Wegener granulomatosis: three cases

Wegener granulomatosis (WG) is characterized by granulomatous vasculitis that involves multisystem, including upper and lower airways and kidney. WG may be a mortal disease if the diagnosis is delayed. The aim of this study is to present three patients admitted with different prediagnosis but after the investigations were diagnosed as WG and followed in our clinic. The cases were discussed with the literature knowledge. All three patients were diagnosed as WG with clinical, radiological and pathological findings. c-ANCA was positive in two patients, and negative one. Complete remission was established with treatment in one case. The treatment of other patients going on, however, the third patient was lost to follow up.     

Massive intracerebral hemorrhage associated with Wegener granulomatosis

Wegener granulomatosis (WG) is a necrotizing granulomatous vasculitis that predominantly affects airways and kidneys. But central nervous system involvement (7–11%) is an uncommon. Massive ICH may occur in the course of WG, and this serious condition is related with high risk of mortality. Therefore, the new treatment strategies may be considered in addition to classical practices in serious organ involvement and recurrent attack. Here, we present an adult patient with WG whose disease was complicated by a massive intracerebral hemorrhage (ICH), which subsequently led to death.     

3例韦格纳肉芽肿误诊分析及文献回顾

目的阐述韦格纳肉芽肿(WG)的诊治经验及误诊原因。方法分析3例WG患者的临床表现、影像学特点、诊断及治疗经验,并复习相关文献。结果 3例WG患者曾被误诊为肺癌、肺结核、肺脓肿、多形性红斑,提示WG和肺癌、结核、肺脓肿有许多相似之处,且可合并严重皮肤损害,容易误诊。结论 WG临床表现复杂多样,缺乏特异性,临床医师对本病认识不足是导致误诊的主要原因,提高对WG临床特点、影像学特征的认识、建立良好的临床思维是减少误诊的关键。     

韦格纳肉芽肿病23例临床分析

目的分析韦格纳肉芽肿病(Wegener granulomatosis，WG)的临床和病理特点，提高对本病的认识。方法对23例确诊的WG病人的临床表现、辅助检查及病理特点进行回顾性分析。结果发病年龄20．57岁，平均37．2岁，平均病程5．8个月。首发症状以上呼吸道为主(48％)，可累及多个系统或器官，肺脏受累87％，肾脏受累78%。胞质型抗中性粒细胞胞质抗体(cANCA)阳性率100%，病理表现为坏死性肉芽肿性炎症、炎细胞浸润的血管炎。结论WG的临床表现复杂多样，有多系统或器官病变的症候群，以上、下呼吸道及肾脏受累最多见：病理特点为坏死性肉芽肿和血管炎。     

Mononeuritis multiplex as a presenting feature of Wegener granulomatosis: a case report

We report the case of a man presenting with clinical features of a mononeuritis multiplex, a perinuclear-ANCA (p-ANCA), and a renal biopsy suggestive of Wegener granulomatosis (WG). We wish to highlight this case as a learning point for clinicians as WG rarely presents in this form, and can be easily overlooked as a cause of mononeuritis multiplex.     

Central nervous system involvement in Wegener granulomatosis

Wegener granulomatosis (WG) is an antineutrophil cytoplasmic antibody (ANCA)-associated granulomatous vasculitis of small and medium-sized vessels. This vasculitis involves mainly the upper and lower respiratory tracts and kidneys, although WG may affect any organ. Central nervous system (CNS) involvement is an uncommon manifestation of WG, reported in 7%-11% of patients. Three major mechanisms have been incriminated as causing CNS disease in WG: contiguous invasion of granuloma from extracranial sites, remote intracranial granuloma, and CNS vasculitis. Herein we describe 6 patients with WG-related CNS involvement, 2 of whom had chronic hypertrophic pachymeningitis, 3 with pituitary involvement, and 1 with cerebral vasculitis. CNS involvement was present at disease onset in 2 patients and occurred 5-18 years after WG diagnosis in the remaining 4. Based on these observations and a review of the literature, we discuss the pathogenic mechanisms, clinical features, imaging findings, treatment, and outcome of meningeal, pituitary, and vascular involvement, with an emphasis on differential diagnoses, prognosis, and therapeutic management of WG-related CNS involvement.     

