Hypersensitivity pneumonitis associated with azathioprine therapy in a patient with granulomatosis with polyangiitis

Granulomatosis with polyangiitis (GPA), an autoimmune disease characterized by inflammatory granulomas and necrotizing small-vessel vasculitis, primarily affects the respiratory tract and kidneys. Azathioprine (AZA) is a purine analog that is commonly used for maintaining GPA remission after induction therapy with cyclophosphamide. While the dose-dependent side effects of AZA are common and well known, hypersensitivity reactions such as pulmonary toxicity are rare. Here, we describe a case involving a 38-year-old man with GPA-associated pauci-immune crescentic glomerulonephritis who developed subacute hypersensitivity pneumonitis (HP) during AZA maintenance therapy. Five months after the initiation of AZA administration (100 mg/day), the patient was admitted with a 7-day history of cough, dyspnea, and fever. High-resolution computed tomography of the chest showed ill-defined centrilobular nodules and diffuse ground-glass opacities in both lung fields. Bronchoscopy with bronchoalveolar lavage was negative for infectious etiologies. A transbronchial lung biopsy specimen revealed poorly formed non-necrotizing granulomas. A chest radiograph obtained at 2 weeks after discontinuation of AZA showed normal findings. The findings from this case suggest that AZA-induced HP should be considered as a differential diagnosis when a patient with GPA exhibits fresh pulmonary lesions accompanied by respiratory symptoms during AZA therapy.     

Granulomatosis with Polyangiitis in Childhood

Granulomatosis with polyangiitis (GPA) is a rare yet frequently organ- or life-threatening systemic vasculitis affecting small- to medium-sized arteries in multiple organs. It characteristically leads to alveolar hemorrhage and destructive, pauci-immune glomerulonephritis. GPA is also characterized by granulomas in the upper and lower respiratory tract causing erosive sinusitis and nodular or even cavitating lesions in the respiratory tract. Antineutrophil cytoplasmic antibodies, a hallmark of GPA, are likely integral to the pathogenesis and recently have become a therapeutic target. International collaborations in childhood vasculitis have led to the development and validation of childhood vasculitis classification criteria, advanced our understanding of the clinical phenotype at presentation of GPA, and improved our ability to capture disease activity and determine treatment choices. Treatment efficacy and safety data continue to be largely derived from adult GPA studies. This review focuses on the recent publications on epidemiology, pathogenesis, and treatment in childhood GPA and relevant publications from the adult GPA literature.     

Airway manifestations in childhood granulomatosis with polyangiitis (Wegener's)

Objective

Granulomatosis with polyangiitis (Wegener's) (GPA) is a necrotizing granulomatous vasculitis affecting the upper and lower respiratory tract, kidneys, and other small vessels throughout multiple organ systems. Recently, classification criteria for childhood GPA have been proposed and include the addition of airway stenosis. Airway inflammation occurs more frequently in children than adults and often proves difficult to diagnose and treat. Our objectives were to 1) determine the frequency of airway involvement in a cohort of children with GPA as defined by the European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Pediatric Rheumatology European Society (EULAR/PRINTO/PRES) criteria, 2) document the frequency of specific airway findings, and 3) review our treatment approach to children with GPA‐related airway disease.

Methods

A retrospective chart review was performed on patients ages <18 years with a diagnosis of vasculitis evaluated at the Cleveland Clinic between 2004 and 2010.

Results

Twenty‐eight patients fulfilling the EULAR/PRINTO/PRES classification criteria for the diagnosis of childhood GPA were included in the analysis. There was a mean followup time of 3.1 years. The overall prevalence of any airway disease was 86%, with upper airway involvement in 86% and laryngotracheobronchial (LTB) disease in 50% of patients. LTB disease was present at diagnosis in 36%, while in the remaining 14% it developed on immunosuppressive therapy. Ten patients underwent a successful endoscopic intervention.

