Therapy For ANCA-associated Vasculitis Research Articles

Relapses and serious adverse events during rituximab maintenance therapy in ANCA-associated vasculitis: a multicentre retrospective study.

There are limited real-life data regarding the efficacy and safety of rituximab (RTX) as a remission-maintenance agent in microscopic-polyangiitis (ΜPA) and granulomatosis-with-polyangiitis (GPA). We aimed to estimate the incidence and risk factors for relapses, as well serious-adverse-events (SAEs) in MPA/GPA patients during RTX-maintenance. Retrospective cohort of newly-diagnosed/relapsing GPA/MPA patients who received RTX-maintenance (≥1 RTX-cycle, ≥6 months follow-up) following complete-remission (Birmingham-Vasculitis-Activity-Score-version-3 = 0 plus prednisolone ≤7.5 mg/day) with induction regimens. SAEs included serious-infections, COVID-19-associated hospitalizations, deaths, cardiovascular-events, malignancies and hypogammaglobulinemia. Incidence-rates (IR) and relapse-free survival through Kaplan-Meier plots were estimated. Cox-regression was conducted to investigate factors associated with the time-to-relapse. 101 patients were included; 48% females, 69% GPA, 53% newly diagnosed, median age: 63 years. During follow-up (294.5 patient-years, median: 3 RTX-cycles), 30 relapses (57% major) occurred among 24 patients (24%, IR 10.2/100 patient-years). Kidney involvement (adjusted-Hazard-Ratio/aHR: 0.20; 95% CI: 0.06-0.74, p= 0.016), prior induction with RTX plus cyclophosphamide (vs RTX monotherapy: aHR = 0.02; 95% CI: 0.001-0.43, p= 0.012) and shorter time-interval until complete-remission (aHR = 1.07; 95% CI: 1.01-1.14, p= 0.023) were associated with decreased relapse-risk. We recorded 17 serious-infections (IR 5.8/100 patient-years), 11 COVID-19-associated hospitalizations (IR 3.7/100 patient-years), 4 malignancies (IR 1.4/100 patient-years), 6 cardiovascular-events (IR 2/100 patient-years) and 10 deaths (IR 3.4/100 patient-years). In this real-world study, relapses during RTX-maintenance occurred in approximately in 1 out of 4 patients. Kidney involvement, induction with RTX plus cyclophosphamide and earlier achievement of complete-remission were associated with lower relapse-risk. Serious-infections rate was consistent with previous reports, whereas an increased rate of COVID19-associated hospitalizations was observed.

#1484 Development of a relapse risk score in patients with ANCA-associated vasculitis treated with cyclophosphamide induction

