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Objective: Fixed and tailored rituximab retreatment strategies to maintain remission in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) are associated with tradeoffs. The current study was undertaken to develop a simulation model (AAV‐Sim) to project clinical outcomes with these strategies. Methods: We developed the AAV‐Sim, a microsimulation model of clinical events among individuals with AAV initiating treatment to maintain remission. Individuals transition between health states of remission or relapse and are at risk for severe infection, end‐stage renal disease, or death. We estimated transition rates from published literature, stratified by individual‐level characteristics. We performed validation using the mean average percent error (MAPE) and the coefficient of variation of root mean square error (CV‐RMSE). In internal validation, we compared model‐projected outcomes over 28 months with outcomes observed in the Rituximab versus Azathioprine in ANCA‐Associated Vasculitis 2 (MAINRITSAN2) trial, which compared fixed versus tailored retreatment. In external validation, we compared outcomes with fixed rituximab retreatment from the AAV‐Sim to outcomes from the MAINRITSAN1 trial and an observational study. Results: The AAV‐Sim projected outcomes similar to those in the MAINRITSAN2 trial, including minor (AAV‐Sim 6.0% fixed versus 7.3% tailored; MAINRITSAN2 6.2% versus 8.6%; MAPE 3% and 15%) and major relapse (AAV‐Sim 3.5% versus 5.5%; MAINRITSAN2 3.7% versus 7.4%; MAPE 5% and 26%), severe infection (AAV‐Sim 19.4% versus 11.1%; MAINRITSAN2 19.8% versus 10.2%; MAPE 2% and 9%), and relapse‐free survival (AAV‐Sim 84.8% versus 82.3%; MAINRITSAN2 86% versus 84%; CV‐RMSE 2.3% and 2.5%). Similar performance was observed in external validation. Conclusion: The AAV‐Sim projected a range of clinical outcomes for different treatment approaches that were validated against published data. The AAV‐Sim has the potential to inform management guidelines and research priorities. [ABSTRACT FROM AUTHOR]

Objective: To compare rituximab‐ versus cyclophosphamide‐based remission induction strategies for the long‐term risks of kidney failure and death in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) in a real‐world cohort. Methods: We performed a cohort study using the Mass General Brigham AAV Cohort, which includes proteinase 3–ANCA+ and myeloperoxidase (MPO)‐ANCA+ AAV patients diagnosed from January 1, 2002 to December 31, 2019. We included cases in which the initial remission induction strategy was based either on rituximab or cyclophosphamide. The primary outcome was the composite outcome of kidney failure or death. We used multivariable Cox proportional hazards models and propensity score–matched analyses to assess the association of rituximab‐ versus cyclophosphamide‐based treatment strategies with the composite outcome of kidney failure or death. Results: Of 595 included patients, 352 patients (~60%) received rituximab‐based and 243 patients (~40%) received cyclophosphamide‐based regimens. The mean age was 61 years, 58% of patients were female, 70% of patients were MPO‐ANCA+, and 69% of patients had renal involvement (median estimated glomerular filtration rate 37.3 ml/minute/1.73 m2). There were 133 events at 5 years, and the incidence rates in rituximab‐ and cyclophosphamide‐based regimens were 6.8 and 6.1 per 100 person‐years, respectively. The risk of kidney failure or death was similar in both groups in multivariable‐adjusted analyses (hazard ratio [HR] 1.03 [95% confidence interval (95% CI) 0.55–1.93]) and in propensity score–matched analyses (HR 1.05 [95% CI 0.55–1.99]) at 5 years. Our findings were similar when outcomes were assessed at 1 and 2 years as well as in subgroups stratified according to renal involvement and severity as well as major organ involvement. Conclusion: Rituximab‐ and cyclophosphamide‐based remission induction strategies for AAV are associated with similar risks of kidney failure and death. [ABSTRACT FROM AUTHOR]

