Immune Complex Small Vessel Vasculitis Research Articles

Expert perspectives on pathological findings in vasculitis.

Pathological findings are important in the diagnosis of vasculitis. However, due to the rarity of the disease, standard textbooks usually devote only a few pages to this topic, and this makes it difficult for clinicians not specializing in vasculitis to fully understand the pathological findings in vasculitis. To address the paucity of information, we present representative pathological findings in vasculitis classified in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012). The CHCC2012 classifies 26 vasculitides into seven categories: (1) large-vessel vasculitis, (2) medium-vessel vasculitis, (3) small-vessel vasculitis, including antineutrophil cytoplasmic antibody-associated vasculitis and immune complex small-vessel vasculitis, (4) variable-vessel vasculitis, (5) single-organ vasculitis, (6) vasculitis associated with systemic disease, and (7) vasculitis associated with probable aetiology. Moreover, representative pathological findings of vasculitis-related diseases and non-inflammatory vasculopathy not mentioned in the CHCC2012 are also presented. This will be useful for clinicians to refer to typical pathological findings of vasculitis in daily practice.

Acquired aplastic anemia complicated with anti-glomerular basement membrane disease successfully treated with immunosuppressive therapy: a case report

BackgroundAplastic anemia (AA) is a rare but fatal disorder characterized by pancytopenia due to bone marrow hypoplasia. Anti-glomerular basement membrane disease (anti-GBM disease) is an immune complex small-vessel vasculitis that presents as rapidly progressive glomerulonephritis and/or pulmonary hemorrhage. Although both involve autoreactive T cells that are partially triggered by human leukocyte antigen (HLA)-DR15, there have been no reports of their co-existence and the treatment strategy is not well understood.Case presentationA 67-year-old woman presented with fever, malaise, and acute kidney injury with proteinuria and hematuria requiring hemodialysis. She was diagnosed with anti-GBM antibody disease based on high serum anti-GBM antibody titer and crescentic glomerulonephritis on a renal biopsy. Pulse administration of methylprednisolone (MP), oral prednisolone (PSL), and plasmapheresis were performed. Only 2 weeks after the diagnosis of anti-GBM disease, the patient developed pancytopenia requiring frequent blood transfusions. The blood cell count did not recover even 1 month after discontinuing the drugs that could cause pancytopenia. Bone marrow examination showed hypocellularity without abnormal infiltrates or fibrosis, which led to the diagnosis of severe acquired AA. Further HLA phenotyping revealed that she had HLA-DR15. Increased dose of PSL with the secondary MP pulse and the addition of cyclosporine improved pancytopenia. Although she remained dialysis-dependent, anti-GBM disease and pancytopenia did not recur for more than 2 years.ConclusionsWe report the first case of acquired AA complicated with anti-GBM disease in an elderly woman with HLA-DR15, which was successfully treated with immunosuppressive therapy (IST). This report is valuable not only because it shows they may co-occur, but also because it provides a therapeutic option for this complex condition. It was also suggested that pancytopenia in patients with anti-GBM disease recalls serious hematologic diseases including AA that require immediate treatment based on bone marrow examination.

Drug-induced IgA vasculitis in children and adults: Revisiting drug causality using a dual pharmacovigilance-based approach.

IgA vasculitis (IgAV) is an immune complex small-vessel vasculitis. Drug-induced IgAV cases were rarely reported in the literature. Drug causality assessment is challenging as many other etiological factors can be involved. We performed a pharmacovigilance study to identify the main drugs reported to induce IgAV. We used the French pharmacovigilance database (FPVD) and the WHO global individual case safety reports database (VigiBase) to retrieve IgAV cases. Cases from the FPVD were reviewed by two investigators using predefined criteria. Disproportionality analyses (case - non-case approach) were conducted in VigiBase to identify drugs significantly associated with IgAV reporting. Of the 467 IgAV cases retrieved from the FPVD, 115 (47 children and 68 adults) have been assessed as definite or probable, reported with 178 suspected drugs. Overall IgAV cases were mainly male (58%), with a median age of 33.5 (8.0-63.3) years. No death was reported. Besides, we identified 1558 possible IgAV cases in VigiBase. Among them, 40 were associated with a disproportionality in IgAV reporting. Drugs were mainly vaccines, antibiotics and TNF-α blockers, these finding being consistent in both databases. IgAV reporting with TNF-α blockers was significantly associated with their use in inflammatory bowel diseases, psoriasis or ankylosing spondylitis compared to other indications. Our systematic study enables the identification of culprit drugs in drug-induced IgAV. These results strengthen the immune pathophysiology of IgAV and the role of underlying disease. The list of suspected drugs may be useful for physicians to manage patients with IgAV and consider appropriate drug discontinuation. What is already known about this subject? IgA vasculitis has multifactorial etiology. To date, possible culprit drugs have been reported only in case reports. What does this study add? Using a dual pharmacovigilance-based approach, we identified drugs associated with the occurrence of IgA vasculitis, such as all types of vaccines, major antibiotics and immunomodulatory agents, mainly TNF-α blockers. How might this impact on clinical practice or future developments? Physicians should be aware of drug-induced IgA vasculitis and we provide evidence on the most frequent implicated drugs.

