An update on the microbiome in vasculitis.

PURPOSE OF REVIEW: To summarize recent evidence regarding the presence and potential role of the microbiome in systemic vasculitides. RECENT FINDINGS: Microbiomic descriptions are now available in patients with small, medium and large vessel vasculitis. The majority of studies have evaluated gastrointestinal inhabitants, with a smaller number of studies describing the nasal, pulmonary or vascular microbiomes. Most published studies are observational and cross-sectional. Dysbiosis is seen frequently in vasculitis patients with reduced microbial diversity observed in nasal, fecal and vascular samples compared with disease and/or healthy controls. Predominant bacteria vary, but overall, patients with vasculitis tend to have more pathogenic and less commensal bacteria in active disease. In the few longitudinal studies available, improvement or resolution of dysbiosis has been observed following vasculitis treatment and improved disease activity. SUMMARY: Dysbiosis and reduced microbial diversity has been identified in patients with small, medium and large vessel vasculitis. Although limited data suggests microbiomes may 'normalize' following immunosuppression, cause or effect cannot be determined. It is hypothesized that microbial disruption in a genetically susceptible individual may trigger excessive host immune activation and vasculitis; however, larger studies with longitudinal and translational design are needed to further our current understanding.

No evident association of nasal carriage of Staphylococcus aureus or its small-colony variants with cotrimoxazole use or ANCA-associated vasculitis relapses.

OBJECTIVE: To identify the role of Staphylococcus aureus (SA) or its intracellular small-colony variant phenotype (SCV) with co-trimoxazole (CTX) or ANCA-associated vasculitis (AAV) activity. METHODS: All consecutive AAV patients with granulomatosis with polyangiitis (GPA), eosinophilic GPA or microscopic polyangiitis, followed at the French National Vasculitis Referral Center (09/2012-05/2013), and hospitalized non-AAV controls, exclusively for SA/SCV carriage comparisons, were enrolled. All had bilateral anterior nasal swab cultures. Nasal SA or SCV carriage was determined and associations with relapse(s), BVAS, ANCA-positivity, anti-staphylococcal and immunosuppressant use, were analysed ⩾4 years post-inclusion. RESULTS: Nasal SA carriage rates did not differ among AAVs (P = 0.53): GPA (24/80; 30%), EGPA (7/28; 25%) and microscopic polyangiitis (3/11; 27.3%); and the rate was less frequent in controls than in GPA patients not taking CTX (P = 0.04). AAV patients taking CTX prophylaxis had less nasal SA carriage (8.7% vs 36.2%; P = 0.02). Nasal SA carriage or CTX use did not modify relapse rates, BVAS or ANCA-positivity at inclusion or during follow-up. Nasal SCV carriage, found in 15/207 (7.2%) patients, was similar for GPA (10/24; 41.7%), microscopic polyangiitis (2/7; 28.6%) and eosinophilic GPA (2/3; 66.7%), but higher (P = 0.02) than controls (1/14; 7.1%). SCV carriage by AAV groups did not modify relapse rates or ANCA positivity at inclusion or during follow-up; a trend towards higher BVAS was observed only for anti-PR3 ANCA patients. CONCLUSION: Nasal SA or SCV carriage was comparable among AAVs but more frequent than in controls. Nasal SA or SCV carriage and CTX use did not modify AAV relapse rates.

Characterizing infection in anti-neutrophil cytoplasmic antibody-associated vasculitis: results from a longitudinal, matched-cohort data linkage study.

OBJECTIVES: Infection exerts a major burden in ANCA-associated vasculitis (AAV), however, its precise extent and nature remains unclear. In this national study we aimed to longitudinally quantify, characterize and contextualize infection risk in AAV. METHODS: We conducted a multicentre matched cohort study of AAV. Complementary data on infections were retrieved via data linkage with the population-based Scottish microbiological laboratory, hospitalization and primary care prescribing registries. RESULTS: A total of 379 AAV patients and 1859 controls were followed up for a median of 3.5 years (interquartile range 1.9-5.7). During follow-up, the proportions of AAV patients with at least one laboratory-confirmed infection, severe infection and primary care antibiotic prescription were 55.4%, 35.6% and 74.6%, respectively. The risk of infection was higher in AAV than in matched controls {laboratory-confirmed infections: incidence rate ratio [IRR] 7.3 [95% confidence interval (CI) 5.6, 9.6]; severe infections: IRR 4.4 [95% CI 3.3, 5.7]; antibiotic prescriptions: IRR 2.2 [95% CI 1.9, 2.6]}. Temporal trend analysis showed that AAV patients remained at a higher risk of infections throughout the follow-up period, especially year 1. Although the Escherichia genus was the most commonly identified pathogen (16.6% of AAV, 5.5% of controls; P < 0.0001), AAV patients had the highest risk for Herpes [IRR 12.5 (95% CI 3.7, 42.6)] and Candida [IRR 11.4 (95% CI 2.4, 55.4)]. CONCLUSION: AAV patients have up to seven times higher risk of infection than the general population and the overall risk remains significant after 8 years of follow-up. The testing of enhanced short- to medium-term prophylactic antibiotic regimes should be considered.