Objective: Proteinase 3 (PR3) is the major antigen for antineutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3‐targeting ANCAs (PR3‐ANCAs) recognize different epitopes on PR3. This study was undertaken to study the effect of mutations on PR3 antigenicity. Methods: The recombinant PR3 variants, iPR3 (clinically used to detect PR3‐ANCAs) and iHm5 (containing 3 point mutations in epitopes 1 and 5 generated for epitope mapping studies) immunoassays and serum samples from patients enrolled in ANCA‐associated vasculitis (AAV) trials were used to screen for differential PR3‐ANCA binding. A patient‐derived monoclonal ANCA 518 (moANCA518) that selectively binds to iHm5 within the mutation‐free epitope 3 and is distant from the point mutations of iHm5 was used as a gauge for remote epitope activation. Selective binding was determined using inhibition experiments. Results: Rather than reduced binding of PR3‐ANCAs to iHm5, we found substantially increased binding of the majority of PR3‐ANCAs to iHm5 compared to iPR3. This differential binding of PR3‐ANCA to iHm5 is similar to the selective moANCA518 binding to iHm5. Binding of iPR3 to monoclonal antibody MCPR3‐2 also induced recognition by moANCA518. Conclusion: The preferential binding of PR3‐ANCAs from patients, such as the selective binding of moANCA518 to iHm5, is conferred by increased antigenicity of epitope 3 on iHm5. This can also be induced on iPR3 when captured by monoclonal antibody MCPR2. This previously unrecognized characteristic of PR3‐ANCA interactions with its target antigen has implications for studying antibody‐mediated autoimmune diseases, understanding variable performance characteristics of immunoassays, and design of potential novel treatment approaches. [ABSTRACT FROM AUTHOR]

Objective: Autoreactive B cells are responsible for antineutrophil cytoplasmic antibody (ANCA) production in ANCA‐associated vasculitis (AAV). Rituximab (RTX) depletes circulating B cells, including autoreactive B cells. We aimed to evaluate changes and associations with relapse of the circulating autoreactive B cell pool following therapeutic B cell depletion in AAV. Methods: Sequential flow cytometry was performed on 148 samples of peripheral blood mononuclear cells from 23 patients with proteinase 3 (PR3)–ANCA–positive AAV who were treated with RTX for remission induction and monitored after stopping therapy during long‐term follow‐up in a prospective clinical trial. PR3 was used as a ligand to target autoreactive PR3‐specific (PR3+) B cells. B cell recurrence was considered as the first blood sample with ≥10 B cells/μl after RTX treatment. Results: At B cell recurrence, PR3+ B cell frequency among B cells was higher than baseline (P < 0.01). Within both PR3+ and total B cells, frequencies of transitional and naive subsets were higher at B cell recurrence than at baseline, while memory subsets were lower (P < 0.001 for all comparisons). At B cell recurrence, frequencies of B cells and subsets did not differ between patients who experienced relapse and patients who remained in remission. In contrast, the plasmablast frequency within the PR3+ B cell pool was higher in patients who experienced relapse and associated with a shorter time to relapse. Frequencies of PR3+ plasmablasts higher than baseline were more likely to be found in patients who experienced relapse within the following 12 months compared to those in sustained remission (P < 0.05). Conclusion: The composition of the autoreactive B cell pool varies significantly following RTX treatment in AAV, and early plasmablast enrichment within the autoreactive pool is associated with future relapses. [ABSTRACT FROM AUTHOR]

Objective: To study the longitudinal effects of both glucocorticoids and tocilizumab, an interleukin‐6 receptor inhibitor, on hemoglobin A1c (HbA1c) levels during glucocorticoid tapering. Methods: We analyzed patients with complete data from the Giant Cell Arteritis Clinical Research Study (GiACTA) to investigate the impact of both glycemic and nonglycemic factors on changes in HbA1c levels over the 52‐week trial. Giant cell arteritis (GCA) patients were randomized to receive either tocilizumab or placebo in addition to glucocorticoids. We used a multivariable mixed‐effects model to evaluate associations of HbA1c level with daily glucocorticoid dose, randomization to receive tocilizumab, and red blood cell count in patients with and those without diabetes mellitus at baseline, over 52 weeks. Results: In 209 patients, the median HbA1c level decreased by 0.50% (P < 0.01) in the group that received both tocilizumab and glucocorticoids (tocilizumab/glucocorticoid) and by 0.10% (P < 0.01) in the glucocorticoid‐only group. Randomization to tocilizumab/glucocorticoid was associated with lower HbA1c (β = −0.209% in those without diabetes, P < 0.01; β = −0.290% in those with diabetes, P = 0.23). These changes had a sizable impact on glucose tolerance classification: 42.5% of patients in the tocilizumab/glucocorticoid group improved from prediabetes status to normal, compared to only 12.5% of patients treated with glucocorticoids alone. Daily glucocorticoid dose was associated with HbA1c level in patients with baseline diabetes (β = 0.018%/mg, P < 0.01) and those without baseline diabetes (β = 0.005%/mg, P < 0.01). Conclusion: Tocilizumab treatment was associated with a substantial reduction in HbA1c level, independent of glucocorticoid exposure, which may be achieved through a combination of glycemic and nonglycemic effects. [ABSTRACT FROM AUTHOR]

