Form Of Small-vessel Vasculitis Research Articles

Laboratory diagnostics for vasculitis beyond antineutrophil cytoplasmatic autoantibodies

The diagnosis of systemic vasculitis (SV) is amajor clinical challenge due to the very different forms of presentation and requires an interdisciplinary approach. Targeted laboratory diagnostics support making the diagnosis, differential diagnosis and classification and are also akey component in the detection of active organ manifestations and treatment complications. The basic laboratory tests include the erythrocyte sedimentation rate (ESR), C‑reactive protein (CRP), blood count, serum creatinine, urinalysis, specific autoantibodies, complement, immunoglobulins, cryoglobulins and hepatitisB and C serology. Antineutrophil cytoplasmic autoantibodies (ANCA), antiglomerular basement membrane antibodies (anti-GBM antibodies) and anti-C1q antibodies are valuable laboratory markers for the diagnosis of the various forms of small vessel vasculitis. There are no specific laboratory tests for the diagnosis of medium and large vessel vasculitis. Despite advances in our understanding of the pathogenesis of vasculitis, no biomarkers have yet been identified that can be reliably used to guide treatment or that are useful in distinguishing vasculitis from other inflammatory diseases such as infections or treatment complications.

A Rare Case of Double-antibody-positive Renal Vasculitis: Are we in a Hurry to Start Tuberculosis Medicines?

Double antibody positive renal vasculitis (anti GBM antibody and pANCA) is a rare form of small vessel vasculitis associated with poor outcome. It is difficult to decide which antibody is the precursor in these cases. We report here such a rare case of double antibody positive renal vasculitis which was started on anti tubercular medicine for a positive mantoux test and interferon gamma release assay. The possible reasons for these antibodies in this may be a complication of COVID-19 infection or vaccine, adverse drug effect of antitubercular medicines or a paradoxical reaction during the tuberculosis treatment. The patient could not survive beyond two months of diagnosis because of rapidly declining renal functions. This case highlights the importance of a meticulous clinical approach, supports two week tuberculosis medicines trial and an early and careful dealing of non responders during tuberculosis treatment especially in patients whose diagnosis is not microbiologically confirmed.

IgA Nephropathy Associated with IgA Vasculitis Coexisting with Focal Segmental Glomerulosclerosis Tip Variant: A Case Report

IgA vasculitis (IgAV), previously known as Henoch–Schönlein purpura, is a form of small vessel vasculitis that affects the skin, joints, intestines, and kidneys. The clinical presentation in adults is usually infrequent, more severe, with a worse prognosis and a higher recurrence rate. Due to limited scientific evidence, IgAV is viewed similarly to IgA nephropathy (IgAN), and the renal histopathological lesions are indistinguishable between the two. IgAN is the most prevalent glomerular diseases worldwide. The diagnosis of IgAN is confirmed through a renal biopsy. The most frequently found histopathological lesions are mesangial proliferation and concurrent IgA deposition confirmed by direct immunofluorescence. Focal segmental glomerulosclerosis (FSGS) appears as a glomerular pattern of injury in up to 40% of renal biopsies with IgAN, although there are few reported cases in the international literature where both diseases coexist as primary etiologies. We report a case of a female patient presenting with vasculitic lesions, abdominal pain, and nephrotic syndrome, whose cause is confirmed by a renal biopsy with a diagnosis of IgAN secondary to IgAV and coexistence of FSGS, an unusual presentation with few case reports.

Granulomatosis with polyangiitis with salivary glands involvement: Presenting a case and describing its clinical, pathophysiological, and therapeutic aspects

Key Clinical MessageGranulomatosis with polyangiitis (GPA), a rare form of small vessel vasculitis, may be manifested by multisystem involvement misleading its definitive diagnosis. The involvement of salivary glands is a very rare characteristic of GPA. Herein, we described a case of GPA with submandibular salivary gland involvement followed by reviewing the literature on similar cases. The case was a 31‐year‐old man, a known case of seronegative peripheral arthritis that referred recently with bilateral enlargement of the parotid and submandibular glands. Pulmonary nodules were also evident in the patient's CT scan. Fine‐needle aspiration under ultrasound guidance indicated the presence of degenerated squamoid cells, giant cells, and inflammatory cells with a priority of neutrophils in the submandibular gland, as well as the presence of a cyst containing fluid without the evidence of malignancy in the parotid gland. The positivity for the Anti‐neutrophil Cytoplasmic Antibody (C‐ANCA) marker was also revealed. The patient was treated with methotrexate, prednisolone, and rituximab which led to a gradual reduction in the size of the glands and the improvement of the patient's clinical symptoms within 1 month after the treatment. Enlargement of salivary glands in the context of inflammatory disorders can raise doubts about the existence of GPA, and therefore imaging evaluation and histopathological assessment with an ANCA test will be necessary to confirm or rule out it.