Abstract Background and Aims Cyclophosphamide (CYC), together with rituximab, is the mainstay for induction therapy in ANCA-associated vasculitis (AAV) [1]. The risk factors influencing the likelihood of relapse in individuals undergoing CYC induction are still unclear. This study aims to score the more robust predictors of relapse in these patients, thereby building a clinically useful tool. Method Patients' characteristics were pooled from three cohorts from Italy, Ireland, and Spain. Eligibility criteria were a diagnosis of GPA, MPA, or EGPA, age >18 years, induction treatment with CYC [either as intravenous therapy (IV) and/or oral], and at least 12 months of follow-up. Baseline assessment included clinical data, laboratory testing, and assessment of manifestations of GPA, MPA, and EGPA in each organ system according to the Birmingham Vasculitis Activity Score (BVAS). Relapse was defined as the presence of ≥1 new vasculitis manifestation after a remission lasting at least 3 months; remission was defined as no disease activity (BVAS=0) irrespective of the glucocorticoid use. Time-to-remission and relapse-free survival probabilities were estimated using the Kaplan-Meier method. A multivariate Cox analysis, including the statistically significant factors at a previous univariate analysis, was employed to develop a practical prognostic score, defined as “Relapse Evaluation And Cyclophosphamide Treatment (REACT) score”, in which each independent predictor was assigned a number of weighted points proportional to its β regression coefficient. Results The score development cohort comprised 505 patients. 223 patients (44.2%) had MPA, 217 (43.0%) GPA, and 65 (12.9%) EGPA. 183 patients (36.2%) experienced a relapse, with a median time to relapse of 33 months (IQR: 13-61). A multivariate Cox regression analysis proved that PR3-ANCA (HR: 1, 30, 95% CI 1, 01-1, 87), IV CYC (HR: 1.78, 95% CI 1.31-2.41), cardiovascular involvement (HR: 1.82, 95% CI 1.01-3.25), arthralgias/arthritis (HR: 1.46 95% CI 1.08-1.98) and the absence of rapidly progressive glomerulonephritis (HR: 1.37, 95% CI 1.02-1.85) were all independent risk factors of relapse. These variables were used to build the REACT score, with each item receiving 1 point except for CV involvement and IV CYC, each receiving 2 points. We then identified three risk categories according to the score of each patient (Fig. 1A). We identified 138 (27%) patients with low risk of relapse (score 0-1), 252 (49%) with an intermediate risk (score 2-3), and 115 patients (22%) with a high risk (score 4-7). These three groups showed different relapse probabilities on Kaplan-Meier analysis (pairwise comparisons between the groups were all statistically significant) (Fig. 1B). Conclusion The REACT score can be employed at diagnosis to predict the risk of relapse in patients with AAV treated with cyclophosphamide induction. Its value needs to be confirmed in external cohorts.

Prospective study of complications and sequelae of glucocorticoid therapy in ANCA-associated vasculitis

ObjectiveGlucocorticoids (GC) are a cornerstone in treating antineutrophil cytoplasmic antibodies-associated vasculitides (AAV), however, they add to morbidity and mortality. To date, GC toxicity in AAV has rarely been systematically investigated.MethodsPatients...

Targeting NF-κB signaling in B cells as a potential new treatment modality for ANCA-associated vasculitis

B lineage cells are critically involved in ANCA-associated vasculitis (AAV), evidenced by alterations in circulating B cell subsets and beneficial clinical effects of rituximab (anti-CD20) therapy. This treatment renders a long-term, peripheral B cell depletion, but allows for the survival of long-lived plasma cells. Therefore, there is an unmet need for more reversible and full B lineage cell targeting approaches. To find potential novel therapeutic targets, RNA sequencing of CD27+ memory B cells of patients with active AAV was performed, revealing an upregulated NF-κB-associated gene signature. NF-κB signaling pathways act downstream of various B cell surface receptors, including the BCR, CD40, BAFFR and TLRs, and are essential for B cell responses. Here we demonstrate that novel pharmacological inhibitors of NF-κB inducing kinase (NIK, non-canonical NF-κB signaling) and inhibitor-of-κB-kinase-β (IKKβ, canonical NF-κB signaling) can effectively inhibit NF-κB signaling in B cells, whereas T cell responses were largely unaffected. Moreover, both inhibitors significantly reduced B cell proliferation, differentiation and production of antibodies, including proteinase-3 (PR3) autoantibodies, in B lineage cells of AAV patients. These findings indicate that targeting NF-κB, particularly NIK, may be an effective, novel B lineage cell targeted therapy for AAV and other autoimmune diseases with prominent B cell involvement.

Optimal dose ofintravenous cyclophosphamide during remission induction therapy inANCA-associated vasculitis: A retrospective cohort study ofJ-CANVAS.

To identify the optimal dose of intravenous cyclophosphamide (IVCY) for induction therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis. We retrospectively assessed patients with antibody-associated vasculitis who received IVCY every 2-3 weeks during the remission induction phase. The associations of the IVCY dose with infection-free survival and relapse-free survival were analysed using a Cox regression model. We compared patients in three categories: very low-dose (VLD), low-dose (LD), and conventional dose (CD) (<7.5 mg/kg, 7.5-12.5 mg/kg, and >12.5 mg/kg, respectively). The non-linear association between IVCY dose and the outcomes was also evaluated. Of the 80 patients (median age 72 years), 12, 42, and 26 underwent the VLD, LD, and CD regimens, respectively, of whom 4, 3, and 7 developed infection or died. The adjusted hazard ratios for infection or death were 4.3 (95% confidence interval (CI) 0.94-19.8) for VLD and 5.1 (95% CI 1.21-21.3) for CD, compared with LD. We found the hazard ratio for infection or death increased when the initial IVCY dose exceeded 9 mg/kg. Relapse-free survival did not differ clearly. Low-dose IVCY (7.5-12.5 mg/kg) may result in fewer infections and similar relapse rates compared with the conventional regimen (>12.5 mg/kg).

Future Directions of Maintenance Therapy in ANCA-associated Vasculitis.

Future Directions of Maintenance Therapy in ANCA-associated Vasculitis.

Association between hypogammaglobulinaemia and severe infections during induction therapy in ANCA-associated vasculitis: from J-CANVAS study.

To investigate the association between decreased serum IgG levels caused by remission-induction immunosuppressive therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and the development of severe infections. We conducted a retrospective cohort study of patients with new-onset or severe relapsing AAV enrolled in the J-CANVAS registry, which was established at 24 referral sites in Japan. The minimum serum IgG levels up to 24 weeks and the incidence of severe infection up to 48 weeks after treatment initiation were evaluated. After multiple imputations for all explanatory variables, we performed the multivariate analysis using a Fine-Gray model to assess the association between low IgG (the minimum IgG levels <500 mg/dl) and severe infections. In addition, the association was expressed as a restricted cubic spline (RCS) and analysed by treatment subgroups. Of 657 included patients (microscopic polyangiitis, 392; granulomatosis with polyangiitis, 139; eosinophilic granulomatosis with polyangiitis, 126), 111 (16.9%) developed severe infections. The minimum serum IgG levels were measured in 510 patients, of whom 77 (15.1%) had low IgG. After multiple imputations, the confounder-adjusted hazard ratio of low IgG for the incidence of severe infections was 1.75 (95% confidence interval: 1.03-3.00). The RCS revealed a U-shaped association between serum IgG levels and the incidence of severe infection with serum IgG 946 mg/dl as the lowest point. Subgroup analysis showed no obvious heterogeneity between treatment regimens. Regardless of treatment regimens, low IgG after remission-induction treatment was associated with the development of severe infections up to 48 weeks after treatment initiation.

The Efficacy and Safety of Rituximab in ANCA-Associated Vasculitis: A Systematic Review.

Background and aim: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare multisystem autoimmune disease developed by autoantibody production against human neutrophilic granulocytes, including proteinase-3 (PR3) and myeloperoxidase (MPO). The management of AAV patients is difficult due to the multiorgan involvement, high rate of relapse, and complications of immunosuppressive agents that make it challenging. This study aims to investigate the efficacy and safety of rituximab (RTX) therapy in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) subtypes. Method: The PubMed/Medline database was searched for any studies related to RTX therapy in ANCA-associated vasculitis (GPA and MPA subtypes), from inception to 1 August 2022, and proceeded in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: Our search resulted in 1082 initial records. After the elimination of review papers, irrelevant studies, and non-English records, 223 articles were included, and the data related to the efficacy and safety of RTX therapy were extracted. Several randomized and non-randomized studies showed that RTX is an effective treatment option for patients with AAV. Most of the studies showed the very effective effect of RTX in controlling disease in AAV patients, including pediatrics, adults, and elderlies, although RTX cannot completely prevent relapse. However, maintenance therapy helps delay the disease's relapse and causes sustained remission. Not only the licensed dose (375 mg/m2 intravenous per week for 4 weeks) could induce disease remission, but studies also showed that a single infusion of RTX could be effective. Although RTX could resolve many rare manifestations in AAV patients, there are few reports showing treatment failure. Additionally, few sudies have reported the unexpeted worsening of the disease after RTX administration. Generally, RTX is relatively safe compared to conventional therapies, but some serious adverse effects, mainly infections, cytopenia, hypogammaglobinemia, malignancy, and hypersensitivity have been reported. Conclusions: RTX is an effective and relatively safe therapeutic option for AAV. Studies on the evaluation of the safety profiles of RTX and the prevention of severe RTX-related side effects in AAV patients are required.

Plasma exchange therapy in ANCA-associated vasculitis: A single-center retrospective cohort study

Plasma exchange therapy in ANCA-associated vasculitis: A single-center retrospective cohort study

FC057: Incidence of Infections in the Avacopan Group Versus Prednisone Group in Anca-Associated Vasculitis, Results from the Phase 3 Advocate Study

Abstract BACKGROUND AND AIMS Standard therapy for ANCA-associated vasculitis (AAV) includes glucocorticoids (GC), which are associated with increased infections. Avacopan is an orally administered selective inhibitor of the C5a receptor recently approved for treatment of AAV. The phase 3 ADVOCATE study tested daily avacopan as a substitute for a standard, scheduled, daily oral GC tapered regimen (all with standard background therapy), resulting in a 63% mean reduction in overall GC load for the avacopan group. At week 26, the avacopan group achieved a comparable remission rate to prednisone (72.3% versus 70.1%) and superior sustained remission at Week 52 (65.7% versus 54.9%; one-sided P = 0.0066) (1). The present analysis compared infections in avacopan and prednisone groups in the ADVOCATE trial. METHOD ADVOCATE, a phase 3, randomized, double-blind, controlled trial in 330 patients, evaluated the efficacy and safety of avacopan. AAV patients (new onset or relapsing disease) were randomized to receive avacopan 30 mg twice daily, or a standard 20-week oral prednisone taper, plus matching placebos. Both groups had background therapy of either cyclophosphamide (followed by azathioprine) or rituximab, and additional GC exposure from premedication for rituximab, from taper of pre-randomization GC, and as required per investigator judgment. Patients were on blinded study drug for 52 weeks. Infections occurring from first dose of blinded study drug through day 56 after last dose were analyzed. RESULTS Total mean GC use during the first 26 weeks of the study was 1073 mg with avacopan and 3193 mg with prednisone groups, and in the last 26 weeks, 296 and 489 mg, respectively. Infections were higher in the prednisone group than with avacopan: 291 events (prednisone) versus 233 (avacopan), with a 75.6% incidence (124/164) with prednisone versus 68.1% (113/166) with avacopan (Table 1). During the prednisone taper period (first 20 weeks), infection incidence was 54.9% in prednisone group versus 49.4% for avacopan, and after the first 20 weeks 52.4% in prednisone group versus 44.0% avacopan. Fewer patients in the avacopan group experienced serious AEs of infection (13.3%/25 events) versus prednisone group (15.2%/31 events); also serious opportunistic infections (3.6% versus 6.7%), life-threatening AEs of infection (0.6% versus 1.2%), and infections resulting in death (0.6% versus 1.2%) were fewer with avacopan (Table 1). No Neisseria meningitidis infections occurred in any patient in the trial. CONCLUSION In the ADVOCATE trial, the mean dose of GCs from all sources was 63% lower in the avacopan group than the prednisone group (1349 versus 3655 total mg, respectively). The avacopan group had a numerically lower incidence of infections, including serious, life-threatening, fatal and serious opportunistic infections compared with the prednisone group.

Antibody Deficiency in ANCA Associated Vasculitis (AAV) Patients Treated with Rituximab

ANCA vasculitides are a rare group of systemic inflammatory disorders for which infection is the leading cause of mortality. Rituximab is the only FDA-approved medication for induction and remission maintenance therapy in AAV. Patients treated with Rituximab often experience a decline in their immunoglobulin level for reasons that are poorly understood.