Objective: Giant cell arteritis (GCA) requires treatment with high‐dose, long‐term glucocorticoids (GCs). A score assessing and quantifying patients' baseline GC‐related toxicity may be important to risk stratification and therapeutic decision‐making in patients initiating immunosuppression. Methods: We analyzed patients with GCA enrolled in the Tocilizumab in Giant Cell Arteritis (GiACTA) trial. Baseline GC‐related toxicity scores for 12 domains were derived from the Glucocorticoid Toxicity Index using baseline medications, medical history, vital signs, and laboratory values. The 12 domains examined were body mass index, glucose tolerance, blood pressure, lipid metabolism, bone and/or tendon, GC myopathy, skin toxicity, neuropsychiatric effects, infection, ocular toxicity, gastrointestinal injury, and adrenal function. Potential scores ranged from 0 to 538. We compared differences between those with newly diagnosed versus relapsing disease at baseline. Results: A total of 250 patients were included (75% female, mean age 69 years). The mean ± SD baseline GC‐related toxicity score among all patients was 111.3 ± 53.2. The domains that contributed most to the overall scores were blood pressure (24.0% of the overall score), followed by glucose tolerance (22.6%) and neuropsychiatric effects (15.9%). Baseline GC‐related toxicity scores were higher in patients with relapsing disease compared with those with newly diagnosed disease (mean of 122.5 vs. 98.9; P < 0.001). The body mass index and neuropsychiatric domain scores were significantly higher in patients with relapsing disease. Conclusion: This approach to the assessment of baseline GC‐related toxicity distinguished patients with relapsing GCA from those with newly diagnosed disease. Baseline GC‐related toxicity scores may be useful in therapeutic decision‐making for patients beginning immunosuppressive treatment. [ABSTRACT FROM AUTHOR]

The antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) comprise a major subset of diseases that cause destructive inflammation of small and medium‐sized blood vessels. Although these conditions have a predilection for pulmonary and renal involvement, they are in fact protean diseases that can involve essentially any organ system. AAV is among the most difficult rheumatic diseases to diagnose and treat. Therapy for AAV has evolved over the past two decades. Rituximab, an anti‐CD20 monoclonal antibody, is now the preferred agent for remission induction in conjunction with a reduced‐dose glucocorticoid taper. Rituximab is also often a key therapy for remission maintenance. Glucocorticoid toxicity reduction has become a major priority for treatment regimens. Avacopan, an important new adjunct to remission induction therapy, may reduce glucocorticoid use and its resulting toxicity. The role of avacopan as a remission maintenance agent requires further study. The duration of immunosuppression following remission is guided by a number of factors, including the patient's overall clinical state, the degree of damage from previous disease activity, the tolerability of remission maintenance medications, and SARS–CoV‐2 vaccination and immunity status. Certain features, including history of previous relapse, the presence of ANCA directed against proteinase 3, and a diagnosis of granulomatosis with polyangiitis, favor prolonged remission maintenance therapy. The interval between rituximab doses can usually be lengthened over time during the maintenance phase. [ABSTRACT FROM AUTHOR]

