Rituximab In ANCA-associated Vasculitis Research Articles

Trimethoprim-sulfamethoxazole prophylaxis during treatment of granulomatosis with polyangiitis with rituximab in the United States of America: a retrospective cohort study

BackgroundAntibiotic prophylaxis is recommended during ANCA-associated vasculitis (AAV) induction. We aimed to describe the frequency, persistence, and factors associated with trimethoprim-sulfamethoxazole (TMP-SMX) use in an adult population sample with granulomatosis with polyangiitis (GPA) treated with rituximab (RTX).MethodsWe identified adults with GPA treated with RTX within the Merative™ Marketscan® Research Databases (2011–2020). TMP-SMX prophylaxis was defined as a ge 28-day prescription dispensed within a month of starting RTX. We estimated TMP-SMX persistence, allowing prescription refill gaps of 30 days. Multivariable logistic regression and Cox proportional hazards regression assessed the factors associated with baseline TMP-SMX use and persistence, respectively. Covariates included age, sex, calendar year, insurance type, immunosuppressant use, hospitalization, and co-morbidities.ResultsAmong 1877 RTX-treated GPA patients, the mean age was 50.9, and 54% were female. A minority (n = 426, 23%) received TMP-SMX with a median persistence of 141 (IQR 83–248) days. In multivariable analyses, prophylaxis was associated with prednisone use in the month prior to RTX (ge 20 mg/day vs none, OR 3.96; 95% CI 3.0–5.2; 1–19 mg/day vs none, OR 2.63; 95% CI 1.8–3.8), and methotrexate use (OR 1.48, 95% CI 1.04–2.1), intensive care (OR 1.95; 95% CI 1.4–2.7), and non-intensive care hospitalization (OR 1.56; 95% CI 1.2–2.1) in the 6 months prior to RTX. Female sex (OR 0.63; 95% CI 0.5–0.8) was negatively associated with TMP-SMX use.ConclusionsTMP-SMX was dispensed to a minority of RTX-treated GPA patients, more often to those on glucocorticoids and with recent hospitalization. Further research is needed to determine the optimal use and duration of TMP-SMX prophylaxis following RTX in AAV.

355. Retrospective observational study on the long-term safety of Rituximab in ANCA associated Vasculitis (RIVAS)

355. Retrospective observational study on the long-term safety of Rituximab in ANCA associated Vasculitis (RIVAS)

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.

Kinetics of B Cell Repopulation After Rituximab in ANCA-Associated Vasculitis: Clinical Significance and Predictive Factors

Kinetics of B Cell Repopulation After Rituximab in ANCA-Associated Vasculitis: Clinical Significance and Predictive Factors

Serum B cell activating factor (BAFF) as a biomarker for induction of remission with rituximab in ANCA-associated vasculitis

We examined whether serum B cell activating factor (BAFF) is useful for predicting the remission of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) following rituximab treatment. We used the Birmingham Vasculitis Activity Score (BVAS) 2008 version 3 for the evaluation of 27 patients with AAV 6 months after rituximab treatment. Those with BVAS = 0 achieved remission, whereas those with BVAS score > 0 did not achieve remission. We considered changes in serum BAFF before rituximab treatment, 1 month after treatment, and 6 months after treatment. In the remission group, the serum BAFF increased consistently. In the non-achieved group, serum BAFF was within the normal range. In addition, there was no statistically significant difference between the two groups in terms of serum BAFF before and 1 month after rituximab treatment. However, the serum BAFF level at 6 months after rituximab treatment was significantly higher in the remission group than in the non-achieved group. If serum BAFF does not increase after 6 months of rituximab in AAV, it may be assumed that there are residual B cells and plasma cells in the tissues. Enhanced treatment targeting B cells, including re-administration of rituximab or the addition of other immunosuppressive drugs, should be considered.