Conclusion

Airway manifestations frequently occur in childhood GPA. Inflammatory changes can occur at any point in the disease course, necessitating diligent surveillance. Endoscopic interventions for LTB stenotic lesions represent a safe and effective therapeutic option.     

肺血管炎的临床与影像学特点解析

肺部血管炎包括原发性与继发性两大类.继发性血管炎包括感染性疾病、结缔组织病、恶性肿瘤和过敏性疾病所致肺血管炎.原发性血管炎的分类通常根据受累血管的大小分为大血管炎、中血管炎和小血管炎.肺部血管受累常见于原发性大血管炎[大动脉炎(Takayasu arteritis),巨细胞动脉炎(giant cell arteritis,GCA),白塞病(Behcetdisease)]和原发性抗中性粒细胞胞浆抗体(anti-neutrophil cytoplasmic antibody,ANCA)相关性小血管炎[肉芽肿性多血管炎(granulomatosis with polyangiitis,GPA),显微镜下多血管炎(microscopic polyangiitis),嗜酸性肉芽肿性多血管炎(eosinophilic granulomatosis with polyangiitis,EGPA)].原发性肺血管炎的影像学表现极具多样性,包括血管壁增厚、结节影、空洞、磨玻璃影和实变影等.原发性肺部小血管炎常导致弥漫性肺泡出血(diffuse alveolar hemorrhage,DAH).相比于胸片,胸部CT更能够显示肺血管炎的病变特征和侵及范围.肺部血管炎的诊断极具挑战性,需要通过患者的临床特征、影像学特点、实验室检查结果和组织病理学特征作出综合判断.     

Excessive interleukin‐15 transpresentation endows NKG2D+CD4+ T cells with innate‐like capacity to lyse vascular endothelium in granulomatosis with polyangiitis (Wegener's)

Objective

Granulomatosis with polyangiitis (Wegener's) (GPA) is a rare systemic vasculitis of unknown etiology. Contribution of T cell–mediated immunity is suggested by the presence of granulomatous inflammation and T cell infiltrates in different tissues. We undertook this study to determine whether CD4+ T cells aberrantly expressing the NKG2D activating receptor might participate in the pathophysiology of the disease.

Methods

We performed a detailed phenotype and functional analysis of CD4+ T cells in a cohort of 90 GPA patients (37 with localized GPA and 53 with generalized GPA) in comparison with 39 age‐matched controls.

Results

We observed circulating innate‐like CD4+ T cells expressing an assortment of activating natural killer (NK) cell receptors (NKG2D, 2B4, DNAX‐associated molecule 1, and some killer cell Ig‐like receptors) and their signaling partners. Expansions of NKG2D+CD4+ T cells greater than a critical threshold of 3% yielded 100% specificity for generalized vasculitis versus localized granulomatosis, suggesting their participation in endothelium damage. Excessive interleukin‐15 (IL‐15) transpresentation through increased expression of IL‐15 receptor α (IL‐15Rα), together with abnormal expression of major histocompatibility complex (MHC) class I chain–related A protein on monocyte/macrophages, induced abnormal expansion of NKG2D+CD4+ T cells. These cells were primed in vivo to exert direct, MHC‐independent cytotoxicity toward microvascular endothelial cells expressing the cognate ligands of NK cell receptors.

Conclusion

Our results suggest that NK cell–like CD4+ T cells might be the driving force of the vasculitis in GPA, and point to IL‐15 as an important mediator in the progression of GPA toward generalized vasculitis. IL‐15/IL‐15Rα antagonists may thus become novel therapeutic tools to decrease the pool of NK cell receptor–positive CD4+ T cells in selected GPA patients.

     

Four cases of MPO-ANCA-positive vasculitis with otitis media, and review of the literature

Otitis media is one of the common organ injuries that appear during the course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We experienced four patients with myeloperoxidase (MPO)-ANCA-positive AAV with otitis media. All were elderly Japanese women. MPO-ANCA in our patients was reminiscent of microscopic polyangiitis (MPA), although chest computed tomography (CT) scans revealed characteristics of both granulomatosis with polyangiitis (GPA), showing bronchial lesions and nodule formation, and MPA, showing interstitial changes. Whether our cases should be classified as GPA or MPA is a matter of discussion. We detail their profiles, and review previous literature on MPO-ANCA-positive AAV with otitis media.     

