Impaired phagocytosis and reactive oxygen species production in phagocytes is associated with systemic vasculitis

BACKGROUND: Anti-neutrophil cytoplasmic antibodies associated vasculitides (AAV) is a group of autoimmune diseases, characterized by small vessel inflammation. Phagocytes such as neutrophils and monocytes are the main effector cells found around the inflamed vessel wall. Therefore, we wanted to investigate aspects of function and activation of these cells in patients with AAV.METHODS: Flow cytometry was used to evaluate: the expression of activation markers (CD11c, CD62L, CD177 and C5aR); the number of recently released neutrophils from bone marrow, defined as CD10(-)D16(low) cells in peripheral blood; and the capacity of peripheral blood monocytes and polymorphonuclear leukocytes (PMN) to produce reactive oxygen species and to phagocytose opsonized bacteria.RESULTS: AAV patients (n = 104) showed an increase of CD10(-)CD16(low) neutrophils and total PMN in peripheral blood, suggesting a combination of increased bone marrow release and prolonged survival. An increased percentage of AAV PMN expressed CD177 but no other signs of activation were seen. A decreased production of reactive oxygen species was observed in AAV phagocytes, which was associated with disease activity. Moreover, granulocytes from patients with microscopic polyangiitis showed lower oxidative burst capacity compared to patients with granulomatosis with polyangiitis or eosinophilic granulomatosis with polyangiitis. In addition, decreased phagocytosis capacity was seen in PMN and monocytes.CONCLUSION: Our results indicate that phagocytes from AAV patients have impaired function, are easily mobilized from bone marrow but are not particularly activated. The association between low reactive oxygen species formation in PMN and disease severity is consistent with findings in other autoimmune diseases and might be considered as a risk factor

Alveolar Hemorrhage in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Results of an International Randomized Controlled Trial (PEXIVAS)

Rationale: Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody–associated vasculitis (AAV). The PEXIVAS (Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody–Associated Vasculitis) (NCT00987389) trial was the largest in AAV and the first to enroll participants with DAH requiring mechanical ventilation. Objectives: Evaluate characteristics, treatment effects, and outcomes for patients with AAV with and without DAH. Methods: PEXIVAS randomized 704 participants to plasma exchange (PLEX) or no-PLEX and reduced or standard-dose glucocorticoids (GC). DAH status was defined at enrollment as no-DAH, nonsevere, or severe (room air oxygen saturation of ⩽ 85% as measured by pulse oximetry, or use of mechanical ventilation). Measurements and Main Results: At enrollment, 191 (27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3 (proteinase 3)-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (n = 513; 72.9%). Among those with DAH, 8/95 (8.4%) receiving PLEX died within 1 year versus 15/96 (15.6%) with no-PLEX (hazard ratio, 0.52; confidence interval [CI], 0.21–1.24), whereas 13/96 (13.5%) receiving reduced GC died versus 10/95 (10.5%) with standard GC (hazard ratio, 1.33; CI, 0.57–3.13). When ventilated, ventilator-free days were similar with PLEX versus no-PLEX (medians, 25; interquartile range [IQR], 22–26 vs. 22–27) and fewer with reduced GC (median, 23; IQR, 20–25) versus standard GC (median, 26; IQR, 25–28). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within 1 year versus 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments. Conclusions: Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality.publishedVersio

Diagnostic and prognostic aspects of anti-neutrophil cytoplasmic antibodies in systemic vasculitis

Primary systemic vasculitis is associated with a high mortality if left untreated and it is essential to make the diagnosis before permanent organ damage has occurred. In this thesis the diagnostic and prognostic significance of anti-neutrophil cytoplasmic antibodies (ANCA) in systemic vasculitis is investigated. The clinical significance of a capture enzyme-linked immunosorbent assay (ELISA) based on the monoclonal antibody 4A3 for detection of antibodies against proteinase 3 (PR3-ANCA) was evaluated and found to have a high sensitivity and specificity. It was shown that patients with high levels of PR3-ANCA as measured by the capture ELISA have a poorer survival and worse renal outcome and are more prone to relapse. In comparison the symptoms, signs and clinical course of a cohort of patients with vasculitis but without ANCA, with the diagnosis of polyarteritis nodosa, were described. Recombinant chimeric molecules were produced in order to map epitopes of monoclonal antibodies to PR3. The clinical utility of these chimeric proteins in the diagnosis and follow-up of patients with PR3-ANCA positive vasculitis was studied and these chimeric molecules were not found to be better than capture ELISA using native PR3. It was observed that samples from the same patient during one exacerbation episode always exhibited a similar pattern of reactivity and that some patients exhibited the same pattern at diagnosis and subsequent flares, while in many patients the pattern changed considerably over time indicating epitope shift during the course of disease