[Acute on chronic renal failure in a 62-year-old man with ANCA-associated vasculitis]. / Neue Nierenfunktionsverschlechterung bei einem 62-jährigen Patienten mit ANCA-assoziierter Vaskulitis.

We describe a patient with ANCA (antineutrophil cytoplasmic antibodies) associated vasculitis and acute-on-chronic renal failure. He had initially presented with severe pulmonary hemorrhage and anuric renal failure and improved rapidly with immunosuppressive therapy. Repeat renal biopsy revealed candida interstitial nephritis. Candida was also detected in bronchoalveolar lavage. Kidney function improved with long-term antifungal therapy. This report adds induction therapy for ANCA vasculitis to the conditions where invasive candidal infections including nephritis need to be considered.

Chronic nasal Staphylococcus aureus carriage identifies a subset of newly diagnosed granulomatosis with polyangiitis patients with high relapse rate.

Objective: The aim of this study was to evaluate whether chronic nasal carriage of Staphylococcus aureus (SA) is related to relapses in patients with newly diagnosed ANCA-associated vasculitis (AAV). Methods: In two clinical trials (n = 200), for early systemic (n = 83) and generalized (n = 117) AAV, nasal swabs were obtained monthly and at the time of a relapse. Chronic nasal SA carriage (CNSAC) was defined as ⩾ 75% of cultures being SA positive, with non-carriers being SA negative in all cultures and remaining patients being intermittent carriers. Fifty-five of 200 (27.5%) patients received prophylactic trimethoprim/sulfamethoxazole (T/S) against Pneumocystis jirovecii . Results: Of the total AAV patients, 24/200 (12%) were chronic, 102/200 (51%) intermittent and 74/200 (37%) non-carriers. Of 65 relapsing patients, 10/24 (41.7%) were chronic, 32/102 (31.4%) intermittent and 23/74 (31.1%) non-carriers (P = 0.59). For all AAV patients, CNSAC was not associated with an increased relapse risk [odds ratio (OR) = 1.57, 95% CI: 0.66, 3.76; P = 0.31]. However, 23/24 chronic carriers had granulomatosis with polyangiitis (GPA). In the 73 patients with generalized GPA (hazard ratio = 4.10, 95% CI: 1.37, 12.25; P = 0.01) and the 78 patients with early systemic GPA during immunosuppression (hazard ratio = 2.73, 95% CI: 0.95, 7.87; P = 0.06), relapse rates were higher for chronic SA carriers. Prophylactic T/S was not associated with a reduced relapse risk (OR = 0.71, 95% CI: 0.36, 1.41; P = 0.33). Nevertheless, prophylactic T/S reduced CNSAC (OR = 0.19, 95% CI: 0.04, 0.91; P = 0.04). Conclusion: The frequency of CNSAC in newly diagnosed GPA paralleled that in the general population. This subset of GPA patients (23/151, 15.2%) has a high relapse rate despite immunosuppression and prophylactic T/S treatment, requiring further investigations on pathogenesis and therapy.

Pathogenesis of ANCA-associated vasculitides.

