Expanded spectrum of antineutrophil cytoplasmic antibody–negative vasculitis involving vessels from capillaries to medium-sized arteries

Authors


CASE PRESENTATION

Chief Symptoms

A 74-year-old man transferred to our institution in early April 2011 for weakness, confusion, and kidney dysfunction.

History of the Present Illness

The patient was admitted to a local hospital 2 weeks prior for a 3-month duration of weight loss, generalized weakness, and progressive lower extremity pain. The symptoms started gradually, without any notable antecedent event. He felt weak, lost appetite, and developed intermittent dry cough and pain in the lower extremities, initially in the thighs, and progressed to bilateral legs. In a matter of months, his health deteriorated from being physically active and independent to mostly bedridden.

Evaluation at the local hospital revealed low-grade fever (37.9°C), mild hypertension (140–150/90 mm Hg), multiple new lung nodules on a contrast-enhanced chest and abdominal computed tomography (CT) scan, and an elevated serum creatinine concentration of 2.6 mg/dl (from his baseline of 0.9 mg/dl approximately 6 months ago) with microscopic hematuria. Screening for hepatitis B and C, antinuclear antibodies, complements, and antineutrophil cytoplasmic antibody (ANCA) panel (myeloperoxidase [MPO] and proteinase 3) was negative. His erythrocyte sedimentation rate (ESR) was 49 mm/hour (reference range 0–25). A transbronchial biopsy sample of several lung nodules showed no evidence of malignancy or active infection and was interpreted as nondiagnostic. For his lower extremity pain, he was empirically treated with intravenous (IV) immunoglobulin for possible Guillain-Barré syndrome. The treatment was discontinued 4 days later after an electromyogram sample revealed primary axonal sensory motor peripheral neuropathy. His kidney dysfunction worsened following intravenous contrast exposure for the CT scan; his serum creatinine level rose to 3.4 mg/dl. He underwent a left kidney percutaneous biopsy that was read as possible crescentic glomerulonephritis. IV methylprednisolone, 500 mg once daily, was initiated. During his hospital stay, the patient developed episodic confusion. A spinal tap was performed and showed no abnormality, nor evidence of syphilis or West Nile virus infection. Two days following the initiation of IV methylprednisolone, his condition further deteriorated with worsening extremity weakness to the point that he could not ambulate with assistance and mental confusion. He was then transferred to our institution.

Medical History

His medical history included severe hearing loss from noise trauma, tuberculosis exposure more than 30 years ago, and chronic sinusitis (stable for more than 10 years), and benign prostate hypertrophy, controlled with medication.

Social and Family History

The patient had been smoking cigarettes, one-half pack per day, for more than 20 years and reported using alcohol intermittently. He had no known family history of chronic medical illness.

Medication on Admission

He was receiving prednisone 60 mg once daily (day 1, following a 3-day course of IV methylprednisolone), heparin 5,000 units subcutaneously every 8 hours, amlodipine 5 mg oral twice daily, dutasteride oral 0.5 mg daily, ondansetron IV as needed for nausea, acetaminophen as needed for fever, and diphenhydramine 50 mg IV as needed for itching.

Physical Examination

Upon arrival, his blood pressure was 142/75 mm Hg, pulse was 108 beats/minute, and respiratory rate was 21 breaths/minute. He appeared cachectic (body mass index 17.0 kg/m2) with temporal wasting and older than his age. He was oriented only to his name and followed commands inconsistently. His mucosa was dry, but he had no oral, nasal, or pharyngeal ulcer and no skin rash. Bilateral lung fields were mostly clear with a few bibasilar crackles. He was tachycardic with occasional premature ventricular beats, and no murmurs or rubs. His abdomen was mildly distended, mildly tender at all quadrants, and bowel sounds were normal. Extremities showed pitting edema extending from the feet to thighs. His cranial nerves were intact (although the participation was inconsistent). Upper extremity strength was full with the exception of weakened interosseous strength bilaterally. Deep tendon reflexes of the upper extremities were normal. In the lower extremities, there was flaccid foot drop (left > right) and muscle weakness (distal > proximal). The knee reflex was normal on the left but hypoactive on the right. Ankle jerk was absent bilaterally. Plantar response was muted and cerebellar signs absent.