The effect of various forms of treatment of vasculitis on C3, C4 and C5a complement levels in infants and children attending Assiut University Children Hospital (AUCH)

Vasculitis is an umbrella term for various and heterogeneous disorders sharing the presence of inflammation of blood vessel walls (Geetha & Jefferson, 2020). Immune cell infiltrates involve the presence of leukocytes in the vessel with immune-complex deposition, which implies the activation of the complement system and then the swelling and destruction of vessel mural structures. The lumen is narrowed or occluded leading to ischemia and necrosis (Chimenti et al., 2015). It produces local symptoms resulting in hypoperfusion, infarction and hemorrhage and systemic symptoms with an increase in acute phase reactants (Salvador, 2020). According to the size of the blood vessel affected and the distribution of vascular injury, pediatric vasculitis is classified into small vessel vasculitis as in Henochonlein Purpura (HSP), medium-sized vessel vasculitis as in Kawasaki disease and large vessel vasculitides affecting the aorta and its proximal branches. Some forms of small vessel vasculitis are characterized by the presence of antineutrophil cytoplasmic antibodies (ANCAs), whereas others are associated with immune complex deposition in affected tissues. Clinical presentation supported by specific laboratory test, imaging, and confirmatory histology are necessary in order to perform vasculitides’ diagnosis (Sivaraman et al., 2020). To assess the severity of vasculitis and response to treatment, urinary biomarkers such as albumin/creatinine ratio (A/C ratio) in urine have been proved to be easily done and correlated well with both clinical and serological results (Zhang, 2020). Aim of Work: The aim of this study is to assess the effect of various forms of drugs, used in treatment of vasculitis, on the serum levels of complements (C3, C4, and C5a) and Antineutrophil cytoplasmic antibodies (ANCA), in infants and children attending Assiut University Children Hospital (AUCH). Conclusion: In conclusion, cases on combined Methotrexate and Steroid therapy scored best regarding the lowering of C5a level in serum, however, in our cases as a whole, the level of C5a didn’t differ significantly from its level in control. Although the 3 arms of therapy used in this study had good effect on C3 & C4 levels, yet their effect on C5a level was not significant from control. This finding could be explained by the fact that most of our studied cases were of the immune-complex deposition diseases type (which have no effect on C5a) and were ANCA negative. Therefore, C5a inhibitor drugs probably will not be suitable in treatment of most common causes of pediatric vasculitis encountered in this series. Perhaps, this type of therapy might be used in ANCA-Positive associated vasculitides, e.g. Wegener’s Granulomatosis. Further research with bigger number of ANCA positive cases is needed to decide whether such cases could benefit from the use of C5a inhibitors or not.

Diagnostic and Therapeutic Challenges of Vasculitis.

Systemic vasculitis can be a challenge to differentiate from other forms of vasculopathy. Because treatment for systemic vasculitis is disparate from that for other forms of vasculopathy, clinicians should strive for high diagnostic certainty. This review article aims to highlight the clinical, radiographic, and histologic clues to distinguish systemic vasculitis from mimics. Vasculitis should be considered in patients with preexisting conditions including autoimmune connective tissue diseases, multisystem manifestations, unexplained ischemic events, unusual radiographic findings, or signs of systemic inflammation. A multidisciplinary approach can be used among rheumatologists, vascular cardiologists, radiologists, and vascular interventionalists to raise diagnostic certainty in cases with large- and/or medium-vessel involvement. Recognition of cardiac manifestations, including myocarditis seen in forms of small-vessel vasculitis (eg, eosinophilic granulomatosis with polyangiitis) or coronary arteritis seen in forms of medium-vessel vasculitis (eg, polyarteritis nodosa and Kawasaki disease) is important owing to the associated mortality. Clinical phenotype, radiographic features, laboratory tests, and histology can help to differentiate vasculitis from noninflammatory vasculopathies and define the etiology of the vasculitis to help guide appropriate treatment. Various modalities of imaging can give clues to aid in diagnosis of vasculitis and can be considered in the context of physician preference and patient comorbidity. While conventional angiography can give important details regarding luminal anatomy and pressure gradients in medium- and large-vessel vasculitis, noninvasive imaging modalities such as computed tomographic angiography, magnetic resonance angiography, color Doppler ultrasound, and positron emission tomography/computed tomography are commonly used for both diagnosis and follow-up. Treatment for systemic vasculitis should be coordinated with an experienced rheumatologist.

