Rituximab versus azathioprine in maintenance therapy of patients with granulomatosis with polyangiitis

Maintenance Immunosuppression in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

BackgroundDeficiency of alpha-1 protease inhibitor, or alpha-1-antitrypsin (A1AT) is a frequent genetic disorder, which is characterized by low serum level of A1AT and usually manifests as pulmonary emphysema and liver...

Background:Classification of ANCA-associated vasculitis (AAV) has emerged in order to identify more homogenous subgroups of patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). However, the exact value of classifying patients according to antibody specificity (proteinase 3 [PR3] or myeloperoxidase [MPO]) is still unclear.Objectives:To assess demographic, clinical and prognostic differences among subgroups of AAV patients, according to clinicopathological classification (GPAvs. MPA) and antibody specificity (PR3vs. MPO) in a single-centre cohort.Methods:A clinical retrospective (1990-2019) observational analysis was performed. Among all patients with ANCA positivity, we analysed patients with GPA and MPA diagnosed according to 2018 Draft Classification Criteria for AAV1, who were homogeneously treated and followed by the authors. Demographic, clinical and laboratory data, as well as disease outcomes, particularly BVAS, disease relapses and survival, were reviewed.Results:Among a total 140 patients with any form of AAV, 32 were excluded for a diagnosis of isolated interstitial lung disease (n=10), cocaine-induced AAV (n=3), ANCA negative or undetermined disease (n=16), atypical ANCA or double PR3/MPO positivity (n=3). Finally, 108 patients with MPA (n=66) or GPA (n=42) were included (83 MPO, 25 PR3). GPA was associated with PR3 in 55% and MPO 45% of patients. MPA was associated with MPO in 97% and PR3 in 3% of patients. GPA patients with PR3 or MPO presented with similar clinical features, disease extent and BVAS. However, compared with GPA/PR3, GPA/MPO were more frequently women (p=0.002). MPA patients presented more frequent with renal involvement (p=0.008) and GPA patients with ENT/ocular involvement (p<0.001). Patients with MPO were older (p=0.028) and more frequently women (p=0.001) than PR3 patients. When antibody specificity was compared, differences on organ-specific manifestations were less clear than between clinical phenotypes (GPA vs. MPA), and were only seen in ENT/ocular involvement (more frequent in PR3 than in MPO patients) and in muscle biopsies disclosing vasculitis (more frequent in MPO than in PR3 patients). GPA and PR3 patients presented more frequent relapsing disease than MPA and MPO patients, respectively (GPA 60% vs. MPA 36%; p=0.018 / PR3 60% vs. MPO 41%; p=0.094). While GPA tended to have a better survival rate than MPA patients (p=0.066) (Graph1), the MPO-associated disease (GPA or MPA) had clearly worse survival prognosis than PR3-AAV (p=0.008) (Graph2), similarly to what occurred in GPA-MPO (compared with GPA-PR3).Conclusion:A high proportion of GPA patients with MPO-ANCA (45%) is observed in our series. GPA is associated with a more frequent relapsing disease than MPA. MPA and presence of MPO were more frequent in females and older patients. Clinical features were similar in GPA patients with PR3 or MPO. The presence of MPO (in GPA or MPA) seems to be the main factor associated with mortality in AAV.Table 1.Symptomatology and ultrasound findings in the patients examined. PMR: Polymyalgia RheumaticaUltrasoundSymptomsCranial(n=17)PMR only(n=17)Non-specific symptoms (n=18)PMR (+) (n=7)PMR (-) (n=10)Temporal (+)7301Facial (+)2100Axilliary (+)0031