Objective: The etiology of IgG4‐related disease (IgG4‐RD) is unknown, and there has been controversy over the significance of allergic conditions in IgG4‐RD. We examined the prevalence of lifetime allergy symptoms in IgG4‐RD and the association between these and IgG4‐RD. Methods: We identified IgG4‐RD patients and non‐IgG4‐RD controls without autoimmune conditions seen at a single center. IgG4‐RD patients were classified using the American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria. Allergy symptoms were ascertained by questionnaire. We assessed the association of IgG4‐RD features with allergy symptoms. We compared the proportion of cases and controls with allergy symptoms using conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) after matching cases and controls 1:1 by age and sex. Results: Lifetime allergy symptoms were reported by 165 (71%) of 231 IgG4‐RD patients. Aeroallergen symptoms were most commonly reported (n = 135, 58%), followed by skin allergy symptoms (n = 97, 42%) and food allergy symptoms (n = 47, 20%). IgG4‐RD cases with a history of allergy symptoms were more likely to have head and neck involvement (OR 2.0 [95% CI 1.1–3.6]) and peripheral eosinophilia (OR 3.3 [95% CI 1.2–9.0]) than those without allergy symptoms. The prevalence of any allergy symptoms was similar between cases and controls (OR 0.7 [95% CI 0.4–1.1]); this remained consistent after stratifying by head and neck involvement. Conclusion: Lifetime allergy symptoms are common in IgG4‐RD but are not reported more often in IgG4‐RD compared to non‐IgG4‐RD patients without autoimmune conditions. These findings suggest that allergies are not uniquely associated with the pathogenesis or presentation of IgG4‐RD. [ABSTRACT FROM AUTHOR]

Objective: Immunoglobulin‐G4‐related disease (IgG4‐RD) is a systemic autoimmune disease that can affect nearly any organ, but its epidemiology remains poorly understood. Validated algorithms to identify cases in claims data will enable studies to describe IgG4‐RD epidemiology in the general population. Methods: Potential claims‐based algorithms were developed by IgG4‐RD experts using a combination of International Classification of Diseases, Ninth Revision (ICD‐9) and International Classification of Diseases, 10th Revision (ICD‐10) codes, dispensed medications, and procedure codes for immunoglobulin G (IgG) subclass testing. Algorithms were tested using Medicare Parts A, B, and D linked to medical records (2007‐2017). Classification of cases as IgG4‐RD was determined using the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) classification criteria for IgG4‐RD. We estimated the positive predictive value (PPV) of each algorithm; sensitivity was determined using a cohort of patients with IgG4‐RD also enrolled in Medicare Parts A, B, and D during the study period. Results: We identified seven algorithms that used a combination of ICD‐9 and ICD‐10 codes, medication prescriptions, and/or IgG subclass tests to identify patients with IgG4‐RD. The PPV of algorithms in the derivation cohort ranged from 57% to 100%, and sensitivity ranged from 0% to 58%. The best performing algorithm in the validation cohort had a PPV of 81% and a sensitivity of 58%. Typical IgG4‐RD manifestations were observed in the cohort (n = 36) assembled by this algorithm, including 50% with sialadenitis, 64% with pancreatic disease, 31% with renal disease, and 59% with an elevated IgG4 concentration. Conclusion: We derived and validated a well‐performing algorithm to identify IgG4‐RD cases with typical manifestations of the disease. The claims‐based algorithm can be used in research studies of IgG4‐RD. [ABSTRACT FROM AUTHOR]

This tribute celebrates the life and work of Marian Gray Secundy (1938–2002), who was the first director of the National Center for Bioethics in Research and Health Care, a passionate advocate for health equity, a visionary scholar, and a skilled editor and collaborator. Within the tribute are several short remembrances in which individuals describe their association with Secundy to honor her as a leader, friend, scholar, advocate, and teacher in bioethics. [ABSTRACT FROM AUTHOR]

Introduction: Recent experimental evidence suggests normothermic machine perfusion of the vascularized composite allograft results in improved preservation compared to static cold storage, with less reperfusion injury in the immediate post‐operative period. However, metabolic acidosis is a common feature of vascularized composite allograft perfusion, primarily due to the inability to process metabolic by‐products. We evaluated the impact of combined limb‐kidney perfusion on markers of metabolic acidosis and inflammation in a porcine model. Methods: Ten paired pig forelimbs were used for this study, grouped as either limb‐only (LO, n = 5) perfusion, or limb‐kidney (LK, n = 5) perfusion. Infrared thermal imaging was used to determine homogeneity of perfusion. Lactate, bicarbonate, base, pH, and electrolytes, along with an inflammatory profile generated via the quantification of cytokines and cell‐free DNA in the perfusate were recorded. Results: The addition of a kidney to a limb perfusion circuit resulted in the rapid stabilization of lactate, bicarbonate, base, and pH. Conversely, the LO circuit became progressively acidotic, correlating in a significant increase in pro‐inflammatory cytokines. Global perfusion across the limb was more homogenous with LK compared to LO. Conclusion: The addition of a kidney during limb perfusion results in significant improvements in perfusate biochemistry, with no evidence of metabolic acidosis. [ABSTRACT FROM AUTHOR]

