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Concept: Polyarteritis nodosa

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A patient with a known biopsy of polyarteritis nodosa diagnosis presented with cyclic fevers, acute kidney injury, and progression of rash from macular to pustular, worsening despite being on antibiotics, without evidence of infection on multiple cultures. The patient had a pathological diagnosis from a skin biopsy of acute generalized exanthematous pustulosis syndrome, with a total resolution of rash, fevers, and acute kidney injury on treatment with pulse steroids.

Concepts: Inflammation, Biopsy, Pathology, Rheumatology, Vasculitis, Acute kidney injury, Polyarteritis nodosa, Diseases involving the fasciae

28

To analyze the disease characteristics, treatment modalities and outcome of polyarteritis nodosa (PAN) in Croatian children. Cross-sectional study included all children with PAN diagnosed according to EULAR/PRES/PRINTO criteria during the last two decades. PAN was diagnosed in 12 patients (6 girls and 6 boys) mean age (±SD) 11.33 ± 3.08 years. The share of PAN among all vasculitides was 3.8 %. Systemic PAN was diagnosed in 7 children (58 %), microscopic polyangiitis in 3 (25 %), cutaneous PAN in 2 (17 %). The most consistent symptoms were skin involvement (90 %) and arthritis/arthralgia (60 %). The CNS was affected in 33 % of patients. Inflammatory markers (C-reactive protein and erythrocyte sedimentation rate [ESR]) were elevated in all patients, and anti-neutrophil cytoplasmatic antibodies were positive in all patients with microscopic polyangiitis. Therapy mode for all patients was corticosteroids. Immunosuppressive drugs were used as additional therapy for patients with severe symptoms. Two patients (17 %), both suffering from microscopic polyangiitis, died due to renal failure during the follow-up. In comparison with available studies, we found a difference in distribution of childhood polyarteritis nodosa as well as some clinical characteristics (e.g., higher prevalence of neurological and pulmonary symptoms), while other researched features, laboratory and treatment were similar.

Concepts: Immune system, Inflammation, Red blood cell, Rheumatoid arthritis, C-reactive protein, Erythrocyte sedimentation rate, Polyarteritis nodosa, Microscopic polyangiitis

27

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that typically occurs without detectable antineutrophil cytoplasmic antibody. It leads to aneurysm formation by affecting muscular arteries, usually those of medium size but also occasionally those of small size. Kidney involvement is common, leading to reduced glomerular filtration rate, hypertension, rupture of renal arterial aneurysms causing perinephric hematomas, and renal infarctions in those with severe vasculitis. Similar to PAN, microscopic polyangiitis (MPA) leads to aneurysm formation; however, MPA usually is associated with antineutrophil cytoplasmic antibody, and glomerulonephritis is a more common feature of MPA. Although kidney biopsy may show classic vascular changes in both PAN and MPA, this procedure is not without risk of significant bleeding due to aneurysm rupture. We present 2 cases of renal aneurysms that were diagnosed as MPA using computed tomography angiography (CTA), allowing implementation of appropriate immunosuppressive therapy. Follow-up CTA after treatment showed resolution of all previously observed abnormalities. CTA is a useful alternative to kidney biopsy in establishing both the extent of disease in renal aneurysms and allowing for tracking of disease progression and response to therapy.

Concepts: Renal failure, Kidney, Nephrology, Atherosclerosis, Blood pressure, Vasculitis, Polyarteritis nodosa, Microscopic polyangiitis

27

Testicular infarction is an uncommon finding in paediatric age and is usually due to testicular torsion or trauma causing venous rupture with thrombosis and/or arteriolar obstruction. Other causes of segmental infarction of the testes are represented by polyarteritis nodosa, thromboangioiitis obliterans and hypersensitivity angiitis. A few cases of testicular infarction due to epididymitis have been described in the literature related mainly to adult patients. Epididymitis is usually treated in the outpatient setting with close follow-up, but according to our present experience, and reviewing the literature, there may be some cases in which, surgical exploration is mandatory in order to avoid testicular damage.

Concepts: Hospital, Andrology, Testicle, Testicular cancer, Polyarteritis nodosa, Epididymis, Spermatic cord, Testicular torsion

26

Systemic vasculitides are great masqueraders and at times their presenting manifestations can be very different from the usual recognized patterns. Such uncommon presentations of granulomatosis with polyangiitis (Wegener’s granulomatosis), classical polyarteritis nodosa and unclassifiable vasculitides are described here with the relevant review of literature.