Leukocytoclastic vasculitis following coronavirus disease 2019 (COVID-19): A case report

Leukocytoclastic vasculitis (LCV) refers to the histopathological changes observed in a common form of small vessel vasculitis that can affect skin and/or internal organs. LCV can be precipitated by several causes (including infections, drugs, and collagen vascular diseases) or can be idiopathic. We report a 50-year-old man who presented with fever, parotid enlargement and skin rash (discrete and confluent erythematous macules, papules, and plaques and a few purpuric lesions on the back of trunk and upper limbs), 3 weeks after being diagnosed with coronavirus disease 2019 (COVID-19). The patient showed four out of the five features required to satisfy the working case definition of multisystem inflammatory syndrome in adults (MIS-A). Histopathology of rash was consistent with LCV. Whether, COVID-19 was the cause for LCV in our patient remains unclear. The fever, parotid enlargement and rash showed complete resolution following treatment with systemic corticosteroids and enoxaparin.

Leukocytoclastic vasculitis associated with multifocal sensory neuropathy responsive to intravenous immunoglobulins: a case report.

Leukocytoclastic vasculitis (LCV) is a common form of small-vessel vasculitis, which commonly presents as palpable purpura or petechiae, caused by deposition of circulating immune complexes on vessels walls that attracts granulocytes which damage the vascular endothelium and leading to erythrocytes extravasation. The skin is the most commonly involved organ, but also renal, gastrointestinal, pulmonary, cardiovascular and neurological systems may be affected. Skin lesions may be the initial signs of systemic vasculitis. Systemic symptoms may be present, such us fever, myalgia, abdominal pain and arthralgia. The presence of neuropathy/mononeuritis multiplex is expression of severe vasculitic involvement. Herein, we describe the case of a patient with leucocytoclastic vasculitis associated to sensitive neuropathy, responsive to intravenous immunoglobulins (IVIg) therapy, after the failure of classic systemic treatments.

Antineutrophil cytoplasmic antibodies (ANCA)-positive patient with infective endocarditis and chronic hepatitis B virus:\xa0a case report and review of the\xa0literature

BackgroundAntineutrophil cytoplasmic antibodies comprise a family of autoantibodies that are often used as biomarkers for certain forms of small-vessel vasculitis; however, chronic infections tend to induce the production of antineutrophil cytoplasmic antibodies. Infective endocarditis and hepatitis B virus infection have been reported to exhibit antineutrophil cytoplasmic antibody positivity and to mimic antineutrophil cytoplasmic antibody–associated vasculitis, which may lead to misdiagnosis and inappropriate treatment.Case presentationWe report a case of a 46-year-old Han Chinese man with untreated chronic hepatitis B virus infection who featured proteinase-3 antineutrophil cytoplasmic antibody positivity while hospitalized with infective endocarditis. Cardiac ultrasound echocardiography disclosed mitral and aortic regurgitation with vegetation. On the 15th hospital day, the patient underwent mitral and aortic valve replacement and was then treated with antibiotics for more than 1 month. On the 57th hospital day, the patient was discharged. His urinary abnormalities and renal function were gradually recovering. Four months after being discharged, his proteinase-3 antineutrophil cytoplasmic antibody levels had returned to the normal range.ConclusionsThe findings in this study update and expand current understanding of antineutrophil cytoplasmic antibody positivity in patients with both infective endocarditis and hepatitis B virus. Treatment (including surgery, antibiotics, corticosteroids and/or cyclophosphamide, antiviral agents, and even plasma exchange) is challenging when several diseases are combined. Renal biopsy is suggested if the patient’s condition allows. Antineutrophil cytoplasmic antibody testing should be repeated after therapy, because some cases might require more aggressive treatment.

