A 22-year-old woman with systemic lupus erythematosus (SLE) on immunosuppressive agents and antiphospholipid antibody syndrome (APS) on warfarin was admitted with severe postprandial abdominal pain and recurrent fevers.
History of the present illness
The patient had 2 recent hospital admissions. Two months prior to her current presentation, she presented to the emergency department with a tooth abscess for which she underwent incision and drainage, and received a 1-week course of penicillin. One week later, she was admitted with a fever of 40.8°C and was noted to have tooth decay on panoramic radiographs without evidence of an abscess. She was treated with intravenous vancomycin and piperacillin tazobactam for 48 hours and then switched to oral clindamycin. Because of her elevated international normalized ratio (INR), she was unable to undergo tooth extraction prior to discharge.
Two weeks later, she was readmitted with 4 days of recurrent fevers, malaise, diffuse arthralgias, and increased dyspnea with minimal exertion. Previous lupus exacerbations were characterized by arthralgias, rash, and hemolytic anemia. On this admission, laboratory evaluation revealed leukocytosis, worsening anemia and thrombocytopenia, creatinine of 0.7 mg/dl, alkaline phosphatase of 127 units/liter (normal value <111), spot urine protein-to-creatinine ratio of 1.47 (prior 1.1), low C3 and C4, and an increase in her double-stranded DNA by enzyme immunoassay from 120 to 768 IU/ml (normal value <30). She was empirically treated with vancomycin and piperacillin tazobactam given her recent tooth infection. The elevated alkaline phosphatase level prompted an abdominal ultrasound that showed multiple small hypoechoic areas in the spleen. An extensive infectious evaluation, including blood cultures, fungal serologies, knee arthrocentesis, magnetic resonance imaging of the lumbar spine, transthoracic and transesophageal echocardiograms, and computed tomography of the chest, abdomen, and pelvis, was negative. Her viral serologies were also unremarkable, other than evidence of IgG seropositivity for cytomegalovirus (CMV) with a negative viral load, consistent with prior exposure. Despite broad-spectrum antibiotics, she remained febrile. Her baseline prednisone dose of 12.5 mg was increased to 60 mg daily for possible lupus flare, after which she defervesced within 48 hours. Her thrombocytopenia was thought to be secondary to SLE-related idiopathic thrombocytopenic purpura because it resolved with high-dose steroids and intravenous immunoglobulin. She was discharged home 11 days after admission.
The patient remained afebrile for 1 week at home. During this period she developed new-onset progressive upper abdominal pain with meals lasting 20–30 minutes. She denied associated constitutional symptoms, diarrhea, hematochezia, or melena.
Her medical history included SLE diagnosed in 2006 and manifested by mucocutaneous involvement, biopsy-proven bullous lupus erythematosus, arthritis, autoimmune hemolytic anemia, and positive antinuclear, double-stranded DNA, Sm, and SSA antibodies. APS was diagnosed based on pulmonary embolism and the presence of anticardiolipin antibodies and lupus anticoagulant by hexagonal phase phospholipid assay. The patient also had hypertension and multiple infections between 2009 and 2010, including pyelonephritis, Streptococcus pneumoniae bacteremia, and staphylococcal bacteremia with septic pulmonary emboli.
Social and family history
The patient did not have a history of alcohol, tobacco, or drug use. She was living with her sister and healthy 2-year-old son. She had a cousin with SLE and multiple family members with diabetes mellitus.
Medications on admission
The patient's medications at home included prednisone 60 mg daily (increased from 12.5 mg 10 days prior to this admission), mycophenolate mofetil 1,000 mg 2 times daily, hydroxychloroquine 200 mg daily, warfarin 7.5 mg nightly (held for 4 days for a supratherapeutic INR), labetalol 200 mg twice daily, tramadol as needed for pain, an iron supplement, a stool softener, calcium, and vitamin D.
Upon admission, the patient appeared to be in general discomfort without acute distress. Her temperature was 39.1°C, blood pressure was 135/96 mm Hg, pulse was 117 beats/minute, and respiratory rate was 18 breaths/minute with an oxygen saturation of 100% on room air. She had oral thrush without evidence of mucosal ulcers. Bilateral lung fields were clear to auscultation. She was tachycardic without a friction rub. Her abdomen was soft with mild right upper quadrant tenderness to palpation, but without guarding, rebound, or a Murphy sign. Neurologic examination was notable for left foot paresthesias in a peripheral nerve distribution without associated weakness. Neurologic, joint, and skin examinations were otherwise unremarkable.