IntroductionThis study aims to elucidate the prognosis and the effectiveness of current treatments for Japanese patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA).MethodsPatients with newly diagnosed MPA and GPA were enrolled in a nationwide, prospective, inception cohort study from 22 tertiary Japanese institutions, and treatment patterns and responses were evaluated for 24 months. Primary outcome measures were rates of remission (Birmingham Vasculitis Activity Score, 0) and remission with low-dose glucocorticoids (GC) (prednisolone ≤ 10 mg) (GC remission).ResultsOf 156 enrolled patients, 78 MPA patients and 33 GPA patients were included. Concomitant cyclophosphamide (CY) was used in 24 MPA (31 %) and 20 GPA (60 %) patients during the initial 3 weeks of treatment. After 6 months, remission was achieved in 66 MPA (85 %) and 29 GPA (87 %) patients, while GC remission was obtained in only 31 MPA (40 %) and 13 GPA (39 %) patients. During the 24-month period, 14 MPA patients and 2 GPA patients died; end stage renal disease (ESRD) was noted in 13 MPA patients but no GPA patients. Patients with severe disease, according to the European Vasculitis Study Group (EUVAS) classification, showed poorer ESRD-free and overall survival rates than those with generalized disease (p < 0.0001). There were no differences in relapse-free survival rates between GPA and MPA, among EUVAS-defined disease severity categories, and between anti-neutrophil cytoplasmic antibody subspecialties.ConclusionsThe majority of Japanese patients with MPA and GPA received treatment with high-dose GC and limited CY use, and showed high remission and relapse-free survival rates but low GC remission rates in clinical practice.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry UMIN000001648. Registered 28 February 2009.

Increased Platelet S100A8/S100A9 Associated with Vasculitis in Granulomatosis with Polyangiitis (GPA)

Eye and/or orbit involvement occurs in Granulomatosis with polyangiitis (GPA) patients frequently. The aim of our study was to describe the clinical manifestations, therapy and outcome of ocular involvement in our GPA patients. A retrospective study was conducted including patients with GPA who followed up in Rheumatology clinics during 1990-2016 at King Khalid University Hospital, Riyadh. Information relating to demographics, ocular manifestations, laboratory findings, therapy and outcome of GPA patients were noted. Ocular involvement was detected in 9 (39.1%) of the 23 GPA cases identified. The mean age of ocular GPA patients was 51.8 (range 27 - 62) years, the mean age at onset of disease was 39.6 (range 11 - 57) years and the mean duration of disease was 9.0 (range 2 - 19) years. Concomitant ear, nose, throat and sino-nasal manifestations occurred with ocular symptoms in 77.8% GPA patients. The most frequent manifestations were, eye pain (66.7%), scleritis/episcleritis (55.6%), eye redness and itching (55.6% each). Antineutrophil cytoplasmic antibodies (ANCA) were positive in 88.9% patients, 55.6% had c-ANCA and 33.3% had p-ANCA. Infections were observed in 22.2% of patients, which included pneumonia in one patient and esophageal candidiasis and bacterial meningitis in another. All patients received oral prednisolone, 44.4% received intravenous cyclophosphamide, 22.2% refractory cases received rituximab doses and the disease outcome was good. Comparison of ocular GPA with non-ocular GPA patients showed that 77.8% of ocular GPA patients had concomitant sino-nasal symptoms compared to 42.9% in non-ocular GPA patients and 22.2% of the ocular GPA patients had renal involvement compared to 64.3% in non-ocular GPA patients (p = 0.049). We found that the frequency of ocular manifestations in our GPA patients was similar to reports elsewhere, and the most frequent symptom was eye pain and scleritis/episcleritis.

Background:Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), could appear at any age, but according to a recent meta-analysis,...

ObjectivesTo determine Bruton’s tyrosine kinase (BTK) protein and phosphorylation levels in B cell subsets of granulomatosis with polyangiitis (GPA) patients and to investigate the effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production.MethodsBTK protein and phosphorylation levels were determined by flow cytometry in peripheral blood B cells of 29 untreated GPA patients [9 active and 20 remission GPA patients (10 ANCA– and 10 ANCA+)], 9 age- and sex-matched healthy controls (HCs) and 9 untreated active RA patients. The effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production was determined in the same donors in peripheral blood mononuclear cell cultures.ResultsBTK protein levels were significantly increased in transitional and naïve B cells of active GPA and RA patients compared with remission GPA patients and HCs. Both B cell subsets of active patients were more sensitive to B cell receptor stimulation, as BTK and phospholipase Cγ2 phosphorylation were increased in these patients. In vitro BTK blockade had profound effects on B cell cytokine production, plasma cell formation and (auto)antibody production in both GPA patients and HCs. Interestingly, the effect of BTK blockade was less pronounced in active GPA patients, possibly due to increased activation of B cells.ConclusionWe show that BTK protein and phosphorylation levels are most profoundly increased in newly emerging B cells of active GPA patients compared with remission patients. BTK blockade greatly inhibits in vitro B cell effector functions in GPA patients and HCs. These promising data identify BTK as an interesting novel therapeutic target in the treatment of GPA.