Objective: Improved biomarkers of current disease activity and prediction of relapse are needed in antineutrophil cytoplasmic antibody–associated vasculitis (AAV). For clinical relevance, biomarkers must perform well longitudinally in patients on treatment and in patients with nonsevere flares. Methods: Twenty‐two proteins were measured in 347 serum samples from 74 patients with AAV enrolled in a clinical trial. Samples were collected at Month 6 after remission induction, then every 3 months until Month 18, or at the time of flare. Associations of protein concentrations with concurrent disease activity and with future flare were analyzed using mixed‐effects models, Cox proportional hazards models, and conditional logistic regression. Results: Forty‐two patients had flares during the 12‐month follow‐up period, and 32 remained in remission. Twenty‐two patients had severe flares. Six experimental markers (CXCL13, IL‐6, IL‐8, IL‐15, IL‐18BP, and matrix metalloproteinase‐3 [MMP‐3]) and ESR were associated with disease activity using all three methods (P < 0.05, with P < 0.01 in at least one method). A rise in IL‐8, IL‐15, or IL‐18BP was associated temporally with flare. Combining C‐reactive protein (CRP), IL‐18BP, neutrophil gelatinase‐associated lipocalin (NGAL), and sIL‐2Rα improved association with active AAV. CXCL13 and MMP‐3 were increased during treatment with prednisone, independent of disease activity. Marker concentrations during remission were not predictive of future flare. Conclusion: Serum biomarkers of inflammation and tissue damage and repair have been previously shown to be strongly associated with severe active AAV were less strongly associated with active AAV in a longitudinal study that included mild flares and varying treatment. Markers rising contemporaneously with flare or with an improved association in combination merit further study. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to validate the diagnosis of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) as the primary cause of end‐stage renal disease (ESRD) in the US Renal Data System (USRDS). Methods: We identified patients with ESRD in the Mass General Brigham (MGB) health care system who were enrolled in the USRDS. The health records of those with AAV listed as the primary cause of ESRD in the USRDS were reviewed to confirm the diagnosis and estimate positive predictive value (PPV). Sensitivity was estimated by evaluating the primary cause of ESRD listed in the USRDS for patients with ESRD due to AAV in the MGB AAV cohort. Results: We identified 89 MGB patients with ESRD due to AAV in the USRDS. Of these, 85 cases were confirmed to be true cases of AAV (PPV = 94%). Among the patients classified as having AAV, 84 (99%) had an ANCA test, which was predominantly myeloperoxidase/P‐ANCA (47 [55%]); 36 (42%) had a renal biopsy, and all biopsies were supportive of the diagnosis. The majority (81 [90%]) was identified as AAV by International Classification of Diseases Ninth Revision or International Classification of Diseases 10th Revision codes for granulomatosis with polyangiitis (446.4 or M313.1). Of the 77 MGB AAV cohort patients with ESRD who were linked to the USRDS, 41 (53%) had AAV listed as the cause of ESRD; in the remainder, ESRD was attributed to nonspecific nephritis. Conclusion: The diagnosis of AAV as the cause of ESRD in the USRDS has a high PPV; sensitivity was moderate. These findings support the continued use of the USRDS to study ESRD due to AAV. [ABSTRACT FROM AUTHOR]