POS1412 IDENTIFYING HIGH-COST DRUGS FOR RARE RHEUMATIC DISEASES IN ROUTINELY COLLECTED NHS DATA. RESULTS FROM A PILOT STUDY OF RITUXIMAB USE IN VASCULITIS USING DATA FROM THE NATIONAL DISEASE REGISTRATION SERVICE AND THE REGISTRATION OF COMPLEX RARE DISEASES-EXEMPLARS IN RHEUMATOLOGY (RECORDER) PROJECT

Background:Understanding real-world usage of high-cost drugs is crucial to support planning, adoption of innovation and reduce unwarranted variation in treatment. Hospital Episode Statistics (HES) contain diagnoses (coded by ICD-10) and procedures/treatments (coded by OPCS) for all daycase or inpatient care in England. However, OPCS codes are not specific for individual drugs, for example X921 (cytokine inhibitors band 1) includes rituximab (RTX) and 15 other drugs.Objectives:We aimed to validate the accurate identification of patients treated with RTX for ANCA-associated vasculitis (AAV) using HES data.Methods:We used data from the National Congenital Anomaly and Rare Disease Registration Service (NCARDRS) at Public Health England and their legal permissions (CAG 10-02(d)/2015). We extracted records from HES of all patients treated at two hospitals during financial year 2018/19 who ever had a coded diagnosis of granulomatosis with polyangiitis (GPA, M313), eosinophilic granulomatosis with polyangiitis (EGPA, M301), microscopic polyangiitis (MPA, M317), polyarteritis nodosa (PAN, M300) or arteritis unspecified (I776). Where people had multiple diagnoses of vasculitis, the most specific was considered their diagnosis. Enabled by data sharing agreements, we reviewed hospital records of those patients to validate diagnoses and whether X921 reliably identified RTX. We report the positive predictive value and sensitivity of the coding for X921 and GPA/EGPA/MPA for identifying people with AAV who are treated with RTX.Results:At Trust 1 records ever coded with GPA/EGPA/MPA identified 74 people, 69 of whom had AAV confirmed in their medical notes. Among these 74 patients there were 59 episodes coded with X921 procedure codes, of which 56 correctly identified a RTX infusion given for AAV. A total of 64 RTX infusions were given to people with AAV – 3 missed infusions were X921 procedures in patients who had coded diagnoses of PAN or I776 but never GPA/EGPA/MPA and 5 infusions were not coded as X921.The same analysis at Trust 2 identified 46 people, 44 of whom had AAV confirmed in their medical notes. Among patients identified with AAV there were 17 episodes coded as X921, of which 15 correctly identified a RTX infusion. A total of 23 infusions were given to people with AAV: 4 infusions were X921 procedures in patients who had coded diagnoses of PAN or I776 but never GPA/EGPA/MPA, and 4 infusions were not coded as X921.Table 1. Summary of Positive Predictive Values (PPV) applying our algorithm to identify AAV diagnoses and RTX useTrust 1Trust 2CombinedDiagnosis of AAV and coded as AAV6944113AAV coded7446120Diagnosis of AAV under any code7355128PPV AAV ascertainment (95% CI)93.2% (84.9-97.8)95.7% (85.2-99.5)94.2% (88.4-97.6)Sensitivity of AAV ascertainment (95% CI)94.5% (86.8-98.5)80.0% (67.0-89.6)88.3% (81.4-93.3)RTX given in people coded as AAV561571RTX coded in people coded as AAV591776RTX given for AAV under any diagnostic or procedure code642387PPV RTX ascertainment (95% CI)94.9% (85.9-98.9)88.2% (63.6-98.5)93.4% (85.3-97.8)Sensitivity of RTX ascertainment (95% CI)87.5% (76.8-94.4)65.2% (42.7-83.6)81.6% (71.9-89.1)Conclusion:HES data identified patients treated with RTX for AAV with a PPV of 93.4% (85.3-97.8) and sensitivity of 81.6% (71.9-89.1). This demonstrates the utility of national data to identify people receiving RTX for AAV. The RECORDER project, within the National Disease Registration Service plans to conduct real-world studies of the high-cost drug RTX, given for AAV, across the whole of England, and assess whether geography, demographics or socioeconomic factors influence frequency of prescription of this, and potentially other, high-cost drugs in line with the NHS long term plan.

