Granulomatosis with Polyangiitis with Ocular Manifestations

Granulomatosis with polyangiitis (GPA) is a granulomatous-necrotic systemic vasculitis with a lesion of predominantly the upper and lower respiratory tracts at the onset of the disease (vasculitis, accompanied by granulomatous inflammation), and subsequently renal (glomerulonephritis). In addition, GPA may manifest as inflammation of small arteries and veins. Despite many years of study of this disease, the etiology of GPA remains unknown. The present case is about a 47-year-old female, who had been suffering from necrotizing scleritis, corneal ulcer, and secondary glaucoma in both eyes for 3 months, and she was treated with anti-inflammatory and antimicrobial therapy that showed no effect; the patient’s general condition became worse. In the second week of treatment, multiple abscess ruptures exposed the sclera. Sampling of the affected conjunctival tissue and positive HLA B8 haplotype and ANCA (PR3-ANCA) testings make it clear that GPA was the main reason of necrotizing scleritis with inflammation. The targeted treatment of the underlying disease allows to stabilize an inflammation of corneal and scleral lesions.

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Granulomatous Inflammation in ANCA-Associated Vasculitis

International Journal of Molecular Sciences ◽

10.3390/ijms22126474 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6474

Author(s):

Antje Müller ◽

Bettina Krause ◽

Anja Kerstein-Stähle ◽

Sara Comdühr ◽

Sebastian Klapa ◽

...

Keyword(s):

Respiratory Tract ◽

Granulomatosis With Polyangiitis ◽

Local Development ◽

Systemic Vasculitis ◽

Kidney Tissue ◽

Granulomatous Inflammation ◽

Giant Cells ◽

Eosinophilic Granulomatosis With Polyangiitis ◽

Factors Affecting ◽

Anca Associated Vasculitis

ANCA-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). While systemic vasculitis is a hallmark of all AAV, GPA is characterized by extravascular granulomatous inflammation, preferentially affecting the respiratory tract. The mechanisms underlying the emergence of neutrophilic microabscesses; the appearance of multinucleated giant cells; and subsequent granuloma formation, finally leading to scarred or destroyed tissue in GPA, are still incompletely understood. This review summarizes findings describing the presence and function of molecules and cells contributing to granulomatous inflammation in the respiratory tract and to renal inflammation observed in GPA. In addition, factors affecting or promoting the development of granulomatous inflammation such as microbial infections, the nasal microbiome, and the release of damage-associated molecular patterns (DAMP) are discussed. Further, on the basis of numerous results, we argue that, in situ, various ways of exposure linked with a high number of infiltrating proteinase 3 (PR3)- and myeloperoxidase (MPO)-expressing leukocytes lower the threshold for the presentation of an altered PR3 and possibly also of MPO, provoking the local development of ANCA autoimmune responses, aided by the formation of ectopic lymphoid structures. Although extravascular granulomatous inflammation is unique to GPA, similar molecular and cellular patterns can be found in both the respiratory tract and kidney tissue of GPA and MPA patients; for example, the antimicrobial peptide LL37, CD163+ macrophages, or regulatory T cells. Therefore, we postulate that granulomatous inflammation in GPA or PR3-AAV is intertwined with autoimmune and destructive mechanisms also seen at other sites.

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Uncommon Presentation of Granulomatosis with Polyangiitis Mimicking Metastatic Lung Cancer

Clinics and Practice ◽

10.3390/clinpract11020042 ◽

2021 ◽

Vol 11 (2) ◽

pp. 293-302

Author(s):

Edyta Maria Urbanska ◽

Johanna Elversang ◽

Bonnie Colville-Ebeling ◽

Johan Olof Löfgren ◽

Karl Emil Nelveg-Kristensen ◽

...

