Merkel, Peter A.

Objective This study aims to identify factors associated with patient global assessment (PtGA) and physician global assessment (PhGA) and discordance between them in systemic sclerosis (SSc). Methods Data from adults with early SSc (<5 years) from the Collaborative National Quality and Efficacy Registry were included. PtGA and PhGA (0–10 scale), clinical evaluations, and patient‐reported outcomes (PROs) were collected every six months. Multivariable mixed‐effects linear regression identified factors associated with PtGA and PhGA using (1) clinical variables and (2) clinical variables plus PROs. Relative weight analysis (RWA) determined the relative importance of each variable. Discordance (≥2 points between PtGA and PhGA) was assessed using multinomial mixed‐effects logistic regression. Results Among 956 patients (83% women, 33% limited disease), mean PtGA and PhGA at enrollment were 4.2 (SD 2.6) and 3.4 (SD 2.0), respectively ( P < 0.001). RWA of clinical variables identified modified Rodnan skin score (mRSS) and New York Heart Association (NYHA) functional class as most influential for both global assessments. After including PROs, PtGA was most influenced by measures of pain, skin symptoms, and physical function. Discordance occurred in 53% of patients (35% PtGA worse, 18% PhGA worse). Worse PtGA was associated with higher overall pain and discomfort. Worse PhGA was associated with higher mRSS, worse NYHA class, higher pain interference, and lower diffusing capacity of the lung. Conclusion Discordance between PtGA and PhGA occurs commonly, highlighting the need for comprehensive symptom management and measurement of disease burden in this complex disease. In SSc, differences in PtGA and PhGA reflect dissimilar weighting of data elements.

Objective The objective of the study was to determine risk factors for relapse of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) after reinduction of remission with rituximab and discontinuation of maintenance therapy. Methods This is a post hoc analysis of the RITAZAREM clinical trial. Patients aged 15 years or older with AAV and a positive test for anti–proteinase‐3 or anti‐myeloperoxidase‐ANCA who achieved remission after reinduction with rituximab and glucocorticoids were randomized at month 4 to receive continued rituximab or azathioprine for a maintenance period up to 24 months, followed by observation until relapse or up to 48 months. Generalized estimating equations logistic regression identified baseline and time‐varying risk factors for relapse by the next visit for the two study phases: maintenance (months 4–24) and off‐treatment (months 24–48). Results Among 170 patients (median [interquartile range] age 59 [48–68] years, disease duration 5 [2–10] years), 99 relapses occurred (46 during maintenance). During maintenance, musculoskeletal involvement (odds ratio [OR]: 2.8, 95% confidence interval [CI]: 1.1–7.2; P = 0.03) and higher patient global assessment (OR: 1.1, 95% CI: 1.0–1.2; P = 0.04) were associated with relapse. During the off‐treatment phase, presence of CD19 + B cells (OR: 2.5, 95% CI: 1.2–5.1; P = 0.01) and reappearance of ANCA (OR: 3.2, 95% CI: 1.3–7.7; P = 0.01) were each associated with higher relapse risk. Multivariable analysis identified markers of inflammation (changes in platelets, white blood cells, and IgA) associated with relapse. Conclusion Risk factors for relapse in AAV vary by treatment phase. Monitoring markers of inflammation and immune reconstitution may identify patients at risk for relapse, particularly after treatment withdrawal.

ObjectiveIn the phase 3 head‐to‐head MANDARA study (NCT04157348), benralizumab demonstrated noninferiority to mepolizumab in inducing remission (defined as Birmingham Vasculitis Activity Score [BVAS] of 0 and oral glucocorticoid [OGC] dosage ≤4 mg/day at weeks 36 and 48) in patients with eosinophilic granulomatosis with polyangiitis (EGPA). This analysis investigated a more stringent definition of remission that included discontinuation of OGCs and being relapse‐free.MethodsPatients aged ≥18 years with documented relapsing or refractory EGPA receiving OGCs at ≥7.5 mg/day with or without immunosuppressive therapy for ≥4 weeks before enrollment were randomized (1:1) to benralizumab at 30 mg or mepolizumab at 300 mg subcutaneously every 4 weeks for 52 weeks. The proportion of patients achieving remission off OGCs, defined as BVAS of 0, OGC dose of 0 mg/day (at weeks 36 and 48) and no relapses during the double‐masked period, was assessed.ResultsPatients (n = 140) were randomized to benralizumab (n = 70) or mepolizumab (n = 70). The adjusted percentage of patients with remission off OGCs was 23.5% (n = 16) with benralizumab versus 11.1% (n = 8) with mepolizumab (difference 12.47 [95% confidence interval 0.46–24.48], P = 0.042). Of those who achieved remission off OGCs, 100% of benralizumab‐treated patients and 98.6% of mepolizumab‐treated patients achieved remission within the first 36 weeks of treatment.ConclusionThe administration of anti–interleukin‐5/receptor (IL‐5/R) therapies, benralizumab and mepolizumab, enable discontinuation of OGCs in some patients with EGPA, while avoiding relapses. These findings suggest that adding anti‐IL‐5/R therapy to standard primary treatment for patients with EGPA may improve response.

Objective To compare the efficacy of abatacept to placebo for the treatment of relapsing, nonsevere granulomatosis with polyangiitis (GPA). Methods In this multicenter trial, eligible patients with relapsing, nonsevere GPA were randomized to receive abatacept 125 mg subcutaneously once a week or placebo, both together with prednisone 30 mg/day (or equivalent), tapered and discontinued at week 12. Patients already taking methotrexate, azathioprine, mycophenolate, or leflunomide continued this medication at a stable dose. Patients achieving remission remained on their randomized assignment until relapse, early termination, or the common close date 12 months after enrollment of the last patient. Those who had a nonsevere relapse, had nonsevere worsening, or were not in remission by month 6 had the option to receive open‐label abatacept. The primary end point was the rate of treatment failure, defined as relapse, disease worsening, or failure to achieve a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 0 or 1 by six months. Results Sixty‐five patients were randomized; 34 received abatacept and 31 received placebo. No statistical difference in the treatment failure rate was found between those who received abatacept and those who received placebo ( P = 0.853). Treatment with abatacept did not demonstrate any statistical difference from placebo in key secondary end points, including time to full remission (BVAS/WG = 0), duration of glucocorticoid‐free remission, relapse severity, prevention of damage, and patient‐reported quality‐of‐life outcomes. There was no difference in the frequency or severity of adverse events between treatment arms, including infection. Conclusion In patients with relapsing, nonsevere GPA, abatacept did not reduce the risk of relapse, severe worsening, or failure to achieve remission.

Abstract Rationale: The 1-year double-blind period of the MANDARA trial (NCT04157348) demonstrated non-inferiority of benralizumab to mepolizumab for achieving remission, in adults with relapsing/refractory eosinophilic granulomatosis with polyangiitis (EGPA). Here, we report the 2-year combined double-blind and ongoing open-label extension (OLE) data. Methods: On completion of the double-blind period (n=136/140) comparing benralizumab 1x30mg versus mepolizumab 3x100mg subcutaneously every 4 weeks, patients were invited to enter the OLE where they continued benralizumab (benra/benra) or switched from mepolizumab to benralizumab (mepo/benra). Endpoints included remission (Birmingham Vasculitis Activity Score=0 and oral glucocorticoid [OGC[ dose ≤4 mg/day), OGC use, relapse, blood eosinophil count (bEOS), Asthma Control Questionnaire (ACQ-6), pre-bronchodilator forced expiratory volume in 1 second (pre-BD FEV1), and safety. Results: In total, 128 patients entered the OLE (n=66 benra/benra, n=62 mepo/benra; mean age 52.8 years; 60.2% female), and 119 completed OLE Year 1. Baseline characteristics of those entering the OLE were similar to the double-blind period. At Week 104, over 60% in both groups (41 [62.1%] benra/benra and 42 [67.7%] mepo/benra patients) achieved remission. During the OLE, 51 (77.3%) benra/benra and 42 (67.7%) mepo/benra patients had no relapses. The percentage of benra/benra patients who discontinued OGCs was similar at Weeks 49-52 (27 [40.9%]) and Weeks 101-104 (29 [43.9%]), while the percentage increased for mepo/benra patients between Weeks 49-52 (16 [25.8%]) and Weeks 101-104 (27 [43.5%]; Figure). The median (IQR) OGC dose at Weeks 101-104 was 0.5 (0,5) in benra/benra and 1.36 (0,5) mg/day in mepo/benra patients. The median (IQR) bEOS in benra/benra patients was 20 (10,40) cells/µL at both Weeks 52 and 100; bEOS were depleted in mepo/benra patients from 70 (40,90) cells/µL to 20 (10,50) cells/µL by 4 weeks after switching. Mean (SD) ACQ-6 scores were 0.64 (0.78) in benra/benra patients and 0.60 (0.76) in mepo/benra patients at Week 104 compared with 1.39 (1.18) and 1.11 (0.95) at baseline. Mean (SD) pre-BD FEV1 was 2.59 (0.90) L versus 2.62 (0.84) L in benra/benra versus mepo/benra patients at Week 52, and 2.61 (0.90) versus 2.63 (0.81) L, at Week 100. Safety of mepolizumab and benralizumab was consistent with their known profiles. Conclusions: In patients with EGPA receiving benralizumab, remission rates, OGC discontinuation, and bEOS depletion were durable over 104 weeks with low relapse rates, and without loss of asthma control or lung function decline. Additional bEOS depletion and OGC sparing was observed in patients switching from mepolizumab to benralizumab.

ObjectiveThe ADVOCATE trial demonstrated that treatment of active granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) with avacopan was noninferior in achieving remission at week 26 and superior for sustained remission at week 52 compared with a prednisone taper. This analysis of ADVOCATE evaluated the efficacy and safety of avacopan in patients with ear, nose, throat (ENT), or lung manifestations.MethodsThis post hoc analysis included patients enrolled in ADVOCATE with ENT or lung manifestations at baseline. Outcomes included remission at weeks 26 and 52, respiratory tract manifestations over time, relapse rate, glucocorticoid‐related toxicity, health‐related quality of life (HRQoL), and safety.ResultsADVOCATE included 144 patients with ENT manifestations (avacopan: n = 75, prednisone taper: n = 69) and 142 with lung manifestations (avacopan: n = 71, prednisone taper: n = 71). Among patients with ENT manifestations, remission was achieved at week 26 by 72.0% (avacopan group) and 71.0% (prednisone taper group) and was sustained at week 52 by 62.7% (avacopan) and 53.6% (prednisone taper). Among patients with lung manifestations, remission was achieved at week 26 by 73.2% (avacopan) and 66.2% (prednisone taper) and sustained at week 52 by 67.6% (avacopan) and 53.5% (prednisone taper). The relapse rate, glucocorticoid toxicity, and measures of HRQoL favored avacopan for both respiratory tract manifestation groups. Safety was comparable across treatment groups.ConclusionPatients with GPA or MPA with ENT or lung manifestations demonstrated similar responses to avacopan, reflecting results reported in the overall ADVOCATE trial population and supporting the administration of avacopan in these subgroups.

Abstract Objectives There are an increasing number of centres performing research on high-resolution vessel wall magnetic resonance imaging (VW-MRI) in GCA. However, harmonized approaches to VW-MRI in GCA are lacking and are essential to performing multicentre studies. Using a data-driven, consensus-based approach, an international expert group developed a standardized MRI protocol and scoring system to advance multi-centred research in cranial GCA. Methods A targeted literature review of VW-MRI in cranial GCA was conducted. A working group comprised of radiologists, rheumatologists and ophthalmologists with expertise in VW-MRI and GCA reviewed the results of the literature search, presented relevant data and images from their respective centres, and then reached consensus on recommendations related to key MRI structures, MRI sequences, scoring system and other important considerations. Results A total of 21 relevant articles were identified and reviewed. Based on published literature, structures to be evaluated on MRI were categorized based on anatomic location (extradural cranial, intradural cranial and orbits) and prioritization (core vs elective). Essential and elective sequences to comprehensively image cranial and orbital structures while minimizing scan time were determined along with scoring systems to grade contrast enhancement. Conclusion This report describes a standardized approach to facilitate research of VW-MRI in cranial GCA that is the result of a multidisciplinary, international collaboration of experts in VW-MRI and/or GCA.

Abstract Objectives To evaluate damage and clinical characteristics associated with damage in Takayasu’s arteritis (TAK). Methods Patients with TAK enrolled in a multicentre, prospective, observational study underwent standardized damage assessment every 6 months using the Vasculitis Damage Index (VDI) and the Large-Vessel Vasculitis Index of Damage (LVVID). Results The study included 236 patients with TAK: 92% female, 81% Caucasian; median (25th, 75th percentile) disease duration = 2.6 (0.12, 6.9) years. Eighty-four percent had follow-up: median (25th, 75th) duration 4.1 (1.9, 7.5) years. Items of damage were present in 89% on VDI, 87% on LVVID, in the peripheral vascular (76% VDI, 74% LVVID) and cardiac (40% VDI, 45% LVVID) systems. During follow-up, 42% patients had new damage, including major vessel stenosis/arterial occlusion (8%), limb claudication (6%), hypertension (7%), aortic aneurysm (4%) and bypass surgery (4%). Disease-specific damage accounted for &gt;90% of new items. Older age, relapse and longer duration of follow-up were associated with new damage items; a higher proportion of patients without new damage were on MTX (P &lt;0.05). Among 48 patients diagnosed with TAK within 180 days of enrolment, new damage occurred in 31% on VDI and 52% on LVVID. History of relapse was associated with new damage in the entire cohort while in patients with a recent diagnosis, older age at diagnosis was associated with new damage. Conclusion Damage is present in &gt;80% of patients with TAK even with recent diagnosis and &gt;40% of patients accrue new, mainly disease-specific damage. Therapies for TAK that better control disease activity and prevent damage should be prioritized.