P091 Can use of high cost drugs for rare rheumatic diseases be reliably identified within routinely collected NHS data? Results from a pilot study of rituximab use in vasculitis using data from the National Disease Registration Service (NDRS) and the Registration of Complex Rare Diseases - Exemplars in Rheumatology (RECORDER) project

Abstract Background/Aims Understanding real-world usage of high cost drugs and subsequent outcomes are crucial to support high quality care, adoption of innovation, and reduce unwarranted variation in treatment. Hospital Episode Statistics (HES) contain diagnoses (coded by ICD-10) and procedures/treatment (coded by OPCS) for admissions in England. However, OPCS codes are not specific for individual drugs, for example X921 (cytokine inhibitors band 1) includes rituximab and 15 other drugs. We aimed to validate the accurate identification of patients treated with rituximab for ANCA-associated vasculitis (AAV) using HES data. Methods We used data available to the National Congenital Anomaly and Rare Disease Registration Service (NCARDRS), part of NDRS at Public Health England and their legal permissions (CAG 10-02(d)/2015). We extracted from HES all patients treated at one hospital who ever had a coded diagnosis of either granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis, polyarteritis nodosa or 'arteritis unspecified’, which is applied by coders to several clinical terms including “systemic vasculitis” and “ANCA associated vasculitis”. Enabled by data sharing agreements, we reviewed hospital records of those patients who had a Finished Consultant Episode (FCE) during 2018/19, to validate diagnoses and whether X921 reliably identified rituximab. Results Initially using codes only for granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, or microscopic polyangiitis we identified 65 people, 60 of whom had AAV confirmed in their medical notes (Positive predictive value (PPV) 92.3%; 95% CI 83.0-97.5). When we expanded our search to include in addition people with codes for polyarteritis nodosa or ‘arteritis unspecified’ who had rheumatology or renal follow up, we identified an additional 13 people with AAV and 10 who had other types of systemic vasculitis (PPV for AAV 79.5, 95% CI 69.6-87.4; PPV for systemic vasculitis 90.9%, 95% CI 82.9-96.0). Among patients identified only by the specific ICD-10 codes for the 3 subtypes of AAV there were 51 episodes coded as X921, of which 50 correctly identified a rituximab infusion (and 1 was tocilizumab). No additional infusions for these patients were missed by the coding. The PPV was 98.0% (95% CI 89.6-100). Among patients identified by the more inclusive algorithm, there were 61 episodes coded as X921 in that year. Of these, 59 were for rituximab treatment for AAV and an additional 4 rituximab infusions occurred but were not coded. The PPV was 96.7% (95% CI 88.7-99.6), and the sensitivity was 93.7% (95% CI 84.5-98.2). Conclusion This pilot study demonstrates how the use of novel algorithms within the NDRS RECORDER project can enable the identification and registration of people with AAV and their high-cost treatment at whole-population level. Further work is now underway to study this national cohort, and to apply this methodology to other rare autoimmune diseases and high cost drugs. Disclosure M. Chakravorty: None. F. Pearce: Grants/research support; Recipient of research grant from Vifor Phama. Vifor Pharma had no influence on the design, interpretation or reporting of this work. M. Rutter: None. P. Lanyon: Grants/research support; Recipient of research grant from Vifor Phama. Vifor Pharma had no influence on the design, interpretation or reporting of this work. J. Aston: None. M. Bythell: None. S. Stevens: None.

Non-Linear Rituximab Pharmacokinetics and Complex Relationship between Rituximab Concentrations and Anti-Neutrophil Cytoplasmic Antibodies (ANCA) in ANCA-Associated Vasculitis: The RAVE Trial Revisited.

Rituximab is approved in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and leads to a decrease of ANCA levels. The objectives of this study were to investigate the non-linear pharmacokinetics of rituximab and the relationship between its concentrations and ANCA levels in AAV patients. Ninety-two AAV patients from the RAVE (Rituximab in ANCA-Associated Vasculitis) trial were assessed. Both ANCA anti-myeloperoxidase (MPO-ANCA) and anti-proteinase3 (PR3-ANCA) levels were used as biomarkers. The pharmacokinetics of rituximab were described using a semi-mechanistic two-compartment model that included a latent target antigen turnover and allowed the estimation of specific target-mediated elimination in addition to its non-specific elimination of rituximab. The effect of rituximab on the ANCA level was described using a semi-mechanistic compartment model with a negative feedback (Friberg) model with no transit compartment. A population modeling approach was used. Our pharmacokinetic and pharmacokinetic-pharmacodynamic (PK-PD) models satisfactorily described both concentration-time and concentration-effect relationship data. The mean (inter-individual standard deviation) estimated non-specific clearance was 0.15L/day (0.30%) and the target-mediated elimination rate constant was 2.4 × 10-5 nmol/day. The elimination half-lives for MPO-ANCA and PR3-ANCA were 24 and 18days, respectively. A non-linear target-mediated elimination of rituximab was detected in AAV patients. Our PK-PD model allowed quantification of the association between rituximab concentrations and ANCA levels. This decrease was deep but delayed, and more sustained in patients with MPO-ANCA than in those with PR3-ANCA. Our results suggest that repeating courses of rituximab might improve the clinical response to rituximab.