Keyword(s):

Lung Cancer ◽

Granulomatosis With Polyangiitis ◽

Systemic Vasculitis ◽

Granulomatous Inflammation ◽

Final Diagnosis ◽

Lymph Node Involvement ◽

Metastatic Lung Cancer ◽

Surgical Biopsy ◽

Uncommon Presentation ◽

Metastatic Lung

Diagnosis of anomalous intrathoracic lesions may be challenging and require a multidisciplinary approach. We present a case of granulomatosis with polyangiitis (GPA) clinically and radiologically mimicking metastatic lung cancer with a bilateral pulmonary mass, mediastinal and cervical lymph node involvement, and pleural effusion. Surgical biopsy of the thoracic lesion revealed necrotic granulomatous inflammation, and the final diagnosis was subsequently confirmed by kidney biopsy and biochemical parameters. This case illustrates how comprehensive diagnosis secures timely and relevant treatment. Systemic vasculitis may be one of the key differential diagnoses in patients with multiorgan involvement, especially with pattern-mimicking lung cancer.

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Cutaneous Ulcers as Initial Presentation of Localized Granulomatosis with Polyangiitis: A Case Report and Review of the Literature

Case Reports in Rheumatology ◽

10.1155/2015/517025 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7

Author(s):

Noreen Nasir ◽

Syed Ahsan Ali ◽

Hafiz Mohammed Mehmood Riaz

Keyword(s):

Respiratory Tract ◽

Granulomatosis With Polyangiitis ◽

Systemic Vasculitis ◽

Granulomatous Inflammation ◽

Organ Damage ◽

Recurrent Fever ◽

Small Vessel Vasculitis ◽

Diagnostic Challenge ◽

Extensive Evaluation ◽

Atypical Manifestations

Background. Granulomatosis with polyangiitis (GPA) is an ANCA associated small vessel vasculitis characterized by necrotizing granulomatous inflammation involving the upper and the lower respiratory tract and the kidneys. The disease has a broad clinical spectrum that ranges from limited/localized involvement of a single organ system to a generalized systemic vasculitis that affects several organs with evidence of end organ damage. Atypical forms of the disease have been recognized with or without respiratory tract involvement with a long protracted course before manifesting as generalized disease.Case Presentation. We describe a 57-year-old woman who presented with recurrent fever and cutaneous ulcers on her legs who was diagnosed to have granulomatosis with polyangiitis (GPA) after an extensive evaluation which excluded infectious, other vasculitides, connective tissue disease and malignant etiologies.Conclusion. In the absence of typical manifestations, granulomatosis with polyangiitis (GPA) is indeed a diagnostic challenge to the physician. Atypical manifestations like unexplained recurrent fever and cutaneous ulcers nevertheless call for keeping a low threshold for the diagnosis of GPA as the disease can initially present in localized form before heralding into a generalized disease.

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Dermatologic manifestations of granulomatosis with polyangiitis: A case report and literature review

Case Reports in Internal Medicine ◽

10.5430/crim.v6n4p19 ◽

2019 ◽

Vol 6 (4) ◽

pp. 19

Author(s):

Ashley Thomas ◽

Nithya Krishnan ◽

Nicole Vesely ◽

Myint Thway ◽

Rafik Jacob

Keyword(s):