Vasculitis associated with malignancy. Experience with 13 patients and literature review

Vasculitis is a syndrome which may complicate certain infectious, rheumatic, and allergic diseases. We identified 13 patients, over the past 17 years, who had both vasculitis and lympho- or myeloproliferative disorders and relate their clinical, laboratory, histologic, and immunologic features, course, therapy, and outcome. Nine patients were male, 4 female; ages ranged from 28 to 82 years. Ten of 13 patients presented with cutaneous vasculitis antedating malignancy by an average of 10 months. Three of 13 developed cutaneous vasculitis after malignancy. A statistically significant association between cutaneous vasculitis and lympho- or myeloproliferative malignancies was noted when compared with all other tumors. Dermatologic manifestations included palpable purpura (5 patients), maculopapular eruptions (4), urticarial and petechial lesions (3), and ulcers (1). Hepatitis B surface antigen, Coombs antibodies, rheumatoid factor and antinuclear antibodies were not found. Serum cryoglobulins were detected in 3 patients; serum C3 and C4 were normal in 8 of 9 patients evaluated. Histologic examinations revealed necrotizing leukocytoclastic vasculitis with disruption of endothelial integrity, destruction of endothelium, and neutrophil infiltration. Occasional perivascular mononuclear cell invasion was also noted in 4 patients. Immunofluorescent staining for IgG, IgA, IgM, C3, and C4 was negative in all patients studied. Symptoms were, in general, poorly responsive to therapy, which included nonsteroidal antiinflammatory drugs, antihistamines, antiserotonin agents, and corticosteroids. Chemotherapy directed at the underlying malignancy was also generally ineffective, although the vasculitis appeared to lessen in severity. Vasculitis appeared to lessen in severity as bone marrow function deteriorated. Ten patients died, all as a direct result of their malignancy. We have described a unique clinical syndrome of lympho- and myeloproliferative disease presenting with small-vessel vasculitis. Recognition that rheumatic symptoms may reflect or antedate malignancy may permit early diagnosis, aggressive treatment, and elucidation of pathogenesis.     

Fluorodeoxyglucose (FDG) uptake in pulmonary rheumatoid nodules diagnosed by video-assisted thoracic surgery lung biopsy: two case reports and a review of the literature

Two cases of rheumatoid nodules evaluated by fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and video-assisted thoracic surgery (VATS) biopsy are reported. The first case was that of a 44-year-old woman who presented with a cavitated nodule with intense standardized uptake values (SUVs) both in the early (max 3.4) and delayed (max 4.4) phases, suggesting malignancy. However, after VATS biopsy, she was diagnosed as having a rheumatoid nodule with vasculitis. The second case was that of a 74-year-old woman admitted with bilateral lung nodules, two of which showed intense early (max 2.2) and delayed (max 6.0) phase SUVs, and mild early (max 0.6) and delayed (max 0.9) phase SUVs. These two nodules were finally proven to be a lung cancer and rheumatoid nodule without vasculitis, respectively. These cases show that rheumatoid nodules with an enhanced inflammatory process, such as vasculitis, can appear false-positive for malignancy on FDG-PET/CT scan images.     