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides are characterised by necrotising inflammation of small vessels in conjunction with ANCA directed to either proteinase 3 (PR3) or myeloperoxidase (MPO). The aetiopathogenesis of these disorders is still not fully elucidated but clinical as well as in vitro and in vivo experimental data strongly suggest a role for the autoimmune responses to PR3 and MPO in disease development. Clinically, PR3-ANCA are strongly associated with granulomatous vasculitis as in Wegener's granulomatosis, and MPO-ANCA with necrotising small vessel vasculitis as in microscopic polyangiitis. Levels of PR3-ANCA and MPO-ANCA do, however, not fully reflect disease activity. In vitro, ANCA activate primed neutrophils to release lytic enzymes and reactive oxygen species, a process reinforced by the alternative pathway of complement. In the context of endothelial cells, this process leads to endothelial detachment and lysis. In vivo experimental studies have clearly demonstrated the pathogenic potential of MPO-ANCA for necrotising glomerulonephritis and pulmonary capillaritis. For PR3-ANCA-associated granulomatous vasculitis, an animal model is lacking. Here, effector T cells, in particular Th17 cells, appear to have a major pathogenic role in addition to ANCA. Finally, microbial factors, derived in particular from S aureus and Gram-negative bacteria, could play a part in disease induction and expression. These new insights into the pathogenesis of ANCA-associated vasculitides have opened new ways for targeted treatment.

Serum ratio of soluble triggering receptor expressed on myeloid cells-1 to creatinine is a useful marker of infectious complications in myeloperoxidase-antineutrophil cytoplasmic antibody-associated renal vasculitis.

BACKGROUND: The contribution of infections to the mortality of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis patients is important and should induce early and careful control of these events. However, the differentiation of infection from active vasculitis is often difficult. The usefulness of serum-soluble triggering receptor expressed on myeloid cells-1 (TREM-1) for detecting the presence of infectious complications regardless of disease activity was investigated. METHODS: Soluble TREM-1 in serum obtained from 41 patients with myeloperoxidase (MPO)-ANCA-associated vasculitis was measured by an enzyme-linked immunosorbent assay. Twenty-nine samples were from active vasculitis patients, 27 samples from inactive vasculitis patients without infection and 17 samples from inactive vasculitis patients with infectious complications. Serum-soluble TREM-1 was also measured in 10 patients with acute pyelonephritis and 30 patients with chronic kidney disease (CKD). RESULTS: There was a significant correlation between serum levels of soluble TREM-1 and serum creatinine levels among all patients (r = 0.554, P < 0.0001). The serum-soluble TREM-1/creatinine ratio was higher in inactive vasculitis patients with infectious complications than in active vasculitis, inactive vasculitis without infection and CKD patients (P = 0.0005, P < 0.0001 and P < 0.0001, respectively), but not significantly different to that in acute pyelonephritis patients. On receiver-operating-characteristic curve analysis, a lower-limit value of 9.40 ng/mg for this ratio had a sensitivity of 84.6% and a specificity of 90.8% in differentiating patients with infection from those without infection. CONCLUSIONS: The serum ratio of soluble TREM-1 to creatinine may be a useful marker for detection of infectious complications in MPO-ANCA-associated vasculitis.

Clinical and immunological features of drug-induced and infection-induced proteinase 3-antineutrophil cytoplasmic antibodies and myeloperoxidase-antineutrophil cytoplasmic antibodies and vasculitis.

PURPOSE OF REVIEW: Drugs and infections may induce antineutrophil cytoplasmic antibodies (ANCA) and vasculitic manifestations mimicking ANCA-associated vasculitides (AAV) and mechanisms relevant in their pathogenesis. This review summarizes the most recent findings in this field. RECENT FINDINGS: Drug-induced and infection-induced proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA may be associated with a vasculitis clinically resembling AAV. Mechanisms relevant for the break of tolerance and induction of ANCA (e.g. danger signals, superantigens, neutrophil extracellular traps, protease-activated receptor-2, IL-17 cells) may be shared to some extent between drug-induced and infection-induced ANCA-positive vasculitis and AAV, especially with regard to the potential role of infection in Wegener's granulomatosis. Differences in immunopathology, clinical presentation, and functional aspects of ANCA help to distinguish drug-induced and infection-induced ANCA-positive vasculitis from AAV, and present new avenues for future research in this field. SUMMARY: Medications and infections, which induce PR3-ANCA and MPO-ANCA, have to be considered in the differential diagnosis of primary AAV. Moreover, there is clinical and experimental evidence for an association between certain drugs and infections with ANCA-production. Analysis of ANCA-induction in such conditions also sheds new light on our understanding of immune mechanisms relevant in the break of tolerance and ANCA-production in AAV.

Comparison of lung microbiota between antineutrophil cytoplasmic antibody-associated vasculitis and sarcoidosis.