Granulomatosis With Polyangiitis ◽

Systemic Vasculitis ◽

Clinical Signs ◽

Granulomatous Inflammation ◽

Signs And Symptoms ◽

Organ Damage ◽

Skin Lesions ◽

African American Female ◽

Cutaneous Manifestations ◽

Serologic Testing

Granulomatosis with polyangiitis (GPA) is an ANCA-associated, systemic vasculitis of small and medium-sized blood vessels. GPA causes inflammation and destruction to the vessel wall and eventual tissue and organ damage. It classically affects the tissues and vasculature of the sinuses, lungs, and kidneys. The organ damage results in epistaxis, cough, hemoptysis, shortness of breath and/or even kidney failure. Cutaneous manifestations are rare, but have been reported. We discuss the case of a 27-year-old African American female who presented with skin lesions on her bilateral forearms and hands, several years after diagnosis and treatment for GPA. The lesions were isolated papules, located on bilateral elbows, palms, and the lateral edge of the 3rd digit on her left hand. The lesions were intensely pruritic and non-painful. A skin biopsy of the lesions showed neutrophilic and granulomatous inflammation with nuclear debris, a largely non-specific histopathologic finding. An extensive autoimmune work up revealed elevated c-ANCA/PR3-ANCA levels supporting a diagnosis of cutaneous GPA. GPA is diagnosed by a combination of clinical signs and symptoms, serologic testing, and histology from biopsy of affected organs. Patient’s who meet the criteria should be tested for anti-neutrophil cytoplasmic antibody (ANCA), specifically c-ANCA/PR3-ANCA. A positive ANCA is supportive for GPA diagnosis. However, a negative ANCA does not rule out disease. Patients with cutaneous findings suggestive of GPA and positive c-ANCA/PR3-ANCA serologic testing should be closely followed up, which will lead to overall better prognosis, improved health outcomes and reduced patient and health care expenses.

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Ophthalmic Manifestations of ANCA-Associated Vasculitis

Acta Medica ◽

10.32552/2021.actamedica.551 ◽

2021 ◽

pp. 1-7

Author(s):

Merve İnanç Tekin ◽

Müge Pınar Çakar Özdal

Keyword(s):

Granulomatosis With Polyangiitis ◽

Systemic Vasculitis ◽

Systemic Disease ◽

Retinal Vasculitis ◽

Antineutrophil Cytoplasmic Antibody ◽

Eosinophilic Granulomatosis With Polyangiitis ◽

Ocular Involvement ◽

High Morbidity ◽

Ocular Manifestations ◽

Ocular Findings

Ocular manifestations in antineutrophil cytoplasmic antibody-associated vasculitis can be associated with the general or limited form of disease and can even occur in the absence of systemic disease. Ocular manifestations of associated vasculitis can be the first symptom of previously not manifested or undiagnosed systemic disease, allowing ophthalmologists to contribute to the diagnosis. Although its ocular findings are variable and nonspecific, the presence of necrotizing changes and peripheral corneal involvement accompanying scleral inflammation are important clues suggesting systemic vasculitis, especially associated vasculitis. The disease may affect all layers of the eye; scleritis and orbital involvement being the most common. Conjunctivitis, episcleritis, peripheral ulcerative keratitis, uveitis and retinal vasculitis are other ocular findings that may be observed during the disease course. Ocular involvement is most commonly seen in granulomatosis with polyangiitis followed by eosinophilic granulomatosis with polyangiitis and microscopic polyangiitis. Due to the high morbidity and mortality of associated vasculitis, it is very important to recognize the ocular manifestations of vasculitis as a sign of the underlying systemic disease and an indicator for the disease activity. Treatment varies depending on the location and severity of the ocular involvement. Although localized medical and surgical treatments can help to manage associated ocular disease, systemic immunosuppressive medications are often required to control the underlying disease. With the increasing availability and use of biological agents, prognosis has improved in patients with severe ocular complications. Rituximab appears to be useful in inducing remission and controlling relapses in patients with ocular involvement of associated vasculitis, particularly in cyclophosphamide resistant cases. A multidisciplinary approach in the diagnosis, treatment and follow-up of patients with associated vasculitis is required in order to achieve successful results.

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Atypical Endobronchial Carcinoid with Postobstructive Pneumonia Obscuring the Diagnosis of Granulomatosis with Polyangiitis

Case Reports in Rheumatology ◽

10.1155/2015/513602 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8

Author(s):

Robert Ali ◽

Candice Baldeo ◽

Jesse Onyenekwe ◽

Roshan Lala ◽

Cristian Landa ◽

...