Severe Henoch-Sch?nlein purpura with infliximab for ulcerative colitis

Infliximab (IFX) is an anti-tumor necrosis factor chimeric antibody that is effective for treatment of autoimmune disorders such as Crohn’s disease and ulcerative colitis (UC). IFX is well tolerated with a low incidence of adverse effects such as infections, skin reactions, autoimmunity, and malignancy. Dermatological manifestations can appear as infusion reaction, vasculitis, cutaneous infections, psoriasis, eczema, and skin cancer. Here, we present an unusual case of extensive and sporadic subcutaneous ecchymosis in a 69-year-old woman with severe UC, partial colectomy and cecostomy, following her initial dose of IFX. The reaction occurred during infliximab infusion, and withdrawal of IFX led to gradual alleviation of her symptoms. We concluded that Henoch-Schönlein purpura, a kind of leukocytoclastic vasculitis, might have contributed to the development of the bruising. Although the precise mechanisms of the vasculitis are still controversial, such a case highlights the importance of subcutaneous adverse effects in the management of UC with IFX.     

Multiple malignancies in a patient with limited granulomatosis with polyangiitis without immunosuppressive therapy

Here, we report the case of a 69-year-old man with limited granulomatosis with polyangiitis (GPA; formerly Wegener's granulomatosis) who developed papillary thyroid cancer, adenocarcinoma of the stomach, and myelodysplastic syndrome following glucocorticoid treatment. This is the first report to present multiple malignancies in a patient with limited GPA without immunosuppressive treatment. Thus, our report supports the notion that limited GPA itself can be associated with the development of malignancy.     

Predictors of cardiovascular events in patients with primary systemic vasculitis: A 5 years prospective observational study

Introduction: Granulomatosis with polyangiitis (GPA) is one of antineutrophil cytoplasmic autoantibody (ANCA) – associated systemic vasculitis and is characterised by inflammation of blood vessels. Systemic vasculitis exhibits an enhanced cardiovascular morbidity and cardiovascular disease (CVD) has become a leading cause of death in this group of patients.Objectives: The aim of the present study was to assess the prevalence of clinical manifestation of atherosclerosis and its relation with classic risk factors for atherosclerosis, echocardiographic parameters and laboratory findings in GPA patients.Patients and methods: The group of consecutive patients with GPA were followed in the study.Results: One hundred six patients with GPA (mean age 50.4 ± 14.9 yrs, 67 female) were prospectively followed for 5.1 ± 1.6 yrs. In 19 patients (18%) cardiovascular disease (9 acute coronary syndromes, 4 symptomatic peripheral vascular diseases and 6 strokes) occurred in association with GPA. In a multivariate model, only age was predictive of cardiovascular events in this group of patients (OR=1.078, 95% CI: 1.025–1.134, p = 0.003). During observation in patients without CVD the level of hs-CRP and D-dimer were significantly reduced on the follow-up visit (p = 0.041, p = 0.0002). On the other hand, in patients with CV events there was no significant differences in both markers’ concentrations despite clinical remission.Conclusions: The age was the only independent predictor of cardiovascular events. Persistent elevation of inflammatory and prothrombotic markers despite clinical remission of the disease could be an indicator of premature atherosclerosis development in patients with systemic vasculitis.     

Atteinte du sinus caverneux au cours d’une granulomatose avec polyangéite (maladie de Wegener) sans ANCA

Introduction

Granulomatosis with polyangeitis (Wegener's granulomatosis) (GPA) is a granulomatous vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA). Affected organs usually include upper and lower respiratory tracts, and kidneys. Limited forms of GPA may affect the central nervous system (vasculitis, hypertrophic pachymeningitis, encephalitis), a location in which diagnosis is often uneasy.

Case report

We report a 74-year-old woman who presented with a limited form of GPA affecting the cavernous sinus. Diagnosis was considered in view of a retrospectively suggestive clinical presentation, compatible cerebral MRI and temporal artery biopsy, despite the absence of ANCA. It was supported by a favourable outcome with cyclophosphamide administration.

Conclusion

GPA presenting as a cavernous sinus syndrome is rare. Three co-existing pathogenic mechanisms may be involved in GPA affecting the central nervous system: contiguous invasion from nasal or orbitary granulomatous sites, vasculitis, or primary intra-cerebral granulomatous inflammation. Lack of biopsy evidence of affected tissues and ANCA negativity should not delay diagnosis and appropriate therapeutic management in central nervous system GPA.     