POS-859 Recurrence or reactivation of SARS-CoV-2 infection after immunosuppressive therapy in ANCA-Associated Vasculitis with COVID-19

Not every kidney damage due to COVID-19 is fully understood. Acute tubular injury is the lesion most frequently described in this disease. However, four cases of ANCA-Associated Vasculitis with COVID-19 with immune pauci-glomerulonephritis have recently been described.

ANCA-associated vasculitis with protein-losing enteropathy is characterized by hypocomplementemia.

Protein-losing enteropathy (PLE) has been reported to be associated with various systemic autoimmune diseases. However, reports regarding PLE in ANCA-associated vasculitis (AAV) patients are limited. We herein aimed to describe the clinical characteristics of AAV with PLE. We conducted a retrospective chart review of patients who were diagnosed with AAV and who began treatment at the University of Tokyo Hospital between June 2003 and June 2020. Among 68 AAV patients, there were four patients (5.9%) with PLE, consisting of two patients with MPA, one patient with GPA, and one patient with EGPA. Clinical courses were described, and their data were compared with AAV patients without PLE. Demographic characteristics, disease activity, and the pattern of organ involvement were similar between patients with PLE and without PLE. Patients with PLE had hypocomplementemia more frequently than the patients without PLE (CH50 75.0% vs 1.8%, p < 0.001, C3 50.0% vs 1.8%, p = 0.01, C4 75.0% vs 3.5%, p = 0.001). Although hypoalbuminemia improved with immunosuppressive therapy for AAV, the improvement in hypoalbuminemia was slow in most cases. We also performed a systematic review on PLE associated with vasculitis. Thirteen reports were included, and Henoch-Schonlein Purpura patients with PLE also tended to have hypocomplementemia. In conclusion, PLE is a rare complication of AAV and complement system may associate with the mechanism of PLE.

Lupus nephritis and ANCA-associated vasculitis: towards precision medicine?

Historically the treatment of lupus nephritis (LN) and anti-neutrophil cytoplasmic antibody (ANCA) vasculitis was 'one size fits all'; however, with the emergence of precision medicine initiatives, the field is moving towards more personalized treatment approaches. The recent development of a more accurate and reproducible histopathological classification system for LN could lead to better disease categorization and therefore more targeted therapies. A better understanding of the pathophysiology of LN has provided evidence that not only T but also B cells play an important role, opening new opportunities for individualized treatment approaches. Recent trials have shown calcineurin inhibitors and the anti-CD20 antibodies rituximab and ofatumumab to be effective in the treatment of LN, adding new treatment options. State-of-the-art targeted therapy in ANCA-associated vasculitis (AAV) takes interindividual heterogeneity in disease severity, type of ANCA antibody [myeloperoxidase versus proteinase 3 (PR3)] and the risk for side effects of therapy into consideration. In addition, within an individual, induction therapy differs from maintenance therapy, the same holding true in incident and relapsing disease. Rituximab is now widely used in AAV and it has become clear that prolonged B cell depletion, as in LN, must be achieved to obtain a long-lasting clinical response, especially in anti-PR3-associated disease. Still, despite these advances, molecular and genetic markers are rarely incorporated into diagnostic and treatment algorithms and true precision medicine remains an aspiration that hopefully can be achieved.

Severe infections in patients with ANCA-associated vasculitis treated with rituximab.