Background:ANCA-associated vasculitis (AAV) is a multisystemic autoimmune disease with high mortality and morbidity.Objectives:We aimed to present the long-term follow-up results of our cohort.Methods:Data of patients who fulfilled Chapell Hill Consensus Criteria and followed up at least 6 months between 1999-2019 were analyzed. A standard form including vasculitis damage index (VDI) was used. Multivariable analysis was performed by using logistic regression.Results:Long-term data was available for 197 patients (%53.8 female) from 208 patient records. Mean age at diagnosis was 49.4 years and mean follow-up was 80.7 months. Granulomatosis with polyangiitis (GPA); microscopic polyangiitis (MPA), eosinophilic GPA (EGPA) were 117 (64.5%), 52 (26.4%), 17 (8.6%), respectively. Relapses are observed in 31.6% of patients. Disease relapses were higher in GPA compared to MPA and EGPA (p = 0.014). Relapse rate was higher in patients withs.aureuscarriage (p = 0.037). Cyclophosphamide (CYC) (76.6%) was most commonly used drug for induction, whereas azathioprine (57.3%) was used mostly in maintenance. In multivariate analysis relapse was found to be associated with maintenance treatment with rituximab (p &lt;0.001), venous thrombosis (p=0.046) and serious infection (p&lt;0.004). There was no significant association between relapse and mortality. Five-year survival rates were 98.5% for GPA, 88.5% for MPA and 100% for EGPA. Nineteen patients died during follow-up (9.6%). In univariate analysis mortality were high in MPA patients. Low hemoglobin and increased creatinine at baseline, subglottic stenosis, polyneuropathy, and cerebrovascular events (CVE) were associated with increased mortality. In multivariable analysis, mortality was associated with CVE (p=0.047) and anti-MPO positivity (p=0.014). Malignancy was developed in 9 patients (M / F: 7/2; two lung, three bladder, one cervix, one thyroid papillary, one kidney and one of unknown primary). There was no association between malignancy and cumulative dose of CYC. Venous thromboembolism was developed in 12 (6 %) and avascular necrosis (AVN) was detected in 30 patients (15.4%). Most (88.7%) patients developed damage during follow-up. Mean VDI score was 2.6 and VDI score was found to be higher in GPA (p= 0.035). There was no association between VDI score and mortality.Conclusion:In our AAV cohort, GPA was most frequent. Although survival was improved, permanent organ damage was detected in the majority of patients. Relapse and organ damage were found to be increased in patients with GPA. Relapses are frequent and maintenance with rituximab could not prevent relapses. Also relapses were associated with venous thrombosis and severe infections. Patients should be screened for malignancies especially of the genitourinary tract.Table 2.Damage findings of AAV patients according to VDIOrgan/systemNumber(%)Steroid myopathy23 (%11.7)Osteoporosis31 (%15.9)AVN30 (%15.4)Cataract30 (%15.4)Partial loss of vision6 (%3.1)Blindness (one eye)2 (%1)Subglottic stenosis9 (%4.5)Hearing loss18 (%9.1)Nasal septum perforation21 (%10,7)Chronic nasal crusting9 (%4,6)Chronic ashtma28 (%14,2)Chronic dispnea1 (%0,5)Hypertension60 (%30,5)Coronary artery disease / Angioplasty10 (%5,1)Cardiomyopathy6 (%3)Valvular heart disease5 (%2,5)Myocardial infarction7 (%3,6)Deep vein thrombosis12 (%6)Chronic renal failure (GFR &lt;50 ml/min)51 (%26)End stage renal disease22 (%10.8)Cerebrovascular accident9 (%4,4)Peripheric neuropathy39 (%19.8)Malignancy9 (%4.5)Diabetes mellitus24 (%12.2)Gonadal failure2 (%1)Figure 3.Cumulative Relapse Rate: Hazard ratio of patients treated with Rituximab versus Azathioprine (Log Rank: p&lt;0.001)Disclosure of Interests:None declared