Submandibular salivary gland involvement in granulomatosis with polyangiitis

IntroductionGranulomatosis with polyangiitis (GPA) is one of the forms of small vessel vasculitis. It is a rare condition that needs a high degree of suspicion to reach the diagnosis. It is one of the causes of diffuse parenchymal lung disease, with a very wide differential diagnosis. It is commonly misdiagnosed with malignant, granulomatous, and infectious lung diseases.Case presentationWe report a case of a 31-year-old male who presented with productive cough, shortness of breath, hemoptysis, nasal obstruction, and epistaxis together with submandibular salivary gland swelling. Diagnosis of GPA was based on characteristic cavitary lung lesions, nasal and salivary gland involvement, pathological samples that revealed necrotizing granulomatous inflammation, characteristic positive Cytoplasmic- ANCA (C-ANCA), together with exclusion of malignancy and tuberculosis.ConclusionGPA is a rare condition. Salivary gland involvement should raise suspicion about GPA, in addition to other systemic manifestations.

Neutrophil myeloperoxidase harbors distinct site-specific peculiarities in its glycosylation

Anti-neutrophil cytoplasmic autoantibodies (ANCAs) are directed against lysosomal components of neutrophils. ANCAs directed to proteinase 3 and myeloperoxidase (MPO) in particular are associated with distinct forms of small vessel vasculitides. MPO is an abundant neutrophil-derived heme protein that is part of the antimicrobial defense system. The protein is typically present in the azurophilic granules of neutrophils, but a large portion may also enter the extracellular space. It remains unclear why MPO is frequently the target of antibody-mediated autoimmune responses. MPO is a homodimeric glycoprotein, posttranslationally modified with complex sugars at specific sites. Glycosylation can strongly influence protein function, affecting its folding, receptor interaction, and backbone accessibility. MPO potentially can be heavily modified as it harbors 5 putative N-glycosylation sites (10 in the mature dimer). Although considered important for MPO structure and function, the full scope and relative abundance of the glycans attached to MPO is unknown. Here, combining bottom-up glycoproteomics and native MS approaches, we structurally characterized MPO from neutrophils of healthy human donors. We quantified the relative occupancy levels of the glycans at each of the five sites and observed complex heterogeneity and site-specific glycosylation. In particular, we detected glycosylation phenotypes uncommon for glycoproteins in the extracellular space, such as a high abundance of phosphorylated high-mannose species and severely truncated small glycans having the size of paucimannose or smaller. We hypothesize that the atypical glycosylation pattern found on MPO might contribute to its specific processing and presentation as a self-antigen by antigen-presenting cells.

Clinical impact of endocapillary proliferation according to the Oxford classification among adults with Henoch-Sch\xf6nlein purpura nephritis: a multicenter retrospective cohort study

BackgroundHenoch-Schönlein purpura nephritis (HSPN) is a form of small vessel vasculitis associated with purpura and IgA deposition in the glomeruli. The International Study of Kidney Disease in Children (ISKDC) classification predicts renal prognosis in children with HSPN, but not in adults. Additionally, it is not well known whether the Oxford classification 2016 and/or the Japanese Histologic classification (JHC) are associated with renal outcome. Herein, we investigated the relationship between pathological characteristics and renal outcome among adult patients with HSPN.MethodsA multicenter retrospective cohort study was conducted in adult patients with HSPN who underwent renal biopsy between 2004 and 2014. Two nephrologists classified each patient according to the Oxford classification 2016, JHC, and the ISKDC classification. Renal outcome was defined by a 30% decline in the eGFR and/or end-stage kidney disease.ResultsWe enrolled 74 adult patients with HSPN (mean age, 47.8 ± 17.4 years; mean eGFR, 76.4 ± 25.8 ml/min/1.73 m2; median proteinuria, 1.40 [IQR: 0.70–2.38] g/day). During a mean follow-up period of 68.0 ± 33.0 months, fourteen patients (18.9%) reached the renal outcome, and all 14 had received immunosuppressive therapy. The log-rank test revealed that event-free renal survival was significantly shorter in patients with endocapillary proliferation (E1) according to the Oxford classification than in those with E0 (p = 0.0072). However, the JHC, ISKDC classification and other Oxford lesions could not demonstrate a significant difference in event-free renal survival. In a multivariate Cox model adjusted for clinical and pathological factors, age (HR, 1.57; 95% CI, 1.12–2.21) and E lesion (HR, 6.71; 95% CI, 1.06–42.7) were independent risk factors for renal outcome.ConclusionsEndocapillary proliferation is significantly associated with renal outcome in adult patients with HSPN, including those receiving immunosuppressive therapy. Other Oxford classification lesions, JHC, and ISKDC classification were not associated with renal outcome.