Neoplastic and paraneoplastic vasculitis, vasculopathy, and hypercoagulability

It is essential to be aware of both neoplastic and paraneoplastic vasculitides, vasculopathy, and hypercoagulability, considering the importance of an accurate diagnosis and timely treatment of the underlying malignancy. Characteristics such as the type of vasculitis, age, gender, atypical presentation, and lack of response to common therapies should prompt investigation for an occult malignancy, whereas vasculitis such as GPA require due malignancy vigilance given a significantly increased risk of malignancy at the time of diagnosis and in the following years. Vasculopathies are rarer than vasculitides, but are associated with specific malignancies and, in the context of such malignancies, should be kept in mind. Hypercoagulability is a well-documented neoplastic phenomenon with an increased risk of thrombosis in the setting of positive aPLs. Most neoplastic and paraneoplastic vascular syndromes require no specific treatment outside of treatment of the underlying malignancy. The two key exceptions are PACNS, because of its poor prognosis, and erythromelalgia, in which aspirin is an effective agent.     

Wegener's granulomatosis mimicking paraneoplastic syndrome

Wegener's granulomatosis is a distinct clinico-pathological entity characterised by a triad of upper and lower respiratory disease and renal involvement, although atypical presentations can be seen. These patients characteristically have small vessel vasculitis and or granulomatous vasculitis and are usually anti-neutrophilic cytoplasmic antibody (ANCA) positive. We present a case of Wegener's granulomatosis that clinically mimicked a lung neoplasm with a paraneoplastic syndrome. Biopsy and histopathological evaluation of a readily accessible subcutaneous nodule showed small vessel vasculitis. Correlation with clinical data and ANCA positivity led to a definite diagnosis.     

Cutaneous vasculitis in adult polymyositis/dermatomyositis

Seven (9.2%) of 76 patients with adult-onset polymyositis/dermatomyositis (PM/DM) seen over an 11-year period had cutaneous vasculitis. This was manifest by dermal and/or subcutaneous nodules in 4, periungual infarcts in 3 and digital ulceration in 2. When these 7 patients were compared to the remaining 69, a significant association was noted between cutaneous vasculitis and DM (p = .025); only 1 of 31 patients with primary PM and none of 18 with overlap syndromes had vasculitis. Furthermore, 2 (28.6%) of those with vasculitis had an associated malignancy compared to only 4 (5.8%) of those without vasculitis. These data document the occurrence of cutaneous vasculitis in adult-onset PM/DM and suggest that its presence may be a marker of an underlying malignancy.     

The cancer risk according to three subtypes of ANCA-associated vasculitis: A propensity score-matched analysis of a nationwide study

ObjectiveIt remains unknown whether cancer risk differs among the three subtypes of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and what the cancer risk factors are. We conducted a nationwide study in Korea to evaluate the risk of cancer in patients with AAV and to identify the risk factors for cancer.MethodsWe analyzed the Health Insurance Review and Assessment database of Korea and identified 1982 patients diagnosed with AAV between January 1, 2007 and December 31, 2017. The patients and controls with no history of AAV or cancer were matched 1:4 by propensity scores. The study outcome measure was incidence of cancer during 11 years of follow-up.ResultsPatients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) numbered 684, 606, and 692, respectively. The overall incidence of cancer was higher among patients with AAV than in controls (HR 1.32, 95% CI 1.08–1.61). The risk of hematological malignancy, lung cancer, and bladder cancer in the GPA group, lung cancer in the MPA group, and hematological malignancy in the EGPA group were significantly higher than in controls (HR 7.39, 3.20, 4.20, 2.86, and 4.65, respectively). Age, male sex, GPA subtype, and cyclophosphamide use were significantly associated with cancer risk in patients with AAV.ConclusionOverall cancer incidence was increased in patients with AAV. Cancer risk was higher in patients with GPA than in those with MPA or EGPA. The use of cyclophosphamide was associated with an increased risk of cancer, while rituximab was not.     