Substitution of methotrexate for cyclophosphamide in Wegener granulomatosis: a 12-year single-practice experience

We conducted a retrospective review to assess outcomes of therapy in patients with newly diagnosed Wegener granulomatosis (WG) using methotrexate (MTX) for mild to moderate disease and short-term treatment with cyclophosphamide (CYC) followed by MTX for severe disease. Patients with WG were included if their initial plan of therapy and subsequent care were directly supervised by the Cleveland Clinic Center for Vasculitis Care and Research. Severe disease (immediately life-threatening or involving critical organs) was initially treated with CYC and glucocorticoids. Mild to moderate disease was initially treated with MTX and glucocorticoids if serum creatinine was less than 2 mg/dL. Following initial improvement of severe disease, treatment was changed to MTX if serum creatinine was originally less than 2 mg/dL or had diminished to less than 2 mg/dL. Disease activity was determined at each visit and later converted to a Birmingham Vasculitis Activity Score, as modified for Wegener granulomatosis (BVAS/WG). Laboratory monitoring of disease and treatment toxicity was initially weekly and never less than monthly.Eighty-two (32%) of 253 patients with WG referred to the Center for Vasculitis Care and Research met eligibility criteria. Ineligible patients did not have new-onset disease or were not able to be followed principally in our center. Seventy percent of patients (57/82) initially had severe disease and received a short course of CYC for remission induction. In over half of these patients, illness was judged to be severe because of pulmonary hemorrhage; rapidly progressive glomerulonephritis, including need for dialysis; or neurologic abnormalities.All patients improved: remission was achieved in 50% (41/82) of patients within 6 months and in 72% (59/82) within 12 months. Sustained remission (BVAS/WG = 0 for at least 6 consecutive months) was ultimately achieved in 78% (64/82) of patients. Among the 75 (91%) patients who achieved remission of any duration, 45% relapsed within 1 year and 66% relapsed within 2 years following remission. Eighty-two percent of relapsed patients achieved subsequent remissions after additional treatment. About three-quarters of relapses were mild and promptly responded to treatment.Seventeen percent of patients developed serious infections. CYC-associated cystitis or bladder cancer did not occur in any patients. At least 1 form of permanent morbidity from WG alone was noted in 74.0% of patients. Three patients (3.7%) died over a median follow-up period of 4.5 years; no deaths were due to active disease.Although treatment was primarily directed toward achieving clinical improvement and not calculated to achieve marked lymphopenia, patients in whom treatment produced lymphocyte counts of 1000/mm was associated with a hazard ratio for relapse of 3.0, although the latter difference was not statistically significant.In patients with WG, a strategy that limits or avoids CYC therapy produced a frequency of remission comparable to that achieved with conventional CYC protocols, excellent survival, and avoidance of long-term CYC toxicity. However, relapses were common and incremental permanent morbidity occurred in most patients. While not a goal of therapy, when treatment produced marked lymphopenia, prolonged remissions were more likely.     

A case of ANCA-associated vasculitis presenting with calf claudication

Wegener’s granulomatosis (WG), Churg–Strauss syndrome, and microscopic polyangiitis (MPA) are closely related small vessel vasculitides characterized by anti-neutrophil cytoplasmic antibodies (ANCA). Although there were some reports of MPA presenting with claudication, there are very few reports on WG presenting with claudication of calf muscles. We report an unusual case of ANCA-associated vasculitis in a 75-year-old man who presented with bilateral calf claudication. Comprehensive evaluations, including electromyography, nerve conduction study, lower extremity magnetic resonance imaging, and Doppler scan, did not reveal any other cause of bilateral calf claudication. P-ANCA and anti-myeloperoxidase antibody was positive, but the anti-proteinase 3 antibody was negative. Chest computed tomography scan showed subpleural honeycombing and reticulation, predominantly in both basal lung areas. Biopsy of the calf muscle showed granulomatous vasculitis. Kidney biopsy was also performed which revealed focal necrotizing glomerulonephritis. Our patient does not exhibit typical clinical features for WG, but histopathologic findings of necrotizing granulomatous vasculitis in calf muscle biopsy is highly suggestive of WG.     

Bone Marrow Transplantation with a Reduced-Intensity Conditioning Regimen in a Patient with Wegener Granulomatosis and Therapy-Related Leukemia

We describe a patient with Wegener granulomatosis (WG) who underwent long-term cyclophosphamide treatment and thereafter developed acute myelogenous leukemia (AML). After the AML was induced into remission, the patient received an allogeneic stem cell transplant (allo-SCT) from his sibling after undergoing a reduced-intensity conditioning regimen. His clinical course shortly after allo-SCT was uneventful. No clinically apparent acute or chronic graft-versus-host disease developed. Repeated analysis of the peripheral blood lymphocytes after transplantation showed complete donor chimerism. The level of proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) remained undetectable until 4 months after transplantation, when it began to increase. When the level of PR3-ANCA peaked, the patient suddenly presented with fever and joint pain, which later spontaneously resolved in parallel with the declining titer of PR3-ANCA. He is now in remission for both AML and WG at 22 months after transplantation. The patient's clinical course after allo-SCT may provide us with valuable information regarding the establishment of allo-SCT as a therapeutic option for WG.     

Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway

Autoantibodies to proteinase 3 (PR3) are involved in the pathogenesis of autoimmune-mediated vasculitis in Wegener granulomatosis (WG). To address the question how the autoantigen PR3 becomes a target of adaptive immunity, we investigated the effect of PR3 on immature dendritic cells (iDCs) in patients with WG, healthy blood donors, and patients with Crohn disease (CD), another granulomatous disease. PR3 induces phenotypic and functional maturation of a fraction of blood monocyte-derived iDCs. PR3-treated DCs express high levels of CD83, a DC-restricted marker of maturation, CD80 and CD86, and HLA-DR. Furthermore, the DCs become fully competent antigen-presenting cells and can induce stimulation of PR3-specific CD4(+) T cells, which produce IFN-gamma. PR3-maturated DCs derived from WG patients induce a higher IFN-gamma response of PR3-specific CD4(+) T cells compared with patients with CD and healthy controls. The maturation of DCs mediated through PR3 was inhibited by a serine protease inhibitor, by antibodies directed against the protease-activated receptor-2 (PAR-2), and by inhibition of phospholipase C, suggesting that the interactions of PR3 with PAR-2 are involved in the induction of DC maturation. Wegener autoantigen interacts with a "gateway" receptor (PAR-2) on iDCs in vitro triggering their maturation and licenses them for a T helper 1 (Th1)-type response potentially favoring granuloma formation in WG.     

Laryngopharyngeal reflux mimicking limited wegener granulomatosis

We present a case of subglottic stenosis (SGS) in a young patient with positive ANCA but a wrong diagnosis of Wegener granulomatosis (WG). Instead, she was diagnosed as having laryngopharyngeal reflux (LPR). Pitfalls of ANCA testing in this scenario, the route to diagnosis of LPR and the contribution of this entity to subglottic stenosis (SGS) in WG are discussed. Caution when interpreting ANCA results is mandatory to avoid improper management.     

A case of nasal T cell lymphoma with lethal midline granuloma which is clinically indistinguishable from Wegener’s granulomatosis

We describe a patient who developed fever, bilateral otitis media, destructive necrosis of the nasal cavity and multiple lung nodules. The patient fulfilled the American College of Rheumatology (ACR) classification criteria for Wegener’s granulomatosis (WG) and was also diagnosed as having WG by using the ACR classification tree. However, the diagnosis of T cell lymphoma was finally made by cervical lymph node biopsy, 2 years after disease onset. Rheumatologists should therefore aware of the pitfall of using diagnostic criteria and repetitive biopsy is strongly recommended for accurate diagnosis of WG.     

A case of nasal T cell lymphoma with lethal midline granuloma which is clinically indistinguishable from Wegener’s granulomatosis

Abstract

We describe a patient who developed fever, bilateral otitis media, destructive necrosis of the nasal cavity and multiple lung nodules. The patient fulfilled the American College of Rheumatology (ACR) classification criteria for Wegener’s granulomatosis (WG) and was also diagnosed as having WG by using the ACR classification tree. However, the diagnosis of T cell lymphoma was finally made by cervical lymph node biopsy, 2 years after disease onset. Rheumatologists should therefore aware of the pitfall of using diagnostic criteria and repetitive biopsy is strongly recommended for accurate diagnosis of WG.     

Wegener granulomatosis (granulomatosis with polyangiitis): evolving concepts in treatment

Wegener granulomatosis (WG), the most common of the pulmonary granulomatous vasculitides, typically involves the upper respiratory tract, lower respiratory tract (bronchi and lung), and kidney, with varying degrees of disseminated vasculitis. THE TERM GRANULOMATOSIS WITH POLYANGIITIS (WEGENER) WAS RECENTLY PROPOSED TO REPLACE THE OLDER TERM, WG. THE TERM GRANULOMATOSIS WITH POLYANGIITIS CAN BE ABBREVIATED TO GPA, WITH THE IDEA THAT THE EPONYM WEGENER WOULD BE OMITTED OVER TIME. Cardinal histologic features include a necrotizing vasculitis involving small vessels, extensive "geographic" necrosis, and granulomatous inflammation. Clinical manifestations of WG are protean; virtually any organ can be involved. The spectrum and severity of the disease are heterogeneous, ranging from indolent disease involving only one site to fulminant, multiorgan vasculitis. The pathogenesis of WG has not been elucidated, but both cellular and humoral components are involved. Circulating antibodies against cytoplasmic components of neutrophils [anti-neutrophil cytoplasmic antibodies (c-ANCAs)] likely play a role in the pathogenesis, and often correlate with activity of the disease. Treatment strategies are evolving. Cyclophosphamide (CYC) plus corticosteroids (CSs) is the mainstay of therapy for generalized, multisystemic WG. Historically, the combination of CYC plus CS was used for a minimum of 12 months, but concern about late toxicities associated with CYC has led to novel treatment approaches. Currently, short-course (3 to 6 months) induction treatment with CYC plus CS, followed by maintenance therapy with less toxic agents (e.g., methotrexate, azathioprine) is recommended. Further, methotrexate combined with CS may be adequate for limited, non-life-threatening WG. Recent studies suggest that rituximab may be useful for induction therapy or CYC-refractory WG. The role of other immunomodulatory agents (including trimethoprim-sulfamethoxazole) is also explored.     