Chronic Fibrosing Vasculitis in the Setting of Still Disease

Chronic Fibrosing Vasculitis in the Setting of Still Disease

Churg-Strauss Syndrome in Childhood

Churg-Strauss syndrome is a rare form of small-vessel vasculitis. In the current report, we describe the case of a 17-year-old Czech girl predominantly characterized by peripheral neuropathy, the presence of cardiac and pulmonary involvement, hypereosinophilia, asthma, and sinusitis that led to the diagnosis of Churg-Strauss syndrome.

Monitoring patients with vasculitis

Granulomatosis with polyangiitis is a common form of small-vessel vasculitis, remarkable for its tendency toward multisystem manifestations. Standard induction treatment calls for the use of low-dose daily cyclophosphamide (CYC) and glucocorticoids. Treatment goals for newly diagnosed patients include increased survival, induction of remission, reduction of relapse frequency, and minimization of treatment toxicity. Induction and maintenance treatments with CYC, glucocorticoids, and other immunosuppressive therapies improve the disease course, but relapse- and treatment-related toxicity and infections demand consistent, patient-specific monitoring.

Granuloma faciale with disseminated extra facial lesions

Granuloma faciale (GF) is a rare cutaneous disorder categorized as a localized form of small vessel vasculitis. Clinically, it manifests as single or multiple, well-demarcated, red-brown plaques, papules and nodules, nearly always confined to the face. Herein, we report a 39-year-old man with multiple red-brown, infiltrated plaques on his face and extrafacial lesions on the back, shoulders, and both arms. Skin biopsy revealed typical histopathological findings of GF. The patient failed to respond to pulsed dye laser, but intralesional triamcinolone combined with cryotherapy led to an acceptable response.

Lack of association between NPHS2 gene polymorphisms and Henoch-Schönlein purpura nephritis

Henoch-Schönlein purpura (HSP) is one of the most common forms of small-vessel vasculitis in childhood, and renal involvement (HSP nephritis, HSPN) is the main determinant of morbidity after acute phase. Considering the racial diversity and clinical heterogeneity in the prevalence, genetic factors might play a role in pathogenesis of HSP and HSPN. Direct sequencing was performed after PCR amplification of all 8 exons of the NPHS2 gene in 20 Chinese children with HSPN and 30 controls in present study. The genetic analyses revealed 3 polymorphisms (954T > C heterozygous, 1038A > G heterozygous and homozygous, all in exon 8) in 7 out of 20 patients studied, but there was no significant difference in the genotypic and allelic frequencies of these polymorphisms between the patients and controls. The result did not support the possible role of the NPHS2 gene in susceptibility to HSPN in the population studied. Studies in a larger sample population with different genetic backgrounds will be necessary in the future.

Pathogenesis of Pulmonary Vasculitis

Vasculitis is inflammation of blood vessels and can affect any type of vessel in any organ. Pulmonary vasculitis usually is a component of a systemic small vessel vasculitis. Three major forms of small vessel vasculitis that often affect the lungs are Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. These forms of vasculitis are strongly associated with antineutrophil cytoplasmic autoantibodies (ANCA) directed against enzymes contained in the primary granules of neutrophils and peroxidase-positive lysosomes of monocytes. This review discusses the evidence for a pathogenic role of ANCA. In vitro, ANCAs can activate cytokine-primed neutrophils and monocytes resulting in oxygen radical formation and release of lysosomal enzymes. In vivo, antimyeloperoxidase ANCA has been shown to induce crescentic glomerulonephritis and systemic vasculitis. Overall, the available data suggest that ANCA are indeed a pathogenic factor in the development of small-vessel vasculitis. Antiglomerular basement membrane (anti-GBM) disease also causes pulmonary vasculitis through immune attack on alveolar capillaries and glomerulonephritis through antibody mediated injury to glomerular capillaries. Thus, there is evidence that antibodies are important pathogenic factors in both ANCA disease and anti-GBM disease, however, there are also indications that T cells may play important pathogenic roles in both categories of disease as well.

Pathophysiology of ANCA-associated vasculitides: Are ANCA really pathogenic?

The strong association of antineutrophil cytoplasmic autoantibodies (ANCA) with certain forms of small vessel vasculitis suggests a pathogenic role of these autoantibodies in the disease process. In vitro, ANCA can activate neutrophils and monocytes to produce reactive oxygen intermediates, to release lysosomal enzymes, and to secrete proinflammatory cytokines. More recently, it was demonstrated that antimyeloperoxidase ANCA can induce systemic vasculitis and glomerulonephritis in mice. Taken together, these data provide convincing evidence that ANCA are indeed pathogenic.