Disease Activity, Antineutrophil Cytoplasmic Antibody Type, and Lipid Levels in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have an elevated risk of cardiovascular disease (CVD). This study was undertaken to develop a clearer understanding of the association between changes in disease activity and lipid levels in AAV, which may inform CVD risk stratification in this population. Lipid levels were assessed in stored serum samples (obtained at baseline and month 6) from the Rituximab for ANCA-Associated Vasculitis (RAVE) trial, which randomized patients to receive either rituximab or cyclophosphamide followed by azathioprine. Paired t-tests and multivariable linear regression were used to assess changes in lipid levels. Of the 142 patients with serum samples available, the mean ± SD age was 52.3 ± 14.7 years, 72 (51%) were male, 95 (67%) were proteinase 3 (PR3)-ANCA positive, 72 (51%) had received a new diagnosis of AAV, and 75 (53%) were treated with rituximab. Several lipid levels increased between baseline and month 6, including total cholesterol (+12.4 mg/dl [95% confidence interval (95% CI) +7.1, +21.0]), low-density lipoprotein (+10.3 mg/dl [95% CI +6.1, +17.1]), and apolipoprotein B (+3.5 mg/dl [95% CI +1.0, +8.3]). These changes were observed among newly diagnosed and PR3-ANCA-positive patients but not among those with relapsing disease or myeloperoxidase-ANCA-positive patients. There was no difference in change in lipid levels between rituximab-treated patients and cyclophosphamide-treated patients. Changes in lipid levels correlated with changes in erythrocyte sedimentation rate but not with other inflammatory markers or glucocorticoid exposure. Lipid levels increased during remission induction among patients with newly diagnosed AAV and those who were PR3-ANCA positive. Disease activity and ANCA type should be considered when assessing lipid profiles to stratify CVD risk in patients with AAV.

Biologics for childhood systemic vasculitis.

Recent advances have allowed better understanding of vasculitis pathogenesis and led to more targeted therapies. Two pivotal randomized controlled trials, RITUXVAS and rituximab in ANCA-associated vasculitis (RAVE), provide high-quality evidence demonstrating rituximab (RTX) is efficacious in inducing remission in adult ANCA-associated vasculitis (AAV) patients compared with cyclophosphamide (CYC). RAVE also demonstrated superiority of RTX to oral CYC for induction of remission in relapsing disease. Disappointingly, the RTX regimen was not associated with reduction in early serious adverse events. At least nine randomized trials are in progress, aiming to further delineate optimal dosing and duration of RTX therapy in AAV. In particular, the 6-month interim results of the PEPRS trial provide encouraging data specific to children. Due to special concerns related to growth, preservation of fertility, and potential for high cumulative medication doses, children with AAV should be considered as candidates for RTX even as a first-line remission induction therapy. Two randomized clinical trials have defined the role of infliximab in Kawasaki disease (KD), which appears to be as an alternative to a second infusion of intravenous immunoglobulin (IVIG) for treatment-resistant disease. Support for other biologics in the treatment of AAV or for biologics in the treatment of other vasculidities is largely lacking due to either unimpressive trial results or lack of trials. Except for the KD trials and the PEPRS, trials enrolling children remain scant. This review touches on the key trials and case series with biologics in the treatment of vasculitis that have influenced practice and shaped current thinking.