Keyword(s):

Granulomatosis With Polyangiitis ◽

Systemic Vasculitis ◽

Clinical Manifestations ◽

Granulomatous Inflammation ◽

Lower Limbs ◽

Antineutrophil Cytoplasmic Antibodies ◽

Small Vessel Vasculitis ◽

American College Of Rheumatology ◽

Abnormal Chest ◽

Necrotizing Glomerulonephritis

Granulomatosis with polyangiitis (GPA), previously termed Wegener’s Granulomatosis, is an autoimmune small vessel vasculitis which is highly associated with antineutrophil cytoplasmic antibodies (ANCA) and has varied clinical manifestations. Diagnosis hinges on identifying a combination of clinical features of systemic vasculitis, positive ANCA serology, and histological evidence of necrotizing vasculitis, necrotizing glomerulonephritis, or granulomatous inflammation from a relevant organ biopsy. The American College of Rheumatology has also developed a classification criteria focusing specifically on nasal or oral inflammation, abnormal chest radiograph, and abnormal urinary sediment, along with granulomatous inflammation, which helps to distinguish GPA from other forms of systemic vasculitis. In the case presented below, the diagnosis of GPA was delayed as the patient had a concomitant atypical endobronchial carcinoid which predisposed to postobstructive pneumonia. Fortunately, the papular lesions that developed across her lower limbs prompted further investigations. The return of appropriate serology coincided with progression to alveolar hemorrhage, offering a more complete clinical picture, and when she responded to the combination of steroid, cyclophosphamide, and plasma exchange, the diagnosis of GPA was cinched.

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Pulmonary embolism and diffuse alveolar bleeding: combination options and therapy features

Terapevticheskii arkhiv ◽

10.26442/00403660.2021.03.200657 ◽

2021 ◽

Vol 93 (3) ◽

pp. 311-319

Author(s):

Andrey Yu. Tret’yakov ◽

Stefka G. Radenska-Lopovok ◽

Pavel I. Novikov ◽

Viktoriia A. Tret’yakova ◽

Svetlana P. Zakharchenko

Keyword(s):

Pulmonary Embolism ◽

Lupus Erythematosus ◽

Granulomatosis With Polyangiitis ◽

Systemic Vasculitis ◽

Underlying Disease ◽

Diffuse Alveolar Hemorrhage ◽

Primary Antiphospholipid Syndrome ◽

Systemic Lupus ◽

Chronological Sequence

The analysis of the mechanisms of the formation of a rare clinical combination of pulmonary embolism (PE) and diffuse alveolar hemorrhage (DAH), which are complications of systemic vasculitis associated with antibodies to the cytoplasm of neutrophils (primarily granulomatosis with polyangiitis), systemic lupus erythematosus and secondary antiphlogistic syndrome primary antiphospholipid syndrome and Goodpastures syndrome. Taking into account the chronological sequence of the occurrence of PE and DAH, 3 variants of the onset of these potentially fatal additions to the underlying disease were considered: the anticipatory DAH development of PE, delayed from DAH PE and joint (within 24 hours) formation of PE and DAH. A review of single descriptions of such a combination of complications of granulomatosis with polyangiitis is carried out, criteria are indicated, a working classification of severity is given and, taking this into account, a modern program of therapy for DAH as an independent event and in combination with PE.

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Successful treatment with benralizumab in a patient with eosinophilic granulomatosis with polyangiitis refractory to mepolizumab

Multidisciplinary Respiratory Medicine ◽

10.4081/mrm.2021.779 ◽

2021 ◽

Vol 16 ◽

Author(s):

Francesco Menzella ◽

Carla Galeone ◽

Giulia Ghidoni ◽

Patrizia Ruggiero ◽

Silvia Capobelli ◽

...

Keyword(s):