The challenge of managing patients with polyarteritis nodosa.

Purpose of review In this short review we focus on the problems faced by clinicians caused by the changing definitions of polyarteritis nodosa. Recent findings the term polyarteritis nodosa has been used for more than 100 years as a diagnostic term for patients with systemic vasculitis, however, specific vasculitides have been singled out like branches being chopped off a tree. Now, so little is left of the trunk of that tree that it is questionable to what extent we can trust older literature with respect to clinical features, natural history and response to treatment. Many authors of case reports, as well as authors of reviews and book chapters, claim they adhere to the Chapel Hill Consensus Conference definition of polyartentis nodosa yet still cite almost exclusively studies using older definitions without highlighting this dilemma. In the past year, two proposals affecting classification have been published: one stating that cutaneous polyarteritis nodosa and hepatitis associated polyarteritis nodosa, and one providing an algorithm to separate microscopic polyangiitis from classical polyarteritis nodosa. Summary There is hope that a wide acceptance of the new classification principles will lead to a more uniform way to diagnose classical polyarteritis nodosa, which will facilitate clinical studies and eventually improve management

The challenge of managing patients with polyarteritis nodosa

Purpose of review In this short review we focus on the problems faced by clinicians caused by the changing definitions of polyarteritis nodosa. Recent findings the term polyarteritis nodosa has been used for more than 100 years as a diagnostic term for patients with systemic vasculitis, however, specific vasculitides have been singled out like branches being chopped off a tree. Now, so little is left of the trunk of that tree that it is questionable to what extent we can trust older literature with respect to clinical features, natural history and response to treatment. Many authors of case reports, as well as authors of reviews and book chapters, claim they adhere to the Chapel Hill Consensus Conference definition of polyartentis nodosa yet still cite almost exclusively studies using older definitions without highlighting this dilemma. In the past year, two proposals affecting classification have been published: one stating that cutaneous polyarteritis nodosa and hepatitis associated polyarteritis nodosa, and one providing an algorithm to separate microscopic polyangiitis from classical polyarteritis nodosa. Summary There is hope that a wide acceptance of the new classification principles will lead to a more uniform way to diagnose classical polyarteritis nodosa, which will facilitate clinical studies and eventually improve management

Polyarteritis nodosa when applying the Chapel Hill nomenclature--a descriptive study on ten patients.

Objectives. Polyarteritis nodosa (PAN) is a term that has been used to describe a wide variety of vasculitic conditions. In 1994, the Chapel Hill Consensus Conference on the nomenclature of systemic vasculitides proposed that the name classical PAN should be restricted to diseases where there is arteritis in small and medium-sized arteries without the involvement of smaller vessels. Our aim was to describe the symptoms and course of disease in PAN when the microscopic forms are excluded. Methods. All patients with a diagnosis of PAN treated in our departments during the period 1990-2002 were eligible for this study. The diagnosis had to be confirmed by biopsy, angiography or electromyography. Results. Ten patients were eligible for the study. The median age was 46 yrs. Renal involvement was seen in 70% at diagnosis. After 5 yrs, 57% had experienced a relapse, which is equivalent to the relapse rate seen in microscopic polyangiitis. Organ damage was assessed by the Vasculitis Damage Index (VDI) and after 5 yrs cardiovascular and neuropsychiatric damage dominated, followed by renal damage. During the follow-up, two patients developed end-stage renal disease. The annual incidence of PAN in our local catchment area was estimated to 1.6 per million and year. Conclusions. When applying the Chapel Hill nomenclature, PAN is a rare but severe disease with a high incidence of renal involvement and frequent relapses