Citations

ObjectiveTo examine the relationship of antineutrophil cytoplasmic antibody (ANCA) type and ANCA‐associated vasculitis (AAV) diagnosis with demographic features, disease manifestations, and clinical outcomes. We focused on patients who account for the differences between ANCA type and disease type classifications: anti‐myeloperoxidase (MPO)–ANCA–positive and ANCA‐negative patients with granulomatosis with polyangiitis (Wegener's) (GPA).MethodsWe performed a pooled analysis of the Wegener's Granulomatosis Etanercept Trial and the Rituximab in ANCA‐Associated Vasculitis trial comparing patients with MPO‐ANCA–positive GPA and patients with ANCA‐negative GPA to patients with proteinase 3 (PR3)–ANCA–positive GPA and patients with MPO‐ANCA–positive microscopic polyangiitis (MPA).ResultsOf the 365 patients analyzed, 273 (75%) had PR3‐ANCA–positive GPA, 33 (9%) had MPO‐ANCA–positive GPA, 15 (4%) had ANCA‐negative GPA, and 44 (12%) had MPO‐ANCA–positive MPA. MPO‐ANCA–positive GPA patients were younger at diagnosis compared to MPO‐ANCA–positive MPA patients (53 versus 61 years; P = 0.02). Their disease manifestations and rates of relapse were similar to those of PR3‐ANCA–positive GPA patients. Relapse was more frequent in MPO‐ANCA–positive GPA patients than in patients with MPO‐ANCA–positive MPA at trial entry as well as at 12 and 18 months. ANCA‐negative patients with GPA had lower Birmingham Vasculitis Activity Score for Wegener's Granulomatosis scores at trial entry than PR3‐ANCA–positive patients with GPA (4.5 versus 7.7; P < 0.01), primarily because of a lower prevalence of renal involvement.ConclusionWe were unable to demonstrate important clinical differences between MPO‐ANCA–positive and PR3‐ANCA–positive patients with GPA. The risk of relapse was associated more closely with disease type than with ANCA type in this patient cohort. These findings deserve consideration in the assessment of relapse risk in patients with AAV.

Review of 112 patients with Wegener's granulomatosis showed that 21 (19%) had ear involvement. Conductive deafness, which was present in all 21 patients, was due to serous middle ear fluid, suppurative otitis media with thickening of the tympanic membrane, perforation of the tympanic membrane, or granulation tissue in the middle ear space. Nine patients also had sensorineural hearing loss. Sensorineural hearing loss was improved in five of the nine patients after control of the disease with prednisone and cyclophosphamide.

BackgroundGiven the success of immunotherapeutic approaches in hematologic malignancies, the COG designed a phase I/II study to determine whether the addition of epratuzumab (anti‐CD22) to an established chemotherapy platform improves rates of second remission (CR2) in pediatric patients with B‐lymphoblastic leukemia (B‐ALL) and early bone marrow relapse.ProcedureTherapy consisted of three established blocks of re‐induction chemotherapy. Epratuzumab (360 mg/m2/dose) was combined with chemotherapy on weekly × 4 (B1) and twice weekly × 4 [eight doses] (B2) schedules during the first re‐induction block. Remission rates and minimal residual disease (MRD) status were compared to historical rates observed with the identical chemotherapy platform alone.ResultsCR2 was achieved in 65 and 66%, of the evaluable B1 (n = 54) and B2 patients (n = 60), respectively; unchanged from that observed historically without epratuzumab. Rates of MRD negativity (<0.01%) were 31% in B1 (P = 0.4128) and 39% in B2 patients (P = 0.1731), compared to 25% in historical controls. The addition of epratuzumab was well tolerated, with a similar toxicity profile to that observed with the re‐induction chemotherapy platform regimen alone.ConclusionsEpratuzumab was well tolerated in combination with re‐induction chemotherapy. While CR2 rates were not improved compared to historical controls treated with chemotherapy alone, there was a non‐significant trend towards improvement in MRD response with the addition of epratuzumab (twice weekly for eight doses) to re‐induction chemotherapy. Pediatr Blood Cancer 2015;62:1171–1175. © 2015 Wiley Periodicals, Inc.

ObjectiveTo 1) describe the distribution of patient global assessment (PtGA) scores of disease activity in patients with granulomatosis with polyangiitis (GPA; Wegener's), 2) explore the discordance between PtGA scores and physician global assessment (PhGA) scores of disease activity, and 3) explore whether PtGA scores during disease remission are associated with future disease relapse.MethodsData from the Wegener's Granulomatosis Etanercept Trial (WGET) were used. PtGA and PhGA scores were assessed on 100‐mm visual analog scales (VAS). Presence of active disease was determined using the Birmingham Vasculitis Activity Score for WG (BVAS/WG), and remission was defined as a BVAS/WG score of 0. Disease relapse was defined as a BVAS/WG score of >0 after remission had been achieved. Discordance between PtGA and PhGA scores was defined as a difference of ≥20 points between the two measures. Mixed linear models were used in longitudinal analysis of PtGA scores.ResultsData were obtained from 180 patients in the WGET cohort, seen at a total of 1,719 study visits. The mean ± SD PtGA and PhGA disease activity scores (on 100‐mm VAS) at baseline were 64.2 ± 27.4 and 55.5 ± 23.4, respectively. PtGA–PhGA discordance occurred in 53% of patients at baseline, and this was inversely associated with newly diagnosed disease (as opposed to relapsing disease) at baseline (odds ratio 0.37, 95% confidence interval [95% CI] 0.20–0.68) but not with age, sex, or presence of renal or pulmonary disease. Patients were in disease remission during 62% of the study visits. The mean PtGA score during visits immediately prior to relapse was 4.52 points higher (95% CI 0.66–8.4) than that at other remission visits (P = 0.03).ConclusionPtGA–PhGA discordance is common in GPA. A rise in the PtGA disease activity score during times defined by physicians as periods of remission is associated with subsequent occurrence of disease relapse. These findings support the addition of PtGA as an outcome measure for GPA.

ObjectiveTo identify genetic determinants of granulomatosis with polyangiitis (Wegener's) (GPA).MethodsWe carried out a genome‐wide association study (GWAS) of 492 GPA cases and 1,506 healthy controls (white subjects of European descent), followed by replication analysis of the most strongly associated signals in an independent cohort of 528 GPA cases and 1,228 controls.ResultsGenome‐wide significant associations were identified in 32 single‐nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA–DPB1 and HLA–DPA1 genes encoding the class II major histocompatibility complex (MHC) DPβ chain 1 and DPα chain 1 proteins, respectively. Peak association signals in these 2 genes, emanating from SNPs rs9277554 (for DPβ chain 1) and rs9277341 (DPα chain 1) were strongly replicated in an independent cohort (in the combined analysis of the initial cohort and the replication cohort, P = 1.92 × 10−50 and 2.18 × 10−39, respectively). Imputation of classic HLA alleles and conditional analyses revealed that the SNP association signal was fully accounted for by the classic HLA–DPB1*04 allele. An independent single SNP, rs26595, near SEMA6A (the gene for semaphorin 6A) on chromosome 5, was also associated with GPA, reaching genome‐wide significance in a combined analysis of the GWAS and replication cohorts (P = 2.09 × 10−8).ConclusionWe identified the SEMA6A and HLA–DP loci as significant contributors to risk for GPA, with the HLA–DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of GPA.