Laboratory results included hemoglobin of 8.0 gm/dl (normal range 12–15.5), a leukocyte count of 15.8 × 109/liter (normal range 3.4–10) with neutrophils of 90%, a platelet count of 336 × 109/liter (normal range 140–450), an erythrocyte sedimentation rate of >100 mm/hour (normal value <15), albumin of 2.4 gm/dl (normal range 3.4–4.7), creatinine of 0.6 mg/dl (normal range 0.4–1.1), aspartate aminotransferase of 38 units/liter (normal value <41), alanine aminotransferase of 28 units/liter (normal value <54), total bilirubin of 0.8 mg/dl (normal value <1.3), alkaline phosphatase of 138 units/liter (normal value <111), and a C-reactive protein level of 143 mg/liter (normal value <6.3); urine analysis showed 100 mg/dl of protein, negative hemoglobin, and no evidence of infection.
Electrocardiography showed tachycardia with new deep symmetrical T-wave inversions in the precordial leads. Chest radiographs demonstrated stable, mild globular cardiomegaly with clear lungs. A repeat transthoracic echocardiogram revealed a small pericardial effusion and new mildly decreased left ventricular systolic function of 45–50% with new wall motion abnormalities consistent with dilated cardiomyopathy. Abdominal ultrasound revealed numerous gallstones without evidence of cholecystitis, choledocholithiasis, or a sonographic Murphy sign. Multiple tiny hypoechoic lesions throughout the spleen measuring up to 3 mm were unchanged.
Initial hospital course
In the week following her admission, the patient experienced worsening recurrent postprandial abdominal pain. Given the clinical concern for symptomatic cholelithiasis with possible cholecystitis, she underwent laparoscopic cholecystectomy. Prior to surgery, her elevated INR was reversed with vitamin K and she was placed on a continuous heparin infusion. Intraoperatively, she was noted to have an edematous and chronically inflamed gallbladder containing multiple grey-green stones. Following the procedure, she had a failed extubation with flash pulmonary edema and hypertension, and was transferred to the intensive care unit (ICU).
Pathology of the gallbladder
The surgical specimen consisted of a gallbladder (7.5 cm in length × 2.4 cm in diameter × 0.5 cm in average wall thickness). The wall of the gallbladder was moderately edematous. There were multiple firm, green-brown, multifaceted calculi, ranging in size from 0.2–0.7 cm, present within the lumen of the gallbladder, including a single gallstone present within the cystic duct, with dilatation of the cystic duct to 0.7 cm. Representative sections were submitted for microscopic examination.
Histologic review of the gallbladder showed evidence of chronic cholecystitis, including chronic inflammation, edema, and multiple Rokitansky-Aschoff sinuses. There was no evidence of acute cholecystitis or infection. More notably, there was prominent vasculitis in small- to medium-caliber vessels within the gallbladder wall (Figure 1). Numerous muscular arteries within the gallbladder wall showed markedly active vasculitis with fibrinoid necrosis and transmural inflammation of the vessel wall and occasional fibrin thrombi with focal organization within the vascular lumina.
On postoperative day 4, the patient developed abdominal pain and became hypotensive, with a blood pressure of 80/60 mm Hg and a heart rate of 140 beats/minute. This was associated with a supratherapeutic prothrombin time of >100 seconds on a heparin drip and a decline in her hemoglobin from 11.6 gm/dl to 6.2 gm/dl. Antineutrophil cytoplasmic antibodies were negative for myeloperoxidase and proteinase 3. Computed tomography of the abdomen and pelvis demonstrated a large intraperitoneal hematoma in the left upper quadrant with foci of active extravasation (Figure 2A). There was no evidence of bowel wall thickening or lymphadenopathy. She was again transferred to the ICU for aggressive resuscitation and urgently underwent a visceral arteriogram by interventional radiology. The arteriogram did not show active bleeding. However, angiography revealed diffuse pan-vasculitis of the small, medium, and larger mesenteric arteries (Figure 2B). The splenic arteriogram demonstrated multifocal areas of stricturing as well as rounded aneurysms, particularly of the splenic and gastroduodenal arteries (Figure 2C).
In light of her gallbladder pathology and angiographic findings, the patient was treated with intravenous methylprednisolone, 1 gm daily for 3 days, and intravenous cyclophosphamide. Two weeks following her initial intraperitoneal bleed, she was readmitted to the ICU with hypotension and concern for bowel ischemia with possible bacteremia. Empirical antibiotic coverage was started with intravenous vancomycin and ertapenem. Her blood cultures remained negative throughout her hospital course. She remained persistently tachycardic, with heart rates of 130–140 beats/minute. A repeat transthoracic echocardiogram showed global hypokinesis, with a further decrease in her ejection fraction to 25%. Further evaluation, including cardiac catheterization, magnetic resonance imaging, or cardiac biopsy, was not pursued given her critical condition and ongoing treatment for systemic vasculitis. Several days later, after cautious reinitiation of intravenous heparin for APS and her history of pulmonary embolus, she developed a second massive intraabdominal hemorrhage that was treated with resuscitation and urgent interventional radiology embolization of the splenic artery (Figure 3).
Her subsequent course was complicated by ICU delirium, catheter-related urinary tract infection, ongoing malnutrition due to difficulty tolerating enteral feeds, and a sacral decubitus ulcer. She continued to have intermittent fevers, with repeated evaluations for hospital-associated infection. She received a second dose of intravenous cyclophosphamide approximately 1 month after her initial dose.
Two months into her hospital course, she was again transferred to the ICU for fever, a heart rate of 170 beats/minute, and diaphoresis. She was treated with broad-spectrum intravenous antibiotics for possible hospital-acquired pneumonia, oral vancomycin for diarrhea, and ganciclovir for recent positive CMV by polymerase chain reaction, which most likely represented reactivation of latent disease in the setting of systemic immunosuppression. Shortly after an attempted bowel movement, she briefly became bradycardic and had a cardiac arrest with pulseless electrical activity. Advanced cardiac life support commenced and after 85 minutes of attempted resuscitation, the patient died. Her family consented to an autopsy.
At autopsy there was dilated cardiomyopathy with cardiomegaly (400 gm), eccentric hypertrophy of the left ventricle, hypertrophy of the right ventricle, and mild myocyte disarray. There was no evidence of pericarditis, myocarditis, or endocarditis. There were no changes to suggest a viral or toxin-related etiology for the cardiomyopathy. The coronary arteries were unremarkable, without evidence of atherosclerosis or coronary artery vasculitis. Passive congestion in her liver was also present, consistent with right-sided heart failure.
In the abdominal cavity, the mesenteric vessels and splenic, gastric, and extrarenal arteries showed dilatation alternating with stricture. There was a large (13.5 cm) organizing hematoma centralized in the upper right quadrant of the abdomen, adjacent to the splenic artery. There was no evidence of bowel ischemia. Histologically, there was concentric medial fibrosis of the mesenteric vessel walls with scattered rare mononuclear infiltrates (Figure 4). There was no evidence of active, acute-phase vasculitis with neutrophilic inflammation or necrosis in any of the vessels. These findings were consistent with the healed or resolving stage of small- and medium-vessel vasculitis.
The lungs showed bilateral necrotizing pneumonitis of an unclear etiology. Immunohistochemical and special stains were performed in an attempt to identify an infectious etiology of the pneumonitis. A Gram stain and a Grocott's methenamine–silver stain were negative for bacterial and fungal (including Pneumocystis) organisms, respectively. Immunohistochemical stains for adenovirus, CMV, and herpes simplex virus types 1 and 2 were negative. No viral inclusions were identified in the lung or in other tissues. The spleen (150 gm, normal range 150–200) had multiple (>20) irregular, ill-defined, firm, tan-white areas predominantly localized under the splenic capsule, consistent with multiple infarcts throughout the parenchyma, which were confirmed histologically. Additionally, on microscopic evaluation, there was concentric periarterial fibrosis or “onion skinning” of the intraparenchymal arteries.
There was evidence of multiple infarcts without evidence of associated thrombi, including a small infarct in the right lung and multiple old infarcts in her kidneys and spleen, which can be seen with vasculitis or, less likely, thromboembolic events in the absence of associated thrombi. Her kidneys showed no evidence of wire loop glomerular lesions seen with lupus nephritis on both hematoxylin and eosin– and periodic acid–Schiff–/Jones silver–stained sections. Additional findings at autopsy included alopecia, pallor of the conjunctivae and mucosal membranes consistent with anemia, and calcification of the bilateral basal ganglia.
This 22-year-old woman with SLE and APS with systemic vasculitis died of complications from her SLE. The autopsy revealed multiple sequelae of SLE, including dilated cardiomyopathy, evidence of treated/resolved vasculitis, concentric arteriolar fibrosis of the spleen, calcification of the bilateral basal ganglia of the brain, and mild osteoporosis.
We describe a patient with SLE and APS who was diagnosed with fulminant mesenteric vasculitis involving small- and medium-caliber vessels after presenting with high-grade fevers, abdominal pain, and markedly elevated inflammatory markers. Histologically, the diseased vessels demonstrated evidence of response to treatment with high-dose glucocorticoids and intravenous cyclophosphamide. The patient presumably died from cardiac arrhythmia.
The differential diagnosis in this case of severe medium-vessel vasculitis complicated by visceral artery aneurysms includes lupus mesenteric vasculitis versus secondary causes of visceral aneurysms and vasculitis mimickers such as infectious or APS-associated aneurysms.
Visceral aneurysms associated with lupus vasculitis
Multiple arterial microaneurysms involving more than one organ, such as the kidneys, liver, or gastrointestinal (GI) tract, are highly characteristic of medium-vessel vasculitis. Lupus can cause a medium-vessel vasculitis that is pathologically indistinguishable from that seen in polyarteritis nodosa (PAN). In the appropriate clinical setting, diagnosis is based on characteristic angiographic findings and, ideally, confirmed by tissue biopsy demonstrating a panarteritis of small or medium vessels with fibrinoid necrosis.
Our patient had multiple signs and symptoms consistent with an underlying vasculitis. However, the most salient features were her angiographic findings of diffuse saccular aneurysms involving multiple mesenteric organs (Figures 2B and C). Additionally, on histologic examination, her gallbladder showed extensive vasculitis within predominately medium-caliber arteries, demonstrating the prototypical findings of marked fibrinoid necrosis of the vessel wall consistent with a lupus or PAN-like vasculitis.
Visceral aneurysms associated with vasculitis mimickers
Diffuse visceral microaneurysms as seen in lupus or PAN can be mimicked by bacterial, mycobacterial, or fungal infections or APS. Infected aneurysms are called mycotic aneurysms. Acute bacterial endocarditis is the most common cause of mycotic aneurysms and can occur in 3–15% of patients. Although they usually occur in branches of the aorta, they can also involve the visceral arteries. Most reported cases of visceral mycotic aneurysms occur as a single or few aneurysms involving one of the visceral territories. Multiple visceral aneurysms as seen in this case would be extremely rare (1, 2). Our patient's evaluation was negative for infectious etiologies despite thorough evaluations. She had repeatedly negative blood cultures, no evidence of vegetations on multiple echocardiograms, and negative fungal serologies. Additionally, her gallbladder pathology and autopsy results did not identify any evidence of infection.
APS has also been described in association with visceral aneurysms (3, 4). However, this is a very rare occurrence and would be extremely unlikely to occur while a patient is therapeutic on anticoagulation. In our patient, there was no evidence of thrombosis or thrombotic microangiopathy in her gallbladder, mesenteric vessels, or elsewhere in the visceral organs.
Vasculitis is a destructive inflammation of the blood vessel walls (5). This inflammatory vascular process can manifest in different forms due to its ability to affect vessels of different sizes (arteries, veins, and/or capillaries) and sites (involving skin or internal organs). Observational studies have reported an 11–36% prevalence of vasculitis in the setting of SLE (6, 7). The vasculitis is typically limited to small vessels and the primary pathology is leukocytoclastic vasculitis. It is most commonly recognized in the skin (6), but can involve other organ systems, including the GI tract (8–11); its presence is associated with increased mortality (6).
GI symptoms can occur in up to 50% of patients with SLE, but are usually mild (8). SLE can involve the entire GI tract, from the mouth (oral ulcers, dysphagia) to the small and large bowel, and the liver (11). An acute abdomen can be a troubling and not uncommon manifestation of SLE. When evaluating a patient with abdominal pain, it is critical to rule out non-SLE conditions such as pancreatitis, cholecystitis, and a surgical abdomen. In addition, a thorough infectious evaluation must be undertaken given their underlying risk factors (12). Although uncommon, vasculitis of the GI tract also must be considered in the differential diagnosis. Mesenteric vasculitis is a rare manifestation of SLE that can present with a range of symptoms from cramping, bloating, and anorexia to an acute abdomen with diarrhea and GI hemorrhage. An accurate diagnosis and prompt treatment are essential to prevent the potential catastrophic complications of necrotic bowel, perforation, and sepsis. Lupus mesenteric vasculitis typically involves the small vessels of the bowel submucosa (10). Its reported prevalence ranges from 0.2–9.7% among patients with SLE and from 29–65% in patients whose presentation includes acute abdominal pain (10).