Granulomatöse ANCA-assoziierte Vaskulitiden

Wegener’s granulomatosis (WG) is a systemic vasculitis that affects small vessels and primarily involves the upper and lower respiratory tract and the kidneys, although any other organ system may become involved. Before committing patients to long-term treatment with potentially toxic drugs, histopathologic proof should be obtained by tissue biopsy at a site of active disease. In order to distinguish WG from other vasculitides, it is useful to detect ANCA reacting with proteinase 3 as a target antigen. Treatment of patients with WG should take into consideration the disease severity, organ manifestation, the patient’s age and individual risk factors. For remission induction, patients are divided into those with limited or generalized disease with moderate or severe renal involvement. Methotrexate is an alternative for patients presenting with limited disease features and normal renal function, whereas cyclophosphamide in combination with steroids still remains the standard treatment. For patients with organ-threatening disease or frequent relapses, alternative agents have been evaluated as possible alternatives.     

Wegener-Granulomatose und mikroskopische Polyangiitis

Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA) are primary systemic small vessel vasculitides, associated with a positive C/PR3-ANCA in WG and P/MPO-ANCA in MPA. The most prominently involved organs are the upper (only in WG) and lower respiratory tract and the kidneys. The diagnostic work-up is an interdisciplinary approach assessing disease stage and extent. Treatment is adapted to disease stage and extent and relies on a combination of a cytotoxic plus a tapering regimen of corticosteroids. Induction of remission in “early systemic” disease can be achieved with low-dose methotrexate. In severe generalized vasculitis cyclophosphamide (CYC) is the mainstay of therapy, in rapidly progressive glomerulonephritis in combination with plasmapheresis. After 3–6 months of induction CYC is switched to a maintenance treatment with azathioprine. Alternatives are leflunomide, mycophenolate or methotrexate (creatinine < 150 µmol/l). Age ≥ 50 at diagnosis, renal dysfunction and pulmonary involvement are associated with higher mortality rates. The relapse rate is approximately 50% within 5 years, being higher in WG than MPA.     

MPO-ANCA-positive Wegener’s granulomatosis presenting with hypertrophic cranial pachymeningitis: case report and review of the literature

Abstract

We describe a case of hypertrophic cranial pachymeningitis (HCP) associated with Wegener’s granulomatosis (WG) in a 60-year-old man presenting with chronic headache and multiple cranial nerve neuropathies. A test for antibodies to the neutrophil cytoplasmic protein myeloperoxidase (MPO-ANCA) was positive in this case. We review the literature on perinuclear (p)-ANCA-related HCP, including our case. This case indicates the link between MPO-ANCA-positive WG and HCP.     

Wegener’s granulomatosis complicated by pulmonary embolism: a case report and review of the literature

Abstract

We describe the case of a 79-year-old lady who developed pulmonary emboli on a background of active Wegener’s granulomatosis (WG). The literature reports an increased association of venous thromboembolic disease and the small vessel vasculitides, including WG. This case report explores the issues surrounding systemic anticoagulation in the context of a systemic vasculitis that predisposes to severe bleeding, in particular from the respiratory tract.     

Spontaneous pneumothorax in Wegener granulomatosis

Spontaneous pneumothorax in Wegener granulomatosis (WG) is uncommon. Three cases of pneumothorax that occurred early in the course of this vasculitis are reported. In the first patient, the disorder was disclosed by a pyopneumothorax. In the second patient, a rupture of the subpleural cavitary nodule into the pleural space was observed. In the third patient, the pneumothorax was discovered at the same time as a pulmonary hemorrhage. The three patients improved with immunosuppressive therapy. In WG, the pulmonary nodules are predominantly in the subpleural location, which entails the risk of pneumothorax and therefore require particular attention.