BackgroundPersistent expansion of circulating CD4+ effector memory T cells (TEM) in patients with granulomatosis with polyangiitis (GPA) suggests their fundamental role in disease pathogenesis. Recent studies have shown that distinct functional CD4+ TEM cell subsets can be identified based on expression patterns of chemokine receptors. The current study aimed to determine different CD4+ TEM cell subsets based on chemokine receptor expression in peripheral blood of GPA patients. Identification of particular circulating CD4+ TEM cells subsets may reveal distinct contributions of specific CD4+ TEM subsets to the disease pathogenesis in GPA.MethodPeripheral blood of 63 GPA patients in remission and 42 age- and sex-matched healthy controls was stained immediately after blood withdrawal with fluorochrome-conjugated antibodies for cell surface markers (CD3, CD4, CD45RO) and chemokine receptors (CCR4, CCR6, CCR7, CRTh2, CXCR3) followed by flow cytometry analysis. CD4+ TEM memory cells (CD3+CD4+CD45RO+CCR7-) were gated, and the expression patterns of chemokine receptors CXCR3+CCR4-CCR6-CRTh2-, CXCR3-CCR4+CCR6-CRTh2+, CXCR3-CCR4+CCR6+CRTh2-, and CXCR3+CCR4-CCR6+CRTh2- were used to distinguish TEM1, TEM2, TEM17, and TEM17.1 cells, respectively.ResultsThe percentage of CD4+ TEM cells was significantly increased in GPA patients in remission compared to HCs. Chemokine receptor co-expression analysis within the CD4+ TEM cell population demonstrated a significant increase in the proportion of TEM17 cells with a concomitant significant decrease in the TEM1 cells in GPA patients compared to HC. The percentage of TEM17 cells correlated negatively with TEM1 cells in GPA patients. Moreover, the circulating proportion of TEM17 cells showed a positive correlation with the number of organs involved and an association with the tendency to relapse in GPA patients. Interestingly, the aberrant distribution of TEM1 and TEM17 cells is modulated in CMV- seropositive GPA patients.ConclusionsOur data demonstrates the identification of different CD4+ TEM cell subsets in peripheral blood of GPA patients based on chemokine receptor co-expression analysis. The aberrant balance between TEM1 and TEM17 cells in remission GPA patients, showed to be associated with disease pathogenesis in relation to organ involvement, and tendency to relapse.

Objective The complement cascade, especially the alternative pathway of complement, has been shown in basic research to be associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). We aimed to elucidate relationships between serum complement components and clinical characteristics in AAV. Method In a nationwide prospective cohort study (RemIT-JAV-RPGN), we measured the serum levels of C1q, C2, C3, C3b/iC3b, C4, C4b, C5, C5a, C9, factor B, factor D, factor H, factor I, mannose-binding lectin, and properdin in 52 patients with microscopic polyangiitis (MPA) and 39 patients with granulomatosis with polyangiitis (GPA). Results The properdin level of MPA and GPA was significantly lower than that of healthy donors. The properdin level was negatively correlated with the Birmingham Vasculitis Activity Score (BVAS) (ρ = −0.2148, p = 0.0409). The factor D level at 6 months was significantly positively correlated with the Vasculitis Damage Index (VDI) at 6, 12, and 24 months (ρ = 0.4207, 0.4132, and 0.3115, respectively). Patients with a higher ratio of C5a to C5 had higher neutrophil percentage and serum immunoglobulin G levels, and significantly lower creatinine levels. Cluster analysis divided the MPA and GPA patients into three subgroups. A principal component (PC) analysis aggregated 15 types of complements into alternative pathway-related PC 1 and complement classical pathway and common pathway-related PC 2. Conclusions The serum levels of properdin and factor D were correlated with the BVAS and the VDI in MPA and GPA, respectively. Our analyses suggested the pathological heterogeneity of MPA and GPA from the aspect of complement components.

In this study we aimed to compare the effectiveness and safety of rituximab, mycophenolate mofetil (MMF), methotrexate (MTX), and cyclophosphamide (CYC) with azathioprine (AZA) for maintenance treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We searched MEDLINE, EMBASE, and Cochrane databases to retrieve randomized controlled trials (RCTs) examining the efficacy and safety of rituximab, MMF, MTX, CYC, and AZA for maintenance therapy in AAV patients. We applied a random-effects, meta-analytic model in all calculations. We performed a Bayesian fixed-effects network meta-analysis to combine direct and indirect evidence from RCTs. The primary effectiveness outcome was the number of patients who experienced relapse during the maintenance phase, while the primary safety outcome was the number of serious infections. Five RCTs including 667 patients were included. Rituximab demonstrated lower relapse rates than MMF (odds ratio (OR), 0.16; credible interval (CrI), 0.07-0.38). Surface under the cumulative ranking curve (SUCRA)-based likelihood rating revealed that rituximab had the probability of being the best relapse-lowering therapy, followed by CYC, MTX, AZA, and MMF. In SUCRA-based likelihood rating, rituximab showed the greatest probability of being the best major relapse-based therapy, followed by CYC, AZA, and MMF. MMF showed a lower risk of serious infection than MTX did (OR, 0.04, 95% CrI, 0.00-0.53). SUCRA-based rating probability revealed MMF was likely the safest treatment with the lowest incidence of serious infection, followed by CYC, AZA, rituximab, and MTX, although the difference was only significant between MMF and MTX. Rituximab may be an effective relapse-lowering, maintenance treatment for patients with AAV, and MMF showed the lowest rate of serious infections among the drugs investigated.

Azathioprine (AZA), methotrexate, or rituximab is used for the maintenance therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Although the efficacy of tacrolimus (TAC) in various autoimmune diseases has been demonstrated, there have been few reports on the efficacy of TAC in AAV. We investigated the efficacy of TAC as maintenance therapy for AAV and compared its efficacy with that of AZA.We retrospectively analyzed the medical records of 81 patients with AAV who received cyclophosphamide as induction therapy and AZA or TAC as maintenance therapy. All-cause death, relapse, and progression to end-stage renal disease (ESRD) were analyzed.Among 81 patients with AAV, 69 patients received AZA alone, 6 patients received TAC alone, and 6 patients received TAC after AZA for maintenance therapy. Overall, 11 patients (13.6%) died, 30 patients (37.0%) experienced relapse, and 16 patients (19.8%) progressed to ESRD during a median of 33.8 months. No significant differences were observed in cumulative patients’, relapse-free, and ESRD-free survival rates between patients administered AZA alone and TAC alone. There were no significant differences in the cumulative patients’ and relapse-free survival rate between patients who received AZA alone and TAC after AZA. However, the cumulative ESRD-free survival rate was lower in patients who received TAC after AZA than in those who received AZA alone (P = .027).Patients who received TAC as maintenance therapy showed a higher incidence of ESRD than those who received AZA; however, this might be attributed to the lack of efficacy of AZA rather than the low ESRD prevention effect of TAC.

This study aimed to evaluate dialysis and transplant outcomes of patients with ESRD secondary to ANCA-associated vasculitis (AAV). All ESRD patients who commenced renal replacement therapy in Australia and New Zealand between 1996 and 2010 were included. Outcomes were assessed by Kaplan-Meier, multivariable Cox regression, and competing-risks regression survival analyses. Of 36,884 ESRD patients, 228 had microscopic polyangiitis (MPA) and 221 had granulomatosis with polyangiitis (GPA). Using competing-risks regression, compared with other causes of ESRD, MPA patients (hazard ratio [HR], 0.89; 95% confidence interval [95% CI], 0.73-1.08; P=0.24) and GPA patients (HR, 0.94; 95% CI, 0.74-1.19; P=0.62) experienced comparable survival on dialysis. Forty-six MPA patients (21%) and 47 GPA (20%) patients received 98 renal allografts. Respective 10-year first graft survival rates in MPA, GPA, and non-AAV patients were 50%, 62%, 70%, whereas patient survival rates were 68%, 85% and 83%, respectively. Compared with non-AAV patients, MPA transplant recipients had higher risks of graft failure (HR, 1.87; 95% CI, 1.07-3.25; P=0.03) and death (HR, 1.94; 95% CI, 1.02-3.69; P=0.04), whereas GPA transplant recipients experienced comparable renal allograft survival (HR, 0.91; 95% CI, 0.43-1.93; P=0.81) and patient survival (HR, 0.58; 95% CI, 0.23-2.27; P=0.58). AAV recurrence was observed in two renal allografts (2%). Compared with ESRD patients without AAV, those with GPA have comparable renal replacement therapy outcomes, whereas MPA patients have comparable dialysis survival but poorer renal transplant allograft and patient survival rates.

A case of systemic lupus erythematosus with cutaneous granulomatous vasculitis