The Pharmacogenomic Association of Fcγ Receptors and Cytochrome P450 Enzymes With Response to Rituximab or Cyclophosphamide Treatment in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared rituximab to cyclophosphamide as induction therapy for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We undertook the current study to determine whether known single-nucleotide polymorphisms (SNPs) for Fcγ receptors (FcγR) or cytochrome P450 (CYP) enzymes were associated with the response to treatment with rituximab and cyclophosphamide, respectively. Functional SNPs for FcγR (FcγRIIa 519G>A, FcγRIIb 695T>C, FcγRIIIa 559T>G) and CYP enzymes (CYP2B6 1459C>T, CYP2C19 681G>A) were analyzed by direct sequencing of polymerase chain reaction-amplified genomic DNA. Each SNP was tested as a predictor of complete remission at 6 months or remission with continued prednisone administration using logistic regression and including the covariates of baseline Birmingham Vasculitis Activity Score for Wegener's Granulomatosis, ANCA type, and new versus relapsing disease. The associations of these SNPs with the secondary outcomes of time to complete remission, time to relapse, or time to B cell reconstitution were analyzed by Cox proportional hazard tests. No significant associations were identified between complete remission and any FcγR genotype in the rituximab group or any CYP genotype in the cyclophosphamide group. However, when the treatment groups were combined, an association was found between the 519AA genotype of FcγRIIa and complete remission (P = 0.01). The 519AA genotype predicted complete remission (P = 0.006) and a shorter time to complete remission (P < 0.001). The finding that the homozygous FcγRIIa 519AA variant was associated with complete response and a shorter time to complete response in the RAVE trial, independent of treatment type, implies that FcγRIIa may be broadly involved in disease pathogenesis and response to therapy.

Late-onset neutropenia after rituximab in ANCA-associated vasculitis

Background: Rituximab (RTX) is being used increasingly in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV). Late-onset neutropenia (LON) and risks of infections have been observed following RTX therapy in rheumatological diseases including granulomatosis with polyangiitis (GPA) but data on microscopic polyangiitis (MPA) are lacking.Method: We studied the occurrence of LON in 59 AAV (47 GPA/12 MPA) patients treated with RTX. Patient charts were retrospectively reviewed for the occurrence of LON and clinical data were extracted and included in the analysis.Results: Seven of the total 59 patients (11.9%) developed LON after a median time of 86 days (range 56–168 days) since their latest RTX treatment. Of these seven LON patients, 5/47 (10.6%) had a diagnosis of GPA and 2/12 (16.7%) of MPA. Three of the patients developed LON after the first RTX treatment and four had received repeated courses. Five LON patients developed infectious symptoms. Six of the patients were hospitalized. Retreatment with RTX was given in three cases without further LON episodes.Conclusions: LON is a potentially severe side-effect of RTX occurring in both GPA and MPA and may develop after both single and repeated treatment courses. As infections are commonly seen, the condition requires an increased awareness. No predisposing factors for LON were identified.

Low immunoglobulin levels increase the risk of severe hypogammaglobulinemia in granulomatosis with polyangiitis patients receiving rituximab.

BackgroundRandomized controlled trials and retrospective studies in ANCA-associated vasculitis (AAV) concurred that rituximab (RTX) is effective to induce and maintain remission. Infections and hypogammaglobulinemia during RTX were usually infrequent and uncomplicated. But in the Tromsø study cohort, 45 % of patients with granulomatosis with polyangiitis (GPA) developed hypogammaglobulinemia during RTX maintenance leading to its discontinuation in 62 %.MethodsTo explain these differences in outcome when using RTX in AAV to maintain remission, we used statistical structural methods to compare the Tromsø study cohort with other published cohorts.ResultsGPA patients’ characteristics of the Tromsø study cohort were not so different compared with other cohorts. Rates of hypogammaglobulinemia and discontinuation of RTX seemed closely related to the cut-off used and to the levels of immunoglobulin (Ig) at baseline. Combination of low IgG serum levels at baseline (7.7 g/L) and low cut-off to define hypogammaglobulinemia in the Tromsø study cohort explained the high rate of hypogammaglobulinemia and discontinuation of RTX.ConclusionsPatients’ characteristics in the Tromsø study cohort were not skewed, apart from IgG levels. Low IgG level at baseline seemed to contribute the most to hypogammaglobulinemia and its complications.