Medium- and large-vessel vasculitides are distinctly uncommon entities in SLE and are limited only to case reports, as reviewed by Kumar et al (13). Necrotizing medium-vessel vasculitis has previously been reported in gallbladders of patients with SLE (14). Medium-vessel vasculitis of the gallbladder has also been described in a pediatric case of SLE with acalculous cholecystitis (15).
Histopathologic evidence of medium-vessel vasculitis has been reported in the hepatic vessels of SLE patients. Hepatic arteritis resembling PAN, affecting medium-sized vessels, was identified in 18% of 60 patients with SLE at autopsy (16). This suggests that medium-vessel vasculitis may be an underrecognized or difficult-to-diagnose entity in SLE patients with specific organ-limited disease.
Although mesenteric vasculitis due to catastrophic APS has also been described in the literature (17, 18), our patient did not have clinical evidence suggestive of active APS or diffuse thrombotic microangiopathy in her gallbladder or mesenteric vessels. The infarcts in her kidney and spleen noted on autopsy were most likely related to her vasculitis, leading to massive hemoperitoneum and subsequent low output state. Although these infarcts can result from thromboembolic events seen with APS, no thrombi were identified. The splenic infarcts involved less than 50% of the splenic parenchyma, which is unlikely to significantly impair functionality. This is supported by the lack of bacterial infection in any tissues at autopsy, making functional asplenia unlikely.
There have been rare reports of PAN-like vasculitis in SLE with necrotizing vasculitis on biopsy or autopsy (13, 19). In a study by Burke et al (20), 1 of 33 patients with a histopathologic diagnosis of polyarteritis had SLE. Overall, there are limited case reports of a medium-vessel vasculitis developing in patients with SLE/discoid lupus erythematosus (21–23).
The cause of the patient's cardiomyopathy was not clearly elucidated on autopsy. There was no evidence of vasculitis, significant atherosclerosis, or vasculopathy in her cardiac vessels to explain her decline in cardiac function. Cardiac involvement in SLE is well recognized, although the mechanisms involved in cardiac injury have not been well defined. Prior studies have suggested a positive correlation between the degree of immune complex deposition in cardiac tissue from patients with SLE and their disease activity (24). A decline in cardiac function, as measured by cardiac imaging, has also been observed during active disease periods, which normalize or improve after clinical improvement in disease activity (25, 26). While SLE-related dilated cardiomyopathy is largely a diagnosis of exclusion, the lack of findings indicating a secondary etiology in this patient suggests her cardiomyopathy was related to her underlying SLE. It is also possible that the elaboration of cytokines from her fulminant vasculitis together with ongoing pneumonitis and significant tachycardia contributed to the patient's worsening dilated cardiomyopathy.
In summary, we present a case of extensive mesenteric vasculitis in a patient with SLE. The patient's massive hemoperitoneum was successfully managed with splenic artery embolization. The diffuse mesenteric vasculitis demonstrated resolution after pulse steroids and intravenous cyclophosphamide therapy. Unfortunately, our patient died despite evidence of successful treatment of her vasculitis. Given the sudden nature of her death and her severe dilated cardiomyopathy, it is likely that she had a cardiac arrhythmic event leading to death. Angiographic imaging of the mesenteric vessels and pathology of the gallbladder and abdominal arteries showed extensive vasculitis of primarily medium vessels. This case alerts physicians to be mindful of rare, atypical, and extensive-spectrum systemic vasculitis in patients with underlying connective tissue disease.
SLE-associated diffuse small- and medium-caliber–vessel mesenteric vasculitis responsive to intravenous cyclophosphamide therapy and corticosteroids.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Ashouri had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Ashouri, Davis, Farkas, Durack, Dall'Era.
Acquisition of data. Ashouri, Davis, Farkas, Durack, Dall'Era.
Analysis and interpretation of data. Ashouri, Davis, Farkas, Durack, Ramachandran, Dall'Era.