Case Report: Gastrointestinal Amyloidosis Secondary to Hypersensitivity Vasculitis Presenting with Intestinal Pseudoobstruction

Hypersensitivity vasculitis is characterized byinflammation and necrosis of small blood vesselssecondary to allergic or hypersensitivity mechanisms (1,2). Gastrointestinal involvement with edema and bleeding also has been reported (3-5).Long-standing inflammation, such as rheumatic disease,infectious disease, inflammatory bowel disease, familialMediterranean fever, and malignancy, may lead tosystemic amyloidosis (6). Gastrointestinal involvementmay induce anorexia, nausea and vomiting, diarrhea,constipation, bleeding, malabsorption, andpseudoobstruction (6, 10-12). In this report we discussa patient with hypersensitivity vasculitis with severeintestinal bleeding who developed systemic amyloidosiswith intestinal pseudoobstruction 29 months after onset.Secondary amyloidosis due to hypersensitivity vasculitis has not been previously reported,and the causal relationship is discussed in thisreport.     

Cutaneous tuberculosis: a rare presentation of malignancy.

An 88-year-old woman presented with fever, a neck ulcer, and multiple subcutaneous nodules on her upper extremities and thorax. Her condition was initially diagnosed as malignancy associated with metastatic disease to the skin. A subcutaneous nodule was aspirated. A gram stain of the aspirate revealed weakly gram-positive bacilli, and a stain for acid-fast bacilli was positive. Mycobacterium tuberculosis was isolated from a culture of a specimen of the skin lesion.     

Essential mixed cryoglobulinemia type III with leukocytoclastic vasculitis: remission by rituximab

We report about a 39-year-old female patient with severe essential mixed cryoglobulinemia of type III with leukocytoclastic vasculitis. The patient was admitted into our hospital with mesenteric lymphangiitis, which caused enteral perforation, sepsis, and pneumonia. Cryoglobulins, cryocrit, Ig-titers, and biopsy were positive for mixed cryoglobulinemia type III. We detected no signs of hepatitis C, B, or any other infectious disease. At first, disease activity could be kept under control with high doses of glucocorticoids and multiple cyclophosphamide pulses. However, after therapy with three pulses of rituximab, steroids were stopped, and the patient has not presented any symptoms for 2 years. Therefore, we suggest that rituximab affected her disease rapidly and effectively. In conclusion, rituximab is an alternative therapy for mixed cryoglobulinemia of type III with leukocytoclastic vasculitis.     

Malignancy is increased in ANCA-associated vasculitis

OBJECTIVE: In the light of previous reports of an association between malignancy and renal vasculitis, we aimed to investigate the association of malignancy in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, either Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA), and compare it with the general population and disease control groups comprising patients with systemic lupus erythematosus (SLE) or Henoch-Schonlein purpura (HSP). METHODS: A retrospective review of 200 consecutive patients with WG or MPA was performed. Malignancies preceding or concurrent with vasculitis were recorded and the incidence of malignancy was compared with those in a population of 129 patients with HSP, 333 patients with SLE and a normal population in the West Midlands of the UK. RESULTS: Twenty patients had a diagnosis of malignancy, 14 had MPA and six had WG. Patients with ANCA-associated vasculitis had an increased risk of malignancy compared with HSP patients, of whom six patients had malignancy (relative risk 0.85, confidence interval 0.69-1.05; P = 0.034), or SLE patients, of whom five patients had malignancy (relative risk 0.31, 95% confidence interval 0.14-0.7; P<0.0001). The rate of malignancy compared with an age-matched control group was increased in patients with ANCA-associated vasculitis and HSP (ANCA-associated vasculitis, relative risk 6.02, 95% confidence interval 3.72-9.74; HSP, relative risk 5.25, 95% confidence interval 2.4-11.5). The presence of ANCA was not predictive of malignancy. CONCLUSION: In conclusion, patients with ANCA-associated vasculitis have an increased risk of preceding or concurrent malignancy.