Rituximab (RTX) is an anti-CD20 antibody that selectively depletes B cells and has emerged as a therapy for ANCA-associated vasculitis (AAV) during the past decade. This study sought to quantify and determine potential risk factors for severe infections in AAV patients treated with RTX at rheumatology clinics in Mexico City, Mexico and Lund, Sweden. The study consisted of a retrospective case-record review (2005-15) with standardized data collection related to the occurrence of severe infection in 46 patients with AAV in Mexico City (n = 20) and Lund (n = 26) treated with RTX during their disease course. Median duration of follow-up from first RTX dose to death or end of study was 26 months. Eleven (24%) patients suffered a total of 18 severe infections (infection rate of 11.5/100 patient-years). Thirteen of the 18 infections (72%) occurred within the first year of treatment. Risk factors for severe infection were older age at RTX initiation and absence of ENT involvement at diagnosis. In multivariate analyses, age at RTX infusion was the only independent factor predicting severe infection. Four patients (9%) died during follow-up, all as a result of infection. Severe infections are common following RTX treatment, and mortality due to infection is a major concern. Most severe infections occur within the first year of RTX treatment. The negative correlation of ENT involvement with severe infection might reflect granulomatosis with polyangiitis phenotype heterogeneity. Older age at time of RTX treatment independently predicts severe infections.

The Paradoxical Reaction to Rituximab in Six Granulomatosis with Polyangiitis Patients: How Could it be Explained and Managed?

Granulomatosis with polyangiitis is a systemic anti-neutrophil cytoplasmic antibody-associated vasculitides (AAVs), mainly involving the respiratory tract and renal system. Treatment by Rituximab as a next-generation therapy in ANCA-associated vasculitis is associated with promising outcomes in GPA patients. Despite symptoms improvements, disease recurrence and drug reaction are a challenging topic nowadays. In this study, we examined six GPA patients who were confirmed to have paradoxical reactions to rituximab and then described how to control their symptoms. In this study, all the systemic GPA patients (diagnosed based on ACR/EULAR criteria) who received RTX in Amir-Allam hospital were monitored for any sign of disease exacerbation up to 3 months after RTX exposure. From 78 GPA-diagnosed patients, six, including one man and five women with the mean age of 37.3 ± 13.8, were identified for exacerbation after RTX administration. According to our observation, it could be recommended not to deprive the patient of the benefits of RTX treatment due to the early patient's possible complications.

ANCA-associated vasculitis in a 14 years-old patient: a clinical case

Background. ANCA-associated systemic vasculitis is a rare childhood disease. Antineutrophil cytoplasmic autoantibodies (ANCA)-related vasculitises include microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis. Their rarity often leads to a late diagnosis, rapid disability and high mortality in patients due to aggressive respiratory, pulmonary lesion and renal failure.Clinical Case Description. The patient suffered from a recurrent bronchoobstructive syndrome with signs of respiratory failure, obscure origin fever and chronic rhinitis with nasal bleeding for 6 months. The patient was diagnosed with obstructive bronchitis (putative bronchial asthma debut), received antibacterial therapy and inhalation bronchodilators without stable improvement during the entire period. Skin haemorrhages and arthralgia stimulated diagnostic research to establish ANCA-associated systemic vasculitis (presence of proteinase 3-specifi c ANCAs in titre 1/80). CT lung scanning revealed frosted glass foci of reduced pulmonary pneumatisation and signs of bilateral bronchoobstruction. Immunosuppressive therapy with glucocorticosteroids (methylprednisolone pulse therapy No. 3, 1000 mg intravenously on alternate days, subsequent per os administration of 1 mg/kg/day) and cyclophosphamide (500 mg intravenously once per 28 days) was prescribed. This led to the positive dynamics with eliminated fever and skin haemorrhages, as well as essentially reduced signs of respiratory failure.Conclusion. Diagnosis of systemic vasculitis is often complicated and long-term due to commonly non-specifi c debut symptoms of autoimmune disorders. In the described case, the fi rst 6 months of illness displayed intoxication and bronchoobstruction with signs of respiratory failure. Haemorrhagic rashes, arthralgias and the presence of ANCAs are proxy to vasculitis. Standard immunosuppressive therapy for ANCA-associated vasculitis improved the patient’s condition.