Laboratory Evaluation

Laboratory results included hemoglobin of 7.7 gm/dl, leukocyte count of 23.7 × 109/liter with neutrophils of 94%, platelet count of 489 × 109/liter, ESR of 72 mm/hour, albumin of 2.7 gm/dl, potassium of 3.6 mmoles/liter, bicarbonate of 22 mmoles/liter, blood urea nitrogen of 116 mg/dl, and creatinine of 2.4 mg/dl. Urinalysis revealed a protein:osmolality ratio of 1.06 with 3–10 red blood cells (RBCs)/high-power field and >25% of which were dysmorphic. Repeat serologic evaluation, including hepatitis screen, complements, ANCA, anti–glomerular basement membrane, anti–double-stranded DNA, SSA, SSB, RNP/Sm, Jo-1 antibody, and Scl-70, was negative. There were no detectable paraproteins in serum and urine.

Hospital Course

The patient was continued with oral prednisone treatment (60 mg daily). On the third hospital day, he developed acute abdominal pain and distention. Ultrasound-guided paracentesis had hemorrhagic return; shortly after, he collapsed and his blood pressure dropped to 30/20 mm Hg. He was resuscitated and immediately taken to the operating room. A large hematoma was evacuated from the lesser sac. Thorough inspection showed no active bleeding at the time; however, the left hemicolon appeared slightly pale. He was transferred to the intensive care unit and his abdomen was left open (covered with temporary dressing) with an intent for reevaluation. His abdomen was reinspected the following day. The left hemicolon showed evidence of infarction with scattered areas of hemorrhage and intramural necrosis. There were palpable thrombi in the middle colic artery and inferior mesenteric artery. Left hemicolectomy was carried out. During ligation and division of the marginal artery, a large amount of pus was extruded from the mesentery (culture of the extrusion was negative for growth). His hemicolectomy specimen and kidney biopsy slides (from the local hospital) were evaluated by pathology.

Pathology of the Resected Colon

In total, a 33-cm portion of the left colon with a 12 × 10 × 3 cm portion of omentum was present. There were patchy bowel wall ischemic and necrotic changes with corresponding mesenteric hemorrhage. Representative segments were sectioned. Microscopically, noncircumferential fibrinoid necrosis of small and medium-sized mesenteric and colonic arteries was seen, with intervening segments showing intact and normal media. In fibrinoid necrotic areas, the media and adventitia were involved by prominent inflammatory infiltrates that were rich in neutrophils and devoid of giant cells and granulomas. Two distinct abnormalities were noted in the areas of fibrinoid necrosis: multiple arterial aneurysms and luminal obstruction. Some dilated arteries represent true aneurysms, while others represent false aneurysms (i.e., contained ruptures) consistent with a vasculitis-associated aneurysm rupture as the cause of his acute hemoperitoneum. A few arteries showed complete occlusion with varying stages of thrombus and fibrotic plugs consistent with arteritic lesions of various ages (Figure 1).

Figure 1.

Representative pathology images of the patient's resected colon and mesentery, showing necrotizing arteritis, occlusions, aneurysms, and coexistence of acute and healed vasculitic lesions. A and B, Hematoxylin and eosin (H&E) and Verhoeff–van Gieson (VVG) staining showing a cross-section of a normal artery. C, H&E staining of a cross-section of an artery with segmental medial necrosis. D, H&E staining showing circumferential arteritis with fibrinoid necrosis and thrombosis. E and F, VVG staining showing obstructive and occlusive intimal proliferation in subacute healing lesions. G and H, VVG staining of cross-sections of arteries showing aneurysms (a) and rupture (*).

Histologic diagnosis of the colonic specimen consisted of active vasculitis involving small and medium-sized arteries at varying stages, acute colonic infarction, and pericolonic fat necrosis.

Pathology of Kidney Biopsy

A single core of renal tissue, mostly renal cortex, was present. Of the total 18 glomeruli, 3 were globally sclerosed and 4 showed segmental scars with segmental collapse of the sclerosed/scarred segment to the Bowman's capsule. Three showed extracapillary proliferation resulting in the formation of crescents; segmental fibrinoid necrosis was also noted (Figures 2A and B). There was no evidence of endocapillary or mesangial proliferative features. The glomerular basement membranes were of normal thickness. RBC casts were noted in the tubules. Tubules also showed degenerative changes with distention, flattening epithelium, and necrotic debris in the lumen. Moderate interstitial inflammation with a mononuclear cell predominant infiltration was noted. Overall, there was ∼30% tubular atrophy and interstitial fibrosis. Two arteries were present showing evidence of necrotizing arteritis with fibrinoid material within the vessel walls with perivascular inflammation (Figure 2C). Immunofluorescent studies showed no staining signals for IgA, IgG, IgM, C1q, C3, fibrinogen, κ or λ light chains.

Figure 2.

Representative images of the patient's kidney biopsy sample showing necrotizing crescentic glomerulonephritis and intrarenal arteritis. A, Hematoxylin and eosin (H&E) staining showing necrotizing glomerulonephritis with crescent formation. B, Silver stain showing a crescentic lesion (black arrows show ruptures of the Bowman's capsule; the white arrow shows a necrotizing vessel). C, Trichrome stain showing necrotizing arteritis with fibrinoid material within the vessel.

The kidney biopsy diagnosis was pauci-immune necrotizing and crescentic glomerulonephritis and necrotizing arteritis.

Initial Diagnosis

The initial diagnosis consisted of ANCA-negative systemic vasculitis involving the kidney (necrotizing crescentic glomerulonephritis and intrarenal vasculitis) and colon (mesenteric and colonic small and medium-sized arteritis with arterial occlusions, aneurysms, and aneurysm ruptures).

CLINCIAL COURSE AND FOLLOWUP

In light of the patient's acute hemorrhage and biopsy results, IV methylprednisolone was reinitiated. Following appropriate coverage for potential sources of infection, IV cyclophosphamide, a modified dose for his renal failure, was initiated. He remained nonoliguric and his serum creatinine level remained at 2.4–2.7 mg/dl, but his serum urea nitrogen rose to more than 120 mg/dl associated with worsening drowsiness. Several sessions of hemodialysis were provided. His mental status improved considerably; he became coherent and able to carry on meaningful conversations. Ten days following the initiation of steroids plus cyclophosphamide, his ESR reduced to normal range (11 mm/hour), and hemodialysis was discontinued. He was subsequently discharged in stable condition (serum creatinine 2.0 mg/dl). He is being followed at rheumatology and nephrology as an outpatient and has been receiving daily steroids and monthly IV cyclophosphamide.

CASE SUMMARY

We describe a patient with ANCA-negative systemic vasculitis who developed necrotizing crescentic glomerulonephritis and fulminant mesenteric arteritis resulting in kidney failure, bowel infarction, and massive hemoperitoneum from mesenteric aneurysm rupture. Histologically, the disease exhibited features prototypical for both polyarteritis nodosa (PAN) and microscopic polyangiitis (MPA). The patient survived with prompt surgical and medical treatment.

DISCUSSION

Systemic vasculitis has been classified to a number of disease entities based on the size of the affecting vessels and clinical characteristics. In 1994, the Chapel Hill Consensus Conference (CHCC) defined PAN as necrotizing inflammation of small and medium-sized arteries without glomerulonephritis, and MPA as smaller-vessel (arterioles, capillaries, and venules) vasculitis featuring pauci-immune necrotizing glomerulonephritis (1). The majority of MPA cases are associated with positivity to MPO ANCA (2). The 2 entities exhibit distinct features, as summarized in Table 1 (3–6).

Table 1. Clinical and pathologic features of PAN and MPA*
 PANMPA
  • *

    PAN = polyarteritis nodosa; MPA = microscopic polyangiitis; GI = gastrointestinal; ANCA = antineutrophil cytoplasmic antibody.

  • Denotes the features present in our patient.

  • Our patient had new lung nodules on computed tomography.

Incidence0.9/million10.1/million
Age of onset, range years40–5060–70
Small and medium-sized arteritisMedium > smallSmall > medium
Arterial aneurysmsUp to 90%Rare
GlomerulonephritisNo∼90%
GI symptoms (pain, ischemia, infarction, and hemorrhage)∼50–70%∼20–30%
ANCA positivityNo∼80%
Weight loss >4 kg++
Fevers++
Mononeuritis multiplex or polyneuropathy∼60–80%∼14–36%
Skin involvement++
Muscle weakness∼60%, severeMild
Hypertension++
Pulmonary abnormalitiesNo∼50–70%

By CHCC definition, PAN is necrotizing vasculitis confined to the small and medium-sized arteries, whereas MPA primarily affects capillaries, venules, or arterioles (1). MPA may occasionally involve small and medium-sized arteries. However, reports of MPA with small and medium-sized artery involvement were mainly derived from autopsy studies. In 1998, Inoue et al reported an autopsy study of 31 MPA cases (7). Six of the 31 showed evidence of necrotizing vasculitis involving small-sized muscular arteries (interlobular arteries and arterioles) in the kidneys. Three of the 6 cases showed evidence of medium-sized muscular artery involvement (interlobular and/or arcuate arteries of the kidneys). However, prior to death, none of the 6 patients were clinically diagnosed with vasculitis, suggesting either the vasculitis was confined to the kidney or involved other organ systems but was unrecognized premortem. These patients had a more aggressive disease course, and death ensued within 1.5 to 3.5 months. There were no ANCA studies on these patients as the study was conducted in the pre-ANCA testing era. In 2009, Yahata et al described a patient with clinical diagnosis of MPA on the basis of positive MPO ANCA and kidney dysfunction (no biopsy) (8). The patient was treated with steroids for approximately 2 weeks when she died suddenly from acute hemorrhage. Postmortem examination revealed rupture of the left gastric artery, but there was no notable vessel-wall inflammation or aneurysm on the pathologic examination. The authors speculated whether the steroid treatment might have contributed to the gastrointestinal catastrophe. Postmortem examination of the kidneys revealed pauci-immune glomerulonephritis and necrotizing angiitis involving interlobular arteries, similar to what was described by Inoue et al (7). There was only 1 additional case of hemoperitoneum in an MPA patient, who was also MPO ANCA positive but did not survive treatment (9). The definitive diagnosis was made postmortem.

Our patient exhibited features prototypical for PAN and MPA clinically and pathologically (Table 1), making diagnostic categorization difficult. In PAN, aneurysms are demonstrated in up to 90% of affected patients, and the gold standard for the PAN diagnosis lies in the demonstration of focal segmental transmural necrotizing inflammation of medium-sized arteries of varying stages. Characteristically, luminal stenosis and occlusion associated with fibroblastic proliferation of healing-stage vasculitis are coexistent with multiple saccular aneurysms from the weakened vessel wall in the acute stage of vasculitis (10). Our patient's pathology in the resected bowel fits extremely well with the gold standard. On the other hand, he also had pauci-immune necrotizing glomerulonephritis, characteristic for MPA. Strictly applying the CHCC diagnostic criteria, our patient may be categorized as having MPA with an unusual degree of small and medium-sized artery involvement. The extent to which the mesenteric muscular vessels are involved in this case is highly atypical for MPA. This dilemma was highlighted by an expert panel convened to identify areas of concern in the existing definition/criteria in systemic vasculitis (11). The panel indicated that while the predominant vessel size and type remain a major discriminator for different types of vasculitis, a category of “no-predominant vessel size” should be added to the existing categories of small- and large-vessel vasculitis. Our case would fall into the “no-predominant vessel size” category.

The activity and risk of death related to systemic vasculitis have been assessed by 2 major scoring systems, the Birmingham Vasculitis Activity Score (BVAS) (12), which takes symptoms and signs from 9 organ systems to predict the disease activity, and the Five-Factors Score (FFS) (13), which predicts the risk of death incrementally with cumulating variables of proteinuria, kidney dysfunction, gastrointestinal manifestations, and cardiac and central nervous system involvement. Our patient scored 35 on the BVAS (active disease score 1–20, premorbid score 9–30 [12]) and had 4 of the 5 factors in the FFS. His age, renal failure, and gastrointestinal involvement all portend a poor prognosis and high risk of death (5, 14).

Therapy for PAN and MPA, fortunately, is unambiguous. A combination of steroids and cyclophosphamide is the mainstay treatment for both conditions. In our patient, timely detection and resection of the infarcting bowel and initiation of steroids and cyclophosphamide effectively arrested the disease activity.

In summary, we present a case of fulminant vasculitis involving varying-sized vessels from capillaries in the kidney to medium-sized arteries in the mesentery, leading to renal failure, bowel infarction, and massive hemoperitoneum from aneurysm rupture. Pathology of the bowel and kidney showed changes seen in classic PAN and MPA. The patient survived with combined surgical and medical therapy. This case alerts physicians to be mindful of rare, atypical, and extended-spectrum systemic vasculitis. Early recognition and prompt management can avoid mortality.

FINAL DIAGNOSIS

Expanded spectrum of antineutrophil cytoplasmic antibody–negative vasculitis involving vessels from capillaries to medium-sized arteries.

AUTHOR CONTRIBUTIONS

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. Qian 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. Qian, Thanarajasingam, Sawyer, Edwards.

Acquisition of data. Qian, Thanarajasingam, Oeckler, Edwards.

Analysis and interpretation of data. Qian, Thanarajasingam, Oeckler, Sethi, Edwards.

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