Objective: To investigate the perceived risk of coronavirus disease 2019 (COVID‐19) infection and outcomes as well as shielding practices among patients with rheumatoid arthritis (RA) during the COVID‐19 pandemic. Methods: We surveyed participants with RA in a large health care system between July 16 and November 8, 2020. Participants reported RA treatment, COVID‐19 risk perception, and shielding practices (eg, masks, social distancing, and quarantining). We examined the association of demographic and disease‐specific factors with risk perception and the association of risk perception with shielding practices. Results: Of 494 participants, 195 (40%), 169 (34%), and 130 (26%) strongly agreed, agreed, or were uncertain/disagreed that their RA put them at higher risk for COVID‐19 or poor outcomes, respectively. Younger age (odds ratio [OR]: 0.98), having a comorbidity (OR: 1.60), and biologic disease‐modifying antirheumatic drug (bDMARD) use (OR: 1.75) were independently associated with a higher perceived risk. Among those who strongly agreed, agreed, or were uncertain/disagreed that they had greater risk, 165 (85%), 118 (70%), and 69 (53%), respectively, practiced all three shielding measures (P < 0.0001). Those who strongly agreed or agreed that they were at higher risk were more likely to use all three shielding practices (OR: 4.16 and 1.97, respectively). bDMARD use and glucocorticoid use were associated with using all three shielding measures (OR: 1.99 and 1.81, respectively). Conclusion: Perception of COVID‐19 risk among patients with RA varies substantially. Factors associated with perceived risk are different from those found to be associated with worse outcomes in observational studies. Greater perceived risk is associated with more strict shielding, which has implications for patient education and mental health. [ABSTRACT FROM AUTHOR]

Objective: To provide evidence-based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).Methods: Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.Results: We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low-quality evidence supporting the recommendations.Conclusion: This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases. [ABSTRACT FROM AUTHOR]

Objective: To provide evidence-based recommendations and expert guidance for the management of systemic polyarteritis nodosa (PAN).Methods: Twenty-one clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for systemic, non-hepatitis B-related PAN. Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.Results: We present 16 recommendations and 1 ungraded position statement for PAN. Most recommendations were graded as conditional due to the paucity of evidence. These recommendations support early treatment of severe PAN with cyclophosphamide and glucocorticoids, limiting toxicity through minimizing long-term exposure to both treatments, and the use of imaging and tissue biopsy for disease diagnosis. These recommendations endorse minimizing risk to the patient by using established therapy at disease onset and identify new areas where adjunctive therapy may be warranted.Conclusion: These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and imaging for patients with PAN. [ABSTRACT FROM AUTHOR]

Objective: To provide evidence-based recommendations and expert guidance for the management of giant cell arteritis (GCA) and Takayasu arteritis (TAK) as exemplars of large vessel vasculitis.Methods: Clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for GCA and TAK (27 for GCA, 27 for TAK). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. Recommendations were developed by the Voting Panel, comprising adult and pediatric rheumatologists and patients. Each recommendation required ≥70% consensus among the Voting Panel.Results: We present 22 recommendations and 2 ungraded position statements for GCA, and 20 recommendations and 1 ungraded position statement for TAK. These recommendations and statements address clinical questions relating to the use of diagnostic testing, including imaging, treatments, and surgical interventions in GCA and TAK. Recommendations for GCA include support for the use of glucocorticoid-sparing immunosuppressive agents and the use of imaging to identify large vessel involvement. Recommendations for TAK include the use of nonglucocorticoid immunosuppressive agents with glucocorticoids as initial therapy. There were only 2 strong recommendations; the remaining recommendations were conditional due to the low quality of evidence available for most PICO questions.Conclusion: These recommendations provide guidance regarding the evaluation and management of patients with GCA and TAK, including diagnostic strategies, use of pharmacologic agents, and surgical interventions. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of ustekinumab (UST) in giant cell arteritis (GCA).Methods: We conducted a prospective, open-label trial of UST in patients with active new-onset or relapsing GCA. Active disease was defined as the presence of GCA symptoms and elevation of erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level within 6 weeks of baseline. All patients received a 24-week prednisone taper and subcutaneous UST 90 mg at baseline and at weeks 4, 12, 20, 28, 36, and 44. The primary endpoint, prednisone-free remission, was defined as the absence of relapse through week 52 and normalization of the ESR and CRP level. Relapse was defined as the recurrence of GCA symptoms requiring treatment intensification. A sensitivity analysis excluding ESR/CRP level normalization from the prednisone-free remission definition was performed.Results: The study enrolled 13 patients (target sample size 20). Enrollment was closed prematurely after 7 of the initial 10 patients relapsed. Five patients (39%) had new-onset disease. The initial prednisone doses were 20 mg (1 patient), 40 mg (9 patients), and 60 mg (3 patients). All patients entered disease remission within 4 weeks of baseline. Only 3 (23%) achieved the primary endpoint. Of the 10 patients (77%) who failed to achieve the primary endpoint, 7 relapsed after a mean period of 23 weeks. The remaining 3 patients met the alternative definition of prednisone-free remission that did not require ESR/CRP level normalization. One serious adverse event occurred.Conclusion: UST combined with 24 weeks of prednisone was associated with a high rate of treatment failure in this prospective GCA trial. [ABSTRACT FROM AUTHOR]