Microbial involvement in the pathogenesis have been suggested in both antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and sarcoidosis, both of which have lung involvement. However, exhaustive research to assess the bacteria in the lung in AAV and in sarcoidosis have not been performed. We sought to elucidate the distinct dysbiotic lung microbiota between AAV and sarcoidosis. We used 16S rRNA gene high-throughput sequencing to obtain the bacterial community composition of bronchoalveolar lavage fluid (BALF) in patients with AAV (n = 16) compared to patients with sarcoidosis (n = 21). The patients had not undergone therapy with immunosuppressive medication when their BALF was acquired. No difference was observed in α-diversity between patients with AAV and patients with sarcoidosis when using all the detected taxa. We defined the taxa of the oral cavity by using the data of oral microbiota of healthy individuals from the Human Microbiome Project (HMP). The analysis using only oral taxa made the difference in α-diversity between AAV and sarcoidosis clearer compared with those using all the detected taxa. Besides, the analysis using detected taxa except for oral taxa also made the difference in α-diversity between AAV and sarcoidosis clearer compared with those using all the detected taxa. A linear negative relationship between the α-diversity and Birmingham vasculitis activity score (BVAS) was detected in the AAV group. The observed p-value for the effect of the disease groups on the ß-diversity was small while the effect of other factors including sex and smoking status did not have small p-values. By excluding oral taxa from all the detected taxa, we found a cluster mainly consisted of sarcoidosis patients which was characterized with microbial community monopolized by Erythrobacteraceae family. Our results suggested the importance of considering the influence of oral microbiota in evaluating lung microbiota.

Shedding new light on vasculitis: how the LAMP story unfolded.

The last couple of years have brought some major advances both in our understanding of antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis pathogenesis mechanisms and in its treatment options. Recent discoveries of completely new antigens such as lysosome-associated membrane protein-2 (LAMP-2) have meant a huge step forward, and the fact that this antigen is homologous to proteins of bacterial fimbria caused a shift in the focus regarding underlying pathomechanisms of ANCA vasculitis toward bacterial infections, mainly with Klebsiella or Escherichia species, possibly playing a role in triggering the disease. So nephrology has seen real progress in understanding of glomerulonephritis disease mechanisms - not only regarding primary membranous glomerulonephritis (with the recent identification of the phospholipase A2 receptor being the underlying antigen) but also regarding secondary pauci-immune glomerulonephritis due to ANCA-positive vasculitis.

Encrusting cystitis due to Corynebacterium urealyticum in a patient with ANCA-associated vasculitis: case report and review of the literature.

OBJECTIVES: To report a patient with systemic ANCA-associated vasculitis, under maintenance treatment, who had persistent microscopic hematuria and developed recurrent pelvic pain due to Corynebacterium urealyticum encrusting cystitis. The relevant literature on this infection is reviewed. METHODS: Descriptive case report and a review of the literature (PubMed search). RESULTS: A 39-year-old woman on maintenance therapy for systemic ANCA-associated vasculitis, diagnosed 10 months earlier and with persistent microscopic hematuria, developed recurrent pelvic pain. She had received several immunosuppressants (including cyclophosphamide and rituximab) since the onset of her vasculitis, as well as cycles of broad-spectrum antibiotics during the acute initial phase of her disease. Computerized tomography of the pelvis and cystoscopy showed several encrusted calcifications in the bladder mucosa, and, finally, urine culture (selective media) led to the diagnosis of C. urealyticum infection. Most of the bladder-encrusted stones were removed during cystoscopy and daily intramuscular teicoplanin injections were given for 14 days. Her symptoms disappeared rapidly and completely. On reviewing the literature, immunosuppression, previous broad-spectrum antibiotics, urogenital alkaline pH, and prolonged bladder catheterization are predisposing factors for this rare infection. C. urealyticum encrusting cystitis has been reported in patients with systemic diseases but not yet in ANCA-associated vasculitis. Outcome is almost always good under adequate antibiotic therapy, mainly glycopeptides. CONCLUSION: Physicians should be aware of this unusual but potentially emerging infectious complication that can be challenging in ANCA-associated vasculitis, because the urinary tract can be affected by the vasculitis or as a complication of previous cyclophosphamide therapy.

The contribution of genetic variation and infection to the pathogenesis of ANCA-associated systemic vasculitis.

The aetiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis has not been well defined. Here we review two factors which may play a role in the pathogenesis of the disease: genetics and infection. In particular, we discuss the role of autoantibodies to LAMP-2, which may arise following infection with Gram-negative bacteria, and may contribute to the development of ANCA-associated systemic vasculitis in genetically susceptible individuals.