Concepts: Rheumatology, Vasculitis, Wegener's granulomatosis, Arthritis, Polyarteritis nodosa, Vascular-related cutaneous conditions, Microscopic polyangiitis, Diseases involving the fasciae

25

Cutaneous polyarteritis nodosa, a special form of polyarteritis nodosa (PAN) without systemic involvement, is classified as one of the ANCA-negative vasculitides of small and medium-sized vessels. It is a very rare disease with unknown etiology and occurs more commonly in women over the age of 40. Typical skin lesions are subcutaneous nodules, livedo racemosa, and ulcerations. We report the case of a 46-year-old woman presenting to our outpatient department who reported having very painful ulcerations of the lower legs with unknown origin for 6 months.

Concepts: Rheumatology, Vasculitis, Polyarteritis nodosa, Vascular-related cutaneous conditions, Livedo reticularis

3

Background We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood. Methods We performed whole-exome sequencing in the initial three patients and their unaffected parents and candidate-gene sequencing in three patients with a similar phenotype, as well as two young siblings with polyarteritis nodosa and one patient with small-vessel vasculitis. Enzyme assays, immunoblotting, immunohistochemical testing, flow cytometry, and cytokine profiling were performed on samples from the patients. To study protein function, we used morpholino-mediated knockdowns in zebrafish and short hairpin RNA knockdowns in U937 cells cultured with human dermal endothelial cells. Results All nine patients carried recessively inherited mutations in CECR1 (cat eye syndrome chromosome region, candidate 1), encoding adenosine deaminase 2 (ADA2), that were predicted to be deleterious; these mutations were rare or absent in healthy controls. Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p.Gly47Arg mutation. Patients had a marked reduction in the levels of ADA2 and ADA2-specific enzyme activity in the blood. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia - phenotypes that were prevented by coinjection with nonmutated (but not with mutated) human CECR1. Monocytes from patients induced damage in cocultured endothelial-cell layers. Conclusions Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. (Funded by the National Institutes of Health Intramural Research Programs and others.).

Concepts: Inflammation, DNA, Gene, Genetics, Mutation, Evolution, Vasculitis, Polyarteritis nodosa

1

Background Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. Methods We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. Results In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, The German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. Conclusions Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).

Concepts: Immune system, DNA, Genetics, Mutation, Rheumatology, Vasculitis, Zygosity, Polyarteritis nodosa

0

Classical polyarteritis nodosa (PAN) is a necrotizing arteritis affecting medium-sized vessels. A 73-year-old gentleman who presented with progressive anemia and scant hemoptysis developed acute kidney injury over the course of hospital admission. Kidney biopsy was initially interpreted as consistent with cephalosporin-associated acute interstitial nephritis (AIN) and acute tubular injury (ATI). After oral prednisone (5 days), the patient was discharged with improving serum creatinine. Two days later, he presented with diffuse alveolar hemorrhage. C-ANCA, ANA, anti-GBM, C4, cryoglobulin, HIV, HBV, and HCV studies were negative. P-ANCA was positive. Biopsy tissue was revisited, in addition to AIN, ATI, and non-caseating interstitial granulomas, lymphocytic infiltration of medium-sized vessels with endothelitis consistent with a diagnosis of PAN was noted. This case is notable for its atypical clinical presentation - alveolar hemorrhage - and atypical laboratory presentation - P-ANCA positivity for classical PAN. We describe an atypical presentation of PAN as a means of reviewing the range of clinical presentations, criteria for diagnosis, and treatment approaches for PAN and drug-induced vasculitis, which may present similar to PAN.
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Concepts: Kidney, Vasculitis, Wegener's granulomatosis, Interstitial nephritis, Kidney diseases, Polyarteritis nodosa, Nephritis, Anti-neutrophil cytoplasmic antibody

0

Anti-C1q antibodies (Anti-C1q Ab) are seen in hypocomplementemic urticarial vasculitis syndrome (HUVS), infection-associated vasculitis such as hepatitis C virus-related vasculitis and in autoimmune diseases such as rheumatoid vasculitis, polyarteritis nodosa, giant cell arteritis, vascular Behcet’s disease, and cryoglobulin associated vasculitis. Aim of this study is to evaluate the presence of Anti-C1q Ab in vasculitis and to determine if any difference exists between primary and secondary vasculitis in relation to this antibody.

Concepts: Rheumatoid arthritis, Rheumatology, Vasculitis, Hepatitis C, Hepatitis B, Polyarteritis nodosa, Giant cell arteritis, Vascular-related cutaneous conditions