Recruitment of CXCR3+ T cells into injured tissues in adult IgA vasculitis patients correlates with disease activity

ObjectivesAdult immunoglobulin A vasculitis (IgAV) is an immune complex small vessel vasculitis. So far, the involvement of T cells in this pathology has been poorly studied. The aim of this study was to analyze T-cell homeostasis as well as cytokine and chemokine concentrations in the blood and tissues of IgAV patients. MethodsT cells, cytokine and chemokine concentrations were analyzed in peripheral blood using flow cytometry and multiplex assays. T-cell infiltrates in the kidney and the skin were characterized by immunohistochemistry. This study prospectively included 44 adult patients with biopsy-proven IgAV and 24 age- and sex-matched healthy controls. ResultsWe observed reduced proportions of circulating CXCR5-and CXCR3-expressing memory CD4 T cells at diagnosis but normal values at remission. The plasma levels of Th1-related cytokines (IL-12, IL-27 and IFNγ) and of the TFH-related cytokine, IL-21, were paradoxically not reduced in patients. We observed increased plasma concentrations of the CXCR5 ligand, CXCL13, and of the CXCR3 ligands, CXCL10/11, suggesting a potential relocation of the corresponding T cells into inflamed tissues. We then confirmed the recruitment of CXCR3-expressing T cells into the skin and kidneys. In the skin, T-cell infiltrates mainly co-localized with damaged dermal small vessels. Finally, patients with the largest kidney T-cell infiltrates were also those with the highest proteinuria. ConclusionAltogether, our results strongly suggest that, in IgAV patients, CXCL10/11 orchestrate the recruitment of CXCR3-expressing T cells in injured tissues, contributing to tissue damage and disease activity.

Serum angiostatin and endostatin levels in patients with granulomatosis with polyangiitis and immune complex small vessel vasculitis.

ObjectivesInflammation has been revealed to be associated with angiogenesis. Granulomatosis with polyangiitis (GPA) and immune complex small vessel vasculitis (ICSVV) are forms of systemic vasculitides of different pathogenesis. GPA is a necrotizing granulomatosis and ICSVV is associated with inflammation of postcapillary venules induced by deposits of immune complexes. The aim of the study was to determine serum levels of angiostatin and endostatin, natural angiogenesis inhibitors, in patients with GPA and ICSVV as well as healthy individuals.Material and methodsTwo groups of patients with GPA (20 patients) and ICSVV (20 patients) as well as 20 controls were investigated. All patients were investigated before initiation of immunosuppressive therapy or administration of corticosteroids. Angiostatin and endostatin levels were assayed with the ELISA method.ResultsEnhanced serum levels of angiostatin and endostatin were found in patients with GPA but not in those suffering from ICSVV. In patients with GPA increased levels of angiogenesis inhibitors correlated with the disease activity. A correlation between angiostatin and endostatin levels was observed in all groups of investigated individuals.ConclusionsIt is suggested that formation of necrotizing granulation is associated with profound activation of angiogenesis and an increase in serum levels of inhibitors is a phenomenon occurring during blood vessel formation in the granulation tissue. The obtained results confirm involvement of angiogenesis in pathogenesis of at least some forms of vasculitides and suggest the need for continuation of investigations in this field.

Treatment of Pulmonary Vasculitis.

Pulmonary vasculitis can be heterogeneous and have some pathophysiological, clinical, and biological specificities that might influence treatment choices. Main vasculitides associated with pulmonary vasculitis include antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune complex small vessel vasculitis, and antiglomerular basement membrane disease. Patient characteristics and association of lung involvement with other manifestations affecting disease severity may also influence treatment strategy. Alveolar hemorrhage frequently requires urgent treatment to control the underlying disease and provide supportive care such as mechanical ventilation. The level of evidence of each treatment strategy varies according to the underlying disease, but treatment is usually based on a combination of glucocorticoids and immunosuppressive agents, especially cyclophosphamide and rituximab. The role of plasma exchanges, widely used in patients with severe vasculitis, is controversial, based on results from recent prospective randomized controlled trials.

