for superinfected lesions are perhaps the most important therapeutic interventions.

Segmental arterial mediolysis

Segmental arterial mediolysis (SAM) is a rare noninflammatory arteriopathy of unknown cause. This condition has been described in all age groups, but mainly affects adults and elderly individuals, with a slight male predominance. The disease is characterized by the occurrence of vacuolization of tissue in the outer portion of the media. This vacuolization leads to tearing and separation of the media from the adventitia (mediolysis). As the lesion progresses, the internal elastic lamina and the intima are destroyed, creating gaps that allow the blood-filled lumen to dissect into the adventitia. The blood then dissects the vessel wall through the media, presumably because of the action of hemodynamic forces, creating intramural hematomas and dissecting aneurysms. Dissecting aneurysms is a unique arterial lesion combining luminal stenosis with dilatation of the blood vessel diameter. Superimposed thrombosis and arterial rupture are frequently seen.

SAM mainly targets medium-sized arteries within the abdominal cavity. The aorta is almost never involved in SAM, but the celiac trunk, the superior and inferior mesenteric arteries, and their branches are involved in more than 80% of cases. Less frequently, the renal, coronary, carotid, and intracranial arteries are affected. The typical clinical picture consists of acute-onset abdominal pain; usually self-limited. Renal infarctions may prompt further evaluation in either SAM or FMD. Other manifestations of SAM include hematochezia, lumbar or flank pain, gross hematuria, acute coronary syndrome, pancreatitis, subarachnoid hemorrhage, and stroke. Catastrophic presentations caused by arterial rupture, resulting in hemoperitoneum or retroperitoneal bleeding, occur in less than 30% of patients but are associated with high mortality. In addition, SAM can also be subclinical and is sometimes identified incidentally when subjects are imaged for other reasons.

In the absence of easily accessible tissue for biopsy, the diagnosis of SAM relies on identifying representative vascular imaging abnormalities (ie, angiography, CTA, and MRI/MRA) and excluding other entities. Angiographic findings comprise nonspecific arterial aneurysms, stenoses and occlusions, and the characteristic dissecting aneurysms ( Fig. 4 ). The differential diagnosis of SAM includes vasculitides (mainly PAN, Behçet disease, and TAK), mycotic aneurysm, and noninflammatory vasculopathies such as FMD, Ehlers-Danlos syndrome type IV, cystic adventitial artery disease, and cystic medial necrosis (eg, Marfan syndrome). No serum or genetic biomarker is available for the diagnosis of SAM.

SAM. Conventional angiography in a patient with SAM showing aneurysmal dilatation of the right renal artery.

( Courtesy of Dr George Oliveira, Massachusetts General Hospital.)

The treatment of SAM depends on the clinical manifestations. Many presentations resolve spontaneously without major consequences and can be managed conservatively. For cases of arterial rupture and hemorrhagic shock, either intravascular (eg, transarterial coil embolization) or surgical interventions are indicated depending on the gravity of the case. Arterial instrumentation should be avoided whenever possible, because such procedures can lead to arterial dissections.

Antiphospholipid syndrome

The APS is a condition characterized by thrombosis and pregnancy morbidity in the context of circulating antiphospholipid antibodies (aPL). APS can affect all age groups in both genders, but is significantly more common in middle-aged women. The disorder may occur in isolation (ie, primary APS) or in the setting of systemic autoimmune diseases such as SLE.

aPL are a heterogeneous group of immunoglobulins directed against anionic phospholipids or plasma proteins bound to anionic phospholipids (eg, β-2 glycoprotein I or prothrombin). On binding to their antigen, aPL trigger both the clotting and complement cascades and activate cell receptors (eg, apolipoprotein E receptor 2) on the surface of platelets, endothelial cells, and leucocytes. Arterial and venous thromboses are the major features of the syndrome. The most common vascular beds affected are the deep veins of the lower extremities, and the pulmonary, coronary, and intracranial circulation. In addition, several noncriteria clinical features have been described, including thrombocytopenia, hemolytic anemia, valvular heart disease, seizures, cognitive impairment, transverse myelitis, movement disorder (eg, chorea), brain white matter lesions, and renal and skin manifestations (discussed later). An aPL-associated vasculopathy has also been described in association with the mammalian TORC (mTORC) pathway. Some clinical data suggest that sirolimus (rapamycin), an inhibitor of the mTORC pathway, may have therapeutic utility in some APS cases, but this hypothesis requires confirmation. A small percentage of patients with APS develop diffuse alveolar hemorrhage either caused by capillaritis or bleeding diathesis (eg, antithrombin antibodies). Leukocytoclastic vasculitis and responsiveness to the combination of rituximab and anticoagulation have been described in such cases.

APS skin manifestations such as livedo reticularis, livedoid vasculopathy (atrophie blanche), lower extremity ulcers, cutaneous necrosis, digital gangrene, and pseudovasculitic nodules and macules can be difficult to differentiate from PAN, ANCA-associated vasculitis, cryoglobulinemic vasculitis, and Henoch-Schönlein purpura. The distinction between vasculitis and APS is of paramount importance given its therapeutic implications (ie, anticoagulation). aPL nephropathy, which comprises thrombotic microangiopathy and to a lesser extent membranous nephropathy, can represent a challenging differential diagnosis as well. Approximately 1% of patients with APS develop a particularly severe form of disease referred as catastrophic APS (CAPS). Patients with CAPS present with systemic inflammatory response (eg, fever, tachycardia) and widespread macrovascular/microvascular clotting that may lead to encephalopathy, stroke, myocardial infraction, acute respiratory distress, pulmonary embolism, acute kidney injury, and intra-abdominal thrombosis. The clinical picture then may resemble severe sepsis, thrombotic thrombocytopenia purpura, and disseminated intravascular coagulopathy. The mTORC pathway has also been implicated in CAPS.

The key to differentiating APS from vasculitis relies on the presence of persistently circulating aPL (ie, anticardiolipins, anti–β-2 glycoprotein 1 antibodies, and lupus anticoagulant), and the histologic features of the different conditions. Although vasculitides show distinctive anatomopathologic abnormalities (eg, vascular wall fibrinoid necrosis, mural inflammation, immune complex deposition, and even vascular thrombosis as a result of inflammation), the characteristic finding of APS when it affects medium and small vessels is a bland thrombus with absent or minimal vascular or perivascular inflammation. In addition, other serologic markers such as ANCA and cryoglobulins contribute importantly to the approach to diagnosis. The treatment of APS usually requires intravenous heparin followed by oral warfarin. In addition to anticoagulation, patients with CAPS might benefit from high doses of corticosteroids and, at times, plasma exchanges and additional immunosuppression (eg, rituximab, cyclophosphamide). Sirolimus has been proposed for patients with APS-associated vasculopathy in the kidneys and for those with CAPS, but this approach requires further testing.