Granulomatosis With Polyangiitis ◽

Systemic Vasculitis ◽

Pulmonary Function Tests ◽

Treatment Options ◽

Granulomatous Inflammation ◽

Skin Lesions ◽

Eosinophilic Granulomatosis With Polyangiitis ◽

Clinical Effects ◽

Frequent Relapses ◽

Eosinophilic Granulomatosis

Introduction: Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by necrotizing eosinophilic granulomatous inflammation that frequently involves the respiratory tract (90% of cases). Asthma in EGPA is systematically severe and often refractory to common treatment, it is corticosteroid resistant and can often anticipate the onset of systemic vasculitis by many years. A release of cytokines necessary for the activation, maturation and survival of eosinophils, such as IL-4, IL-5 and IL-13 occurs in the activated Th-2 phenotype. In particular, IL-5 level is high in active EGPA and its inhibition has become a key therapeutic target. Oral glucocorticoids (OCS) are effective treatment options but unfortunately, frequent relapses occur in many patients and they lead to frequent side effects. As for now, there are currently no official recommendations on doses and treatment schedules in the management of EGPA.Case presentation: In this article, we describe the case of a man with EGPA, severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), with poor asthma and CRSwNP control despite OCS and mepolizumab treatment. Respiratory and vasculitis symptoms improved markedly after therapeutic switch to benralizumab. During the treatment, in addition to clinical effects, we witnessed a depletion of blood eosinophils, as well as an improvement in both pulmonary function tests, CT scan and skin lesions present initially. Conclusions: While there are many studies confirming the efficacy of benralizumab in EGPA, the most interesting aspect of our report is that efficacy was confirmed in a patient previously unresponsive to mepolizumab, known to be effective in EGPA.

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OP0054 NEW ROLE FOR PROTEINASE 3 IN IL-16 BIOACTIVITY CONTROL IN GRANULOMATOSIS WITH POLYANGIITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1314 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 28.1-29

Author(s):

A. Kerstein-Staehle ◽

C. Alarcin ◽

J. Luo ◽

G. Riemekasten ◽

P. Lamprecht ◽

...

Keyword(s):

Cell Death ◽

Western Blot ◽

Disease Activity ◽

Chronic Inflammation ◽

Immune Cells ◽

Peripheral Blood ◽

Granulomatosis With Polyangiitis ◽

Granulomatous Inflammation ◽

Proteinase 3 ◽

Sds Page

Background:The immunomodulatory cytokine IL-16 is increased in several inflammatory and autoimmune diseases1. IL-16 recruits and activates CD4+ immune cells such as T cells, dendritic cells, or monocytes. IL-16 is produced by various immune and non-immune cells, but synthesis and storage of IL-16 is regulated differentially depending on the cell type and stimulation. For its biological activity, IL-16 cleavage by caspase-3 is required1. Necrotizing granulomatous inflammation is a hallmark of granulomatosis with polyangiitis (GPA) with neutrophil dysregulation as a central driver of chronic inflammation and autoimmunity2. Earlier studies showed a correlation between increased serum IL-16 and disease parameters in AAV, including GPA3, but functional evidence for a direct link between IL-16 and neutrophils in granulomatous inflammation is missing so far.Objectives:In this study we aim to identify a functional link between increased IL-16, neutrophils, and the autoantigen proteinase 3 (PR3) with regard to chronic inflammation and autoimmunity in GPA.Methods:IL-16 was measured in sera of GPA patients (n = 40) and healthy controls (HC, n = 50) by ELISA and correlated with clinical features, such as disease activity (BVAS), creatinine, GFR, VDI and PR3-ANCA status. IL-16 protein expression was analyzed in peripheral blood mononuclear cells (PBMC) and polymorphonuclear cells (PMN) from GPA patients and HC (n = 5, each) by SDS-PAGE and western blot. Binding affinity of recombinant pro-IL-16 to native human PR3 was assessed by microscale thermophoresis. Cleavage of pro-IL-16 by active human PR3 was performed at various time points at 37°C. Cleavage products were analyzed by SDS-PAGE and western blot.Results:Circulating IL-16 was significantly increased in GPA patients compared to HC. Elevated IL-16 positively correlated with BVAS, creatinine, VDI and PR3-ANCA status and negatively correlated with GFR. In PMBC and PMN from GPA and HC we identified different expression patters of precursor and active forms of IL-16. In healthy PBMC we found high amounts of precursor (80kD), pro-IL-16 (55kD) and active IL-16 (17kD). In contrast, PBMC from GPA patients had lower amounts of pro-IL-16 and no active IL-16, indicating activation and secretion of IL-16 due to inflammatory stimulation, as shown earlier5. In GPA PMN we detected no precursor IL-16, but pro-IL-16 and its active form, in contrast to very low amounts of all IL-16 forms in healthy PMN. Processing and release of IL-16 in neutrophils has been linked to apoptosis and secondary necrosis5. By interaction studies we demonstrated direct binding of pro-IL-16 to PR3 with a Kd of 10 nM. In a subsequent cleavage assay we confirmed IL-16 processing by PR3 in a time-dependent manner.Conclusion:Correlation of serum IL-16 with clinical features of GPA suggests that IL-16 is associated with markers of disease activity, tissue damage and autoreactivity. We showed that PBMC and PMN represent a source of IL-16 in GPA. By the identification of PR3 as an additional IL-16-activating enzyme we could demonstrate a potential link between excessive PR3 expression, cell death and IL-16-dependent mechanisms, contributing to chronic granulomatous inflammation and autoimmunity in GPA.References:[1]Glass, W. G. et al. Not-so-sweet sixteen: The role of IL-16 in infectious and immune-mediated inflammatory diseases. J. Interf. Cytokine Res. 26, 511–520 (2006).[2]Millet, A. et al. Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis. J. Clin. Invest. 125, 4107–4121 (2015).[3]Yoon, T. et al. Serum interleukin-16 significantly correlates with the Vasculitis Damage Index in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Res. Ther. 22, 1–6 (2020).[4]Elssner, A. et al. IL-16 Is Constitutively Present in Peripheral Blood Monocytes and Spontaneously Released During Apoptosis. J. Immunol. 172, 7721–7725 (2004).[5]Roth, S. et al. Secondary necrotic neutrophils release interleukin-16C and macrophage migration inhibitory factor from stores in the cytosol. Cell Death Discov. 1, 15056 (2015).Disclosure of Interests:None declared