Vasculite leucocytoclasique annulaire : une forme particulière de vasculite des petits vaisseaux ?

Leukocytoclastic vasculitis is characterized by necrotizing inflammation around small blood vessels, composed mainly of neutrophils. Skin lesions in leukocytoclastic vasculitis are polymorphous, but a rare annular variant exists of which dermatologists must be aware. Herein we present a new case of this entity. We report the case of a 74-year-old man who developed annular purpuric infiltrated lesions mainly on the lower limbs, with leukocytoclastic vasculitis being confirmed by histology. This annular leukocytoclastic vasculitis regressed spontaneously with no recurrence after 6 months. The aetiology was not established. Annular leukocytoclastic vasculitis is rare, and the mechanisms underlying annularity and peripheral spread as well as the aetiology remain unexplained. This form of vasculitis with unusual clinical features may constitute a new entity in the subclass of immune complex small vessel vasculitis within the Chapel Hill classification. While the aetiology and physiopathology of this vasculitis are unknown, despite the possibility of recurrence, skin involvement appears isolated and the condition carries a good prognosis.

Vasculitis: New nomenclature of the Chapel Hill consensus conference 2012

Within the last years, many advances have been made in the understanding of the etiopathology of vasculitis as well as of different disease courses. The revised 2012 Chapel Hill consensus conference (CHCC) nomenclature reflects current knowledge on the etiopathology in addition to the descriptive principles of vessel size and types of inflammation. The anti-neutrophil cytoplasmic antibody (ANCA)-associated forms of vasculitis have been separated as a group, as opposed to immune complex small vessel vasculitis. When consensus was achieved eponyms have been replaced by systematic names, such as granulomatosis with polyangiitis (Wegener's granulomatosis) or eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Moreover, clinically important but less well-known types of vasculitis have now been included in the CHCC nomenclature. This article presents the changes and summarizes the results of important new articles on the clinical picture and morphology of vasculitis.

Vaskulitis

In recent years, many advances have been made in our understanding of vasculitis etiopathology as well as of different disease courses. The revised Chapel Hill Consensus Conference (CHCC) 2012 nomenclature reflects current knowledge about etiopathology, in addition to the descriptive principles of vessel size and type of inflammation. Anti-neutrophil cyptoplasmic antibody (ANCA)-associated vasculitides have been classified as a separate group, as opposed to immune complex small vessel vasculitis. In cases where consensus was achieved, eponyms have been replaced by systematic names, such as granulomatosis with polyangiitis (Wegener's) or eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Moreover, clinically important but less well-known types of vasculitis have now been included in the CHCC nomenclature. This article presents the changes, focussing on those types that are relevant to the histopathologist, and summarizes the results of important new articles on morphology and clinical picture of vasculitis.

Pathologic Classification of Vasculitis

The diagnostic categorization of systemic noninfectious vasculitis rarely can be made definitively based solely on the light microscopic findings but usually requires integration of the pathologic features with immunohistologic, clinical, and/or laboratory data to reach the most clinically useful diagnosis. Nevertheless, knowledgeable pathologic assessment of the histopathology can be critically important in arriving at the appropriate diagnosis. Noninfectious vasculitides can be broadly categorized as large vessel vasculitis, medium-sized vessel vasculitis, and small vessel vasculitis, although it is important to realize that the type of vessel involved is as important as size, and this is only one of many features that must be assessed to reach a diagnosis. Large vessel vasculitides (giant cell arteritis and Takayasu arteritis) have a predilection for the aorta and its major branches, especially those directed to the extremities and the neck and head. Medium-sized vessel vasculitides (polyarteritis nodosa and Kawasaki disease) affect predominantly medium-sized arteries, especially main visceral arteries such as the renal, hepatic, coronary and mesenteric arteries. Small vessel vasculitides (pauci-immune small vessel vasculitis and immune complex small vessel vasculitis) also can affect arteries, but their predominant targets are arterioles, venules, and capillaries. Pauci-immune small vessel vasculitis is associated with circulating antineutrophil cytoplasmic autoantibodies (ANCA) and includes microscopic polyangiitis, Wegener's granulomatosis, and Churg-Strauss syndrome. Precise diagnosis of immune complex small vessel vasculitis often requires immunohistologic characterization of the composition of the immune complexes or serologic detection of pathogenetically related antibodies.