Case Report

ANCA-negative associated vasculitis initially presenting with pulmonary embolism O. Filleul, P. Madhoun, M. Vanhaeverbeek Hoˆpital Andre´ Ve´sale, CHU de Charleroi (Universite´ Libre de Bruxelles), Montigny-Le-Tilleul, Belgium Antineutrophil-cytoplasm antibodies (ANCA)-associated vasculitis are severe inflammatory pathologies that, although rare, may induce significant morbidity or death. Their impact on multiple organ systems implies an important variability in their clinical presentation, which might delay the diagnosis. In this setting we report on a case of ANCA-negative-associated vasculitis, initially presenting as pulmonary embolism with severe pulmonary infarction and digestive involvement. Literature is then discussed on these complications and their implications for therapy. Keywords: Vasculitis, ANCA-negative, Pulmonary embolism, Extracapillary proliferative glomerulonephritis

Introduction Antineutrophil-cytoplasm antibodies (ANCA)-associated vasculitides are rare pathologies, representing about 21 cases per million patient-years.1 They are associated with significant morbidity, whose burden increases over time and includes renal failure, hypertension, airway involvement and peripheral neuropathy,2 with as much as 77% of patients developing renal failure.1 Although ANCA secretion constitutes the serological hallmark of these diseases, there exists considerable heterogeneity in clinical and serological presentations.3 Four clinical presentations are classically described, based on the revised Chapel-Hill classification: these include micro-polyangeitis, associated with anti-Myeloperoxydase antibodies, granulomatosis with polyangeitis, associated with antiProteinase 3 antibodies, eosinophilic granulomatosis with polyangeitis, whose serological profile may be mixed, and finally ANCA-negative associated vasculitis. They differ mainly in the frequency of targetorgan involvement, with respiratory airway impairment being more prevalent in granulomatosis with polyangeitis than in micropolyangeitis, fuzzed by an important overlap due to classification conflicts.3,4 In this work, we report on a patient whose vasculitis first manifestation was pulmonary embolism.

Case Description The patient is a 43-year-old male, initially admitted to our hospital for dry cough, dyspnea and paroxysmal Correspondence to: O. Filleul, Hoˆpital Andre´ Ve´sale, Universite´ Libre de Bruxelles, Route de Goze´e 706, 6110 Montignies-Le-Tilleul, Belgium. Email: [email protected]

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left-sided thoracic pain, which had developed over a few days. His medical history was positive for atrial fibrillation, atrial flutter that manifested with left amaurosis fugax, anal condyloma, appendicitis and traumatic sternal fracture years before, alcohol, cannabis and tobacco abuse; he did not take any regular medications, had not traveled recently and lived single as an unemployed hotel receptionnist. On admission to our emergency departement, he was apyretic, with an arterial blood pressure of 130/ 90 mmHg, heart rate of 101 bpm, temperature 36.2uC and 96% of oxygen saturation while breathing ambient air. Thoracic wall tenderness and left basal hypoventilation were found, as well as hyperleucocytosis, an inflammatory syndrome and metabolic alkalosis. Thoracic computed tomography demonstrated bilateral lower lobes infiltrates (Fig. 1a), and he was subsequently treated with levofloxacin for seven days, with a provisional diagnosis of atypical pneumonia. Worsening of the inflammatory syndrome after 48 hours of therapy prompted the realisation of a thoracic angiographic computed tomography (angioCT), which demonstrated left inferior lobar artery embolism (Fig. 1b). Lower limbs Doppler ultrasonography and abdominal and pelvic computed tomography did not reveal any sign of deep vein thrombosis, and therapeutic-regimen enoxaparin was started; right ventricle dilatation and pulmonary artery hypertension were ruled out by echocardiography. Transverse and right colic submucosal edema was incidentally noted on the abdominal CT. Hemoptysis developed two weeks after admission, and worsening of the left pulmonary condensation

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Figure 1 Medical imaging. (a) Admission CT displaying faint infiltrates. (b) Angio-CT displaying left pulmonary embolus (arrow) and associated pulmonary infarct. (c) Control CT demonstrating pleural effusion worsening. (d) Abdominal CT displaying duodenal parietal edema (arrow). (e) PET-CT showing right colic hypermetabolism. (f) Kidney biopsy showing extracapillar inflammatory crescent (arrow, trichrome stain). (g) Extracapillar crescent with rupture of Bowman’s capsule (arrow, hematoxylin-eosin and PAS stain).

and of the associated pleural effusion was noted, with worsening of the biological inflammatory syndrome (Fig. 1c). Empirical antibiotherapy with piperacillintazobactam was prescribed, without resolution. The pleural effusion proved to be a sterile hemothorax, and extensive microbiological studies, including bronchiolo-alveolar lavage, remained negative; serological tests for Chlamydia pneumoniae were positive. Three weeks after admission, daily vesperal and night fever developed, accompanied by rigors, diffuse myalgias, shoulder and knee bilateral arthralgias, loss of visual acuity, sterile hematuria, weight loss, arterial hypertension and rapidly progressive kidney failure; creatinine level reached 3.8 mg/dl (estimated clearance 17 ml/minute following the MDRD formula). No signs of bucco-genital ulcerations, adenomegaly or uveitis were found. Twenty-four-hour proteinuria was 1.56 g/24 hours. Testing for antinuclear factors, ANCA, rheumatoid factor and anti-glomerular basal membrane antibodies was negative. Renal venous and arterial thrombosis were excluded by contrast-enhanced computed tomography. On this examination, parietal duodenal and mesenteric edema was also incidentally noted; no corresponding abnormalities were found on endoscopy two days later (Fig. 1d). F18-labelled fluorodeoxyglucose positon emission tomography ordered a few days later showed light left pleural hypermetabolism and marked terminal ileal and right colic captation (Fig. 1e). Ordered after discussion of the thrombo-embolic risk of anticoagulation cessation in this patient with newly diagnosed pulmonary embolism, kidney biopsy finally revealed active extra-capillary, proliferative and necrotizing vasculitis with vasa recta angiitis sequelae (Fig. 1f and g). On basis of the clinical features and negative ANCA testing, a diagnosis of ANCA-negative associated vasculitis was made, based on the revised Chapel-Hill classification. The patient was then treated with acenocoumarol anticoagulation, high-dose methylprednisolone and oral cyclophosphamide. Progressive kidney function recuperation, inflammatory syndrome response and symptom clearance were achieved within five days, and despite condyloma recurrence, he is at least in partial remission. Nearly 3 months after treatment initiation, creatinine level decreased to 1.4 mg/dl and urinary sediment was less active.

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Discussion Following the revised Chapel-Hill classification, ANCA-negative associated vasculitis is grouped with granulomatosis with polyangiitis and microscopic polyangiitis. Despite lacking the characteristic antibodies of these pathologies, assumed to have pathogenetic properties, its clinical course most closely mimics that of seropositive disease, and gastrointestinal involvement is an adverse prognostic factor.3,4 Prognosis of these diseases is usually unfavorable, with most patients suffering significant morbidity in the long term.2 Suspecting these pathologies, and obtaining rapid definite histopathologic diagnosis in time, can decrease patient impairment by intensive treatment when lesions are still reversible. In our patient, suspicion of a progressive vasculitis came from the association of lesions in multiple systems following an identification pattern, in the absence of proven underlying infection. Worsening pulmonary embolism, without active neoplasia, obvious venous thromboses nor overt thrombophilia, suggested an inflammatory condition, as did the general symptoms and fever kinetics. The conjunction of sterile worsening pulmonary condensations, hematuria and rapidly progressive kidney failure then led us to suspect a systemic vasculitis, whose renal involvement appeared most significant for our patient’s outcome. This is why kidney biopsy was finally considered. Although inflammatory conditions are a recognized predisposing factor of venous thromboembolic disease, only seldom are they initial manifestation of vasculitis. In their series, Stassen et al. showed that only 8% of thrombo-embolic events associated with ANCA-associated vasculitis occured before diagnosis; they were correlated with disease activity.5 As a second particularity, this case displayed unusual probable digestive involvement. Although not characterized precedently in ANCA-negative associated vasculitis, digestive complications – frequently viscera wall ulceration and perforation – are described in 7% of ANCA-associated vasculitides.4 However, its fluctuant course in our patient prevented us from obtaining endoscopic or histological confirmation. Besides anticoagulation in our case, currently recommended therapy for these pathologies includes corticosteroids and immunosuppressive agents.

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Cyclophosphamide is the most studied agent, having proved its efficiency in renal-impairing inflammatory vasculitis. A few dosing regimens have been studied, without demonstrating any superiority of intravenous therapy over oral treatment; this latter approach was then chosen in our patient, supported by results of CYCLOPS study from the European Vasculitis Study Group.

Conclusion ANCA-associated vasculitides are a group of heterogenous, systemic inflammatory conditions that result in important morbidity if not diagnosed and treated early. The case we describe here highlights the need of close follow-up of patients whose clinical course is unfavorable despite seemingly appropriate therapy; a high clinical suspicion is needed to diagnose these

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pathologies and avoiding further complications or death.

References 1 Kobayashi S, Fujimoto S. Epidemiology of vasculitides: differences between Japan, Europe and North America. Clin Exp Nephrol. 2013;17(5):611–4. 2 Harper L. Morbidity in patients with ANCA-associated vasculitis. Presse Med. 2013;42(4 Pt 2):612–6. 3 Lionaki S, Blyth ER, Hogan SL, Hu Y, Senior BA, Jennette CE, et al. Classification of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis. Arthritis Rheum. 2012;64(10):3452–62. 4 Mahr A, Katsahian S, Varet H, Guillevin L, Hagen EC, Ho¨glund P, et al. Revisiting the classification of clinical phenotypes of anti-neutrophil cytoplasmic antibody-associated vasculitis: a cluster analysis. Ann Rheum Dis., 72(6):1003–10, June 2013. 5 Stassen PM, Derks RP, Kallenberg CG, Stegeman CA. Venous thromboembolism in ANCA-associated vasculitis–incidence and risk factors. Rheumatology (Oxford). 2008;47(4):530–4.

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ANCA-negative associated vasculitis initially presenting with pulmonary embolism.

Antineutrophil-cytoplasm antibodies (ANCA)-associated vasculitis are severe inflammatory pathologies that, although rare, may induce significant morbi...
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