Rapid progressive glomerulonephritis

The rapid progressive glomerulonephritis is an emergency case. Renal function is rapidly lost within weeks or afew months (rarely within days) due to necrotizing extracapillary proliferative crescentic glomerulonephritis. Early diagnosis and treatment improve prognosis, as the best prognostic marker is creatinine when treatment is initiated. Three classes can be distinguished by immunofluorescence in histology. Firstly, there are no or only few immunoglobulins found (anti-neutrophil cytoplasmic antibody [ANCA]-associated vasculitis). Secondly, there is linear immunofluorescence due to antibodies against the glomerular basement membrane (anti-glomerular basement membrane [GBM] disease or Goodpasture syndrome); and thirdly, there is agranular pattern of immunoglobulin deposition (for example systemic lupus erythematosus [SLE], Schoenlein-Henoch purpura or cryoglobulinaemia). The immunosuppressive repertoire has improved (such as induction therapy in ANCA-associated vasculitis with lower total steroid dose, cyclophosphamide pulses or rituximab). New treatment approaches are on their way and the prognosis regarding life expectancy and renal function has improved. There are still challenging questions to answer like treatment duration and markers of recurrence.

271. SEVERE INFECTIONS IN PATIENTS WITH ANCA-ASSOCIATED VASCULITIS TREATED WITH RITUXIMAB

Background and objectives Rituximab (RTX) is an anti-CD20 antibody that selectively depletes B-cells and has emerged as a therapy for ANCA-associated vasculitis (AAV) during the past decade. This study sought to quantify, and determine potential risk factors for, severe infections in AAV patients treated with RTX at rheumatology clinics in Mexico City, Mexico and Lund, Sweden. Methods The study consisted of a retrospective case-record review (2005-2015) with standardized data collection related to the occurrence of severe infection in 46 patients with AAV in Mexico City (n = 20) and Lund (n = 26) treated with RTX during their disease course. Median duration of follow-up from first RTX dose to death or end of study was 26 months. Results Eleven (24%) patients suffered a total of 18 severe infections (infection rate of 11.5/100 patient-years). Thirteen of the 18 infections (72%) occurred within the first year of treatment. Risk factors for severe infection were older age at RTX initiation and absence of ENT-involvement at diagnosis. In multivariate analyses, age at RTX infusion was the only independent factor predicting severe infection. Four patients (9%) died during follow-up, all as a result of infection. Conclusions Severe infections are common following RTX treatment, and mortality due to infection is a major concern. Most severe infections occur within the first year of RTX treatment. The negative correlation of ENT involvement with severe infection might reflect GPA phenotype heterogeneity. Older age at time of RTX treatment independently predicts severe infections.

Estimating the Change in Renal Function During the First Year of Therapy in ANCA-Associated Vasculitis

IntroductionStudies in antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) consistently show that the months following diagnosis have the greatest impact on the long-term renal function. Yet, it remains uncertain how much early gain should be expected with treatment. We sought to determine the factors associated with the change in glomerular filtration rate (GFR) throughout the first year.MethodsWe retrospectively reviewed patients from 3 university hospitals who received treatments. We assessed the proportions of glomeruli with crescents, with global sclerosis, the AAV glomerulonephritis classification, the severity of chronic vascular and tubulo-interstitial disease, and the presence of acute tubular injury (ATI). We used repeated-measures analyses of variance (ANOVAs) to determine factors associated with the change in GFR throughout the first year.ResultsThere were 162 individuals with AAV identified, 96 with a valid renal biopsy and 82 with at least 12 months of follow-up. The initial GFR of 30 ± 25 ml/min per 1.73 m2 rose by 15 ± 20 during the first year. The severity of pathology findings, myeloperoxidase positivity, and those with kidney- and lung-limited disease presented with a lower GFR. Younger patients with a lower initial GFR and the presence of ATI correlated with a greater increase in GFR by 12 months. A higher proportion of crescents did not predict the change in GFR, contrary to global glomerulosclerosis, where each 10% increase added a loss of 2.7 ± 1.3 ml/min per 1.73 m2 per year (P = 0.03). These factors remained independent of each other.ConclusionMultiple factors influence renal recovery during the first year of therapy. Estimating the change in GFR early on will help identify and reassess outliers.