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Intravenous Immunoglobulin Treatment in Kawasaki Disease Decreases the Incidence of Myopia

Journal of Clinical Medicine ◽

10.3390/jcm10071381 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1381

Author(s):

Hun-Ju Yu ◽

Meng-Ni Chuang ◽

Chiao-Lun Chu ◽

Pei-Lin Wu ◽

Shu-Chen Ho ◽

...

Keyword(s):

Kawasaki Disease ◽

Intravenous Immunoglobulin ◽

Systemic Vasculitis ◽

Age Distribution ◽

Population Based ◽

Research Database ◽

Ocular Manifestations ◽

Missing Data Treatment ◽

The Difference ◽

Age Range

Kawasaki disease (KD) is a systemic vasculitis that primarily affects children under the age of 5 years old. The most significant complication is coronary artery lesions, but several ocular manifestations have also been reported. Recently, one study revealed an increasing incidence of myopia among KD patients. Therefore, the aim of this study was to assess the difference in myopic incidence between Kawasaki disease (KD) patients treated with aspirin and intravenous immunoglobulin (IVIG). Materials and methods: We carried out a nationwide retrospective cohort study by analyzing the data of KD patients (ICD-9-CM code 4461) from Taiwan’s National Health Insurance Research Database (NHIRD) during the period of 1996–2013. Results: A total of 14,102 diagnosed KD were found in Taiwan during the study period. After excluded missing data, treatment strategy and age distribution, a total of 1446 KD patients were enrolled for analysis including 53 of which received aspirin (without IVIG) and 1393 of which were treated with IVIG. Patients who had myopia, astigmatism, glaucoma, cataract, etc. prior to their KD diagnosis were excluded. The age range was 0 to 6 years old. According to the cumulative curves, our results demonstrated that the myopic incidence in the IVIG group was significantly lower than the aspirin group (hazard ratio: 0.59, 95% confidence intervals: 0.36~0.96, p = 0.02). Treatment with IVIG for KD patients may have benefit for myopia control. Conclusion: Compared to aspirin, IVIG may decrease the myopic risk in KD patients. However, it needs further investigation including clinical vision survey of myopia due to the limitations of this population-based study.

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