Response of Chronic, Relapsing Wegener's Granulomatosis with Severe Pulmonary Involvement to Anti-CD20 Monoclonal Antibody (Rituximab)

Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) are primary systemic small vessel vasculitides with predilection for the respiratory tract and kidneys. Most patients have circulating antineutrophil cytoplasmic antibodies (ANCAs) reacting either with neutrophil proteinase-3 (PR3) or myeloperoxidase (MPO). The combination of glucocorticoids and cylophosphamide is the standart therapy for patients with severe WG or MPO. ANCA-associated vasculitis has a high relapse rate, and some patients do not respond satisfactory to this treatment. Rituximab is a chimeric monoclonal antibody directed against CD20, a cell surface antigen expressed almost exclusively on cells of B-lymphocytes lineage. A rationale for Rituximab in ANCA-associated vasculitis was based on its potential to deplete CD20+ precursors of ANCA-secreting plasma cells. Rituximab is an advanced in the treatment of ANCAassociated vasculitis and has a place in the therapeutic armament as an alternative to Cyclophosphamide or for refractory disease. We present a case of a young patient with chronic, relapsing ANCA-associated vasculitis (Wegener's granulomatosis) with severe pulmonary involvement in whom the use of Cyclophosphamide failed to control disease activity. Subsequently the patient was treated successfully with Rituximab. The most frequent complications after the applications of Rituximab are different infections. Some months after the use Rituximab we diagnosed a lobar pneumonia in the patient. The patients with autoimmune diseases are immunosuppressive and are disposed to infections. The aim of the present article is to present the use Rituximab as a future option in the treatment of ANCA-associated vasculitis.

Outcomes of nonsevere relapses in antineutrophil cytoplasmic antibody-associated vasculitis treated with glucocorticoids.

Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated with prednisone according to a prespecified protocol. RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission. Patients who experienced nonsevere relapses between months 1 and 18 were treated with a prednisone increase without a concomitant change in their nonglucocorticoid immunosuppressants, followed by a taper. Forty-four patients with a first nonsevere relapse were analyzed. In comparison to the 71 patients who maintained relapse-free remission over 18 months, these patients were more likely to have proteinase 3-ANCAs, diagnoses of granulomatosis with polyangiitis (Wegener's), and a history of relapsing disease at baseline. A prednisone increase led to remission in 35 patients (80%). However, only 13 patients (30%) were able to maintain second remissions through the followup period (mean 12.5 months); 31 patients (70%) had a second disease relapse, 14 of them with severe disease. The mean time to second relapse was 9.4 months (4.7 months in the group treated with RTX versus 13.7 months in the group treated with CYC/AZA; P < 0.01). Patients who experienced nonsevere relapses received more glucocorticoids than those who maintained remission (6.7 grams versus 3.8 grams; P < 0.01). Treatment of nonsevere relapses in AAV with an increase in glucocorticoids is effective in restoring temporary remission in the majority of patients, but recurrent relapses within a relatively short interval remain common. Alternative treatment approaches are needed for this important subset of patients.

Con: Should all patients with anti-neutrophil cytoplasmic antibody-associated vasculitis be primarily treated with rituximab?

Rituximab has enriched our armamentarium in the treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Two randomised controlled trials have shown that rituximab is non-inferior compared with cyclophosphamide followed by azathioprine for the induction of remission. The newly diagnosed patients in the Rituximab in ANCA-Associated Vasculitis (RAVE) and Rituximab Versus Cyclophosphamide in ANCA-Associated Vasculitis (RITUXVAS) trials had a numerically higher response rate in the cyclophosphamide/azathioprine arm, and the number of such patients treated with rituximab numbered <90. We are arguing that in newly diagnosed patients, the evidence for rituximab requires further confirmation and the length of experience with a cyclophosphamide-based induction therapy supports it continuing as the preferred first choice for induction. Also, there is an absence of information regarding rituximab as 'sole' remission induction along with steroids in patients with advanced renal presentations or lung haemorrhage. Reported side effects were similar in both trials; however, the number of participants with at least one serious adverse event following rituximab induction treatment was numerically higher in the RAVE trial. In addition, hypogammaglobulinaemia with the need of substitution in some cases and late-onset neutropaenia are complications not seen with cyclophosphamide. Over the longer term it is unclear what relapse prevention strategy should be employed after rituximab, and there was a trend to a higher relapse risk after rituximab in the RITUXVAS trial at 2 years. Further health economic studies are required to understand all the costs associated with rituximab. In the context of concomitant underlying infectious complications, in terms of fertility concerns, especially in young patients, and when malignancy is underlying we would recommend the use of rituximab as first-line therapy.

Pro: Should all patients with anti-neutrophil cytoplasmic antibody-associated vasculitis be primarily treated with rituximab?