Objective: Prior authorizations (PAs) are commonly used by health payers as cost‐containment strategies for expensive medications, including infused biologics. There is scarce data about the effect of PA requirements on patient‐oriented outcomes. Methods: We included patients for whom an infusible medication was prescribed for a rheumatologic condition. The exposures of interest were a PA requirement and whether or not the PA was denied. The primary outcome was the difference in days from medication request to infusion. Secondary outcomes included the proportion of denied PAs and differences in glucocorticoid exposure following a PA request. Results: Of the 225 patients, the infusible medications of 160 (71%) required a PA. PAs were associated with a greater number of days to infusion compared to cases in which no authorization was required (median 31 days [interquartile range (IQR) 15–60 days] versus median 27 days [IQR 13–41 days]; P = 0.045), especially among the 33 patients (21%) whose PA was denied initially (median 50 days [IQR 31–76 days] versus median 27 days [IQR 13–41 days]; P < 0.001). PA denials were associated with greater prednisone‐equivalent glucocorticoid exposure in the 3 months following the request than when a PA was not required (median 605 mg [IQR 0–1,575] versus median 160 mg [IQR 0–675]; P = 0.01). Twenty‐seven of the 33 PA requests that were initially denied (82%) were eventually approved. Thus, 96% of all PAs were ultimately approved. Conclusion: PA requirements are associated with treatment delays and denials are associated with greater glucocorticoid exposure. Because the great majority of PA requests are ultimately approved, the value of PA requirements and their impact on patient safety should be reevaluated. [ABSTRACT FROM AUTHOR]

Background: Diarrhea is a common problem in the pediatric post‐solid organ transplant and post‐hematopoietic stem cell transplant populations. Infectious etiology incidences are poorly defined, and the possibility of multi‐organism positivity is often uninvestigated. The aim of this study is to utilize stool multiplex GIP assays to compare the PTP and NTP regarding the incidence and profiles of single‐organism and multi‐organism infectious diarrhea. Methods: A single‐center retrospective review was conducted, investigating stool multiplex GIP panel results over a more than 3‐year period, for pediatric patients. Assays test for 23 viral, bacterial, and protozoal organisms. Results: Positive assays in the PTP and NTP were 70/101 (69.3%) and 962/1716 (56.1%), respectively (P =.009). Thirty‐two percent (32/101) of assays within the PTP were multi‐organism positive, significantly more than 14.8% (254/1716) in the NTP (P <.00001). There was no significant difference in the incidence of single‐organism positives, 37.6% (38/101) in PTP and 41.3% (708/1716) in the NTP. The PTP demonstrated a statistically significantly higher incidence of the following organisms within multi‐agent positive GIPs (P <.05 for each): Clostridioides difficile, Cryptosporidium, EPEC, norovirus, and sapovirus. Conclusions: The pediatric PTP demonstrates higher incidence of positive GIPs, higher rate of multi‐organism positivity, and unique infectious organism incidence profiles. These data can provide a framework for understanding organism‐specific pathogenicity factors, assessing the clinical impact of enteric co‐infection, and understanding the utility of this testing modality in this unique population. [ABSTRACT FROM AUTHOR]

Objective: Originator intravenous rituximab is an important rheumatology treatment but is costly, and administration requires several hours. Because biosimilar rituximab may cost less and subcutaneous rituximab requires a shorter visit, both may reduce costs and increase treatment capacity (infusions per year). Methods: We implemented time‐driven activity‐based costing (TDABC), a method to assess costs and opportunities to increase capacity, throughout the care pathway for 26 patients receiving a total of 30 rituximab infusions. Using the TDABC estimates, we created a base case, which included provider time, salaries, infusion rates and times, and drug formulation, to simulