MANIFESTASI OTOLOGIK PADA GRANULOMATOSIS DENGAN POLIANGIITIS (GPA)

Granulomatosis dengan polyangiitis (GPA) merupakan penyakit sistemik yaitu vaskulitis pada pembuluh darah kecil dan sedang yang terkait dengan anti-neutrophil-cytoplasmic-antibody (ANCA). Gejala klinis GPA yaitu vaskulitis nekrotikans sistemik, inflamasi granulomatosa dan glomerulonefritis nekrosis. Sebagian besar pasien dengan GPA memiliki manifestasi sistem telinga, hidung dan tenggorokan (THT) dan mencari intervensi medis untuk manifestasi ini. Lebih dari 80% memiliki masalah rinologi dan 20-40% memiliki masalah otologik. Angka kejadian GPA di Amerika Serikat menunjukkan peningkatan prevalensi sebesar 21,8 per 100.000 dan peningkatan insiden tahunan 1,3 kasus per 100.000. Sedangkan di Indonesia belum ada data pendukung terkait dengan insiden GPA. Insiden puncak pada usia 65-74 tahun. GPA disebabkan oleh multifaktorial yaitu infeksi, lingkungan dan induksi obat. Pada patofisiologi GPA, terdapat dua ANCA yang berperan yaitu proteinase 3 (PR3) dan myeloperoxidase (MPO). Keduanya akan mengativasi monosit dan neutrofil yang pada akhirnya melakukan reaksi inflamasi yang merusak pembuluh darah. Manifestasi otologik yang paling sering muncul pada pasien GPA adalah otitis media unilateral atau bilateral dengan efusi serosa. Pengobatan GPA dibagi menjadi terapi induksi meliputi kombinasi siklofosfamid dan kortikosteroid, rituximab, metotreksat dan glukokortikosteroid. Terapi pemeliharaan meliputi azathioprine, metotreksat, leflunomide, rituximab, cotrimoxazole dan plasma exchange. Jika tidak diobati, penyakit ini biasanya menjadi fatal dan 82% pasien meninggal dalam waktu 1 tahun.Kata kunci: Granulomatosis dengan polyangiitis; manifestasi otologic; etiologic; patofisiologi; diagnosis; tatalaksana; prognosis

Experimentally induced anti-myeloperoxidase vasculitis is not attenuated in factor B or VISTA deficient mice

Background: Anti-neutrophil cytoplasmic antibody vasculitis is characterised by antibodies to myeloperoxidase or proteinase 3. Previous work in murine anti-myeloperoxidase vasculitis has shown a role for the alternative pathway complement component factor B and the anaphylotoxin C5a. However, mice deficient in properdin, which stabilizes the alternative pathway convertase, were not protected. VISTA-deficient mice were protected in the nephrotoxic nephritis model but the role of VISTA in anti-myeloperoxidase vasculitis is unknown. Objectives: This study had two aims. Firstly, we attempted to reproduce previous findings on the role of factor B in anti-myeloperoxidase vasculitis. Secondly, we examined the role of VISTA in this model, in order to see if the protection in the nephrotoxic nephritis model extended to anti-myeloperoxidase vasculitis. Methods: Anti-myeloperoxidase vasculitis was induced in wildtype, factor B, or VISTA deficient mice. Disease was assessed by quanitfying glomerular crescents and macrophages, in addition to albuminuria and serum creatinine. Results: When wild type and factor B deficient mice were compared, there were no differences in any of the histological or biochemical parameters of disease assessed. Similarly, when wild type or VISTA defiicent mice were compared, there were no differences. Conclusions: Factor B deficient mice were not protected which is in contrast to previous studies. Therefore alternative pathway activation is not essential in this model, under the conditions used in this study. VISTA deficient mice were not protected, suggesting that therapies targetting VISTA may not be effective in vasculitis.

Patients with recurrent PVL+-Staphylococcus aureus infections show enhanced sensitivity to PVL-mediated formation of atypical NETs

Panton-Valentine leukocidin (PVL) is a Staphylococcus aureus (S. aureus) toxin that binds to and kills human neutrophils, resulting in the formation of neutrophil extracellular traps (NETs). Some individuals colonized with PVL-positive S. aureus (PVL-SA) suffer from recurring infections whereas others are asymptomatically colonized. We found that neutrophils from affected patients express higher levels of CD45, one of the PVL receptors, and are more susceptible to killing at a low concentration of recombinant PVL than control neutrophils. We verified that PVL induces the formation of NETs and provide genetic and pharmacological evidence that PVL-induced NET formation is independent of NADPH-oxidase and reactive oxygen species (ROS) production. Through NET proteome analysis we identified that the protein content of PVL-induced NETs is different from NETs induced by mitogen or the microbial toxin nigericin. The abundance of the proteins cathelicidin (CAMP), elastase (NE), and proteinase 3 (PRTN3) was lower on PVL-induced NETs, which were inefficient in killing S. aureus. Neutrophils from patients that suffer from recurring PVL-positive infections may be more sensitive to PVL-induced NET formation, which may impair their ability to combat the infection.