Randomized controlled trials have shown that rituximab is non-inferior to cyclophosphamide followed by azathioprine (CYC/AZA) for remission induction in severe granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). The efficacy of rituximab is on par with CYC/AZA for 18 months, for patients with GPA and MPA alike, and for patients with any degree of renal impairment. The Rituximab in ANCA-associated Vasculitis (RAVE) trial also showed superiority of rituximab for patients presenting with a severe disease relapse. An exploratory analysis of the RAVE data further suggests that rituximab may be preferable for PR3-ANCA-positive patients as superiority was also achieved in that subset. When considering treatment options for patients with disease presentations for which only non-inferiority has been documented, safety concerns, compliance issues, the overall cost of each treatment approach to the patient, to society and to insurers, as well as individual patient preferences all should affect the decision-making process. The trials failed to uncover any difference in adverse events between rituximab and CYC/AZA. However, daily oral cyclophosphamide given for 3-6 months has measurable negative effects on fertility. Rituximab has certain compliance and convenience advantages. When assessing cost, the overall cost of a treatment, the societal context of the individual patient and not merely the sticker price of the drug should be considered. For all of these reasons, the author believes that CYC/AZA should be reserved for patients with newly diagnosed, MPO-ANCA-positive disease who raise no fertility, compliance or malignancy concerns.

Moderator's view: Should all patients with ANCA-associated vasculitis be primarily treated with rituximab?

Experience with rituximab in patients with new ANCA-associated vasculitis (AAV) is still very limited, especially in patients with severe (organ- or life-threatening) AAV. Rituximab may be more effective in anti-PR3 AAV, but potentially less effective in some granulomatous manifestations of AAV. We do not know what the response is to rituximab on the tissue level. Rituximab induction needs to be followed by maintenance treatment, and potentially very long rituximab maintenance may result in higher risk of rituximab-related complications (e.g. decrease in IgG levels). Long-term experience with rituximab in AAV is insufficient. Treatment with rituximab is more expensive than the standard treatment with cyclophosphamide and corticosteroids and seems to be cost-effective only in patients primarily treated with cyclophosphamide. Rituximab can be used in some newly diagnosed patients with AAV (e.g. women with child-bearing potential, or patients with active vasculitis and severe infection), but with the available information, it may be too early to use it as a first-line treatment in all new AAV patients.

65-Year-Old Woman With Intermittent Fevers, Lower Extremity Paresthesia, Weight Loss, and Malaise

65-Year-Old Woman With Intermittent Fevers, Lower Extremity Paresthesia, Weight Loss, and Malaise

Peripheral CD5+ B cells in antineutrophil cytoplasmic antibody-associated vasculitis.

CD5+ B cells have been conceptualized as a possible surrogate for Breg cells. The aim of the present study was to determine the utility of CD5+ B cells as biomarkers in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The absolute and relative numbers (percentages) of CD5+ B cells (explanatory variables) were measured longitudinally during 18 months in 197 patients randomized to receive either rituximab (RTX) or cyclophosphamide (CYC) followed by azathioprine (AZA) for the treatment of AAV (Rituximab in ANCA-Associated Vasculitis [RAVE] trial). Outcome variables included disease activity (status of active disease versus complete remission), responsiveness to induction therapy, disease relapse, disease severity, and, in RTX-treated patients, relapse-free survival according to the percentage of CD5+ B cells detected upon B cell repopulation. CD5+ B cell numbers were comparable between the treatment groups at baseline. After an initial decline, absolute CD5+ B cell numbers progressively increased in patients in the RTX treatment arm, but remained low in CYC/AZA-treated patients. In both groups, the percentage of CD5+ B cells increased during remission induction and slowly declined thereafter. During relapse, the percentage of CD5+ B cells correlated inversely with disease activity in RTX-treated patients, but not in patients who received CYC/AZA. No significant association was observed between the numbers of CD5+ B cells and induction treatment failure or disease severity. The dynamics of the CD5+ B cell compartment did not anticipate disease relapse. Following B cell repopulation, the percentage of CD5+ B cells was not predictive of time to flare in RTX-treated patients. The percentage of peripheral CD5+ B cells might reflect disease activity in RTX-treated patients. However, sole staining for CD5 as a putative surrogate marker for Breg cells did not identify a subpopulation of B cells with clear potential for meaningful clinical use. Adequate phenotyping of Breg cells is required to further explore the value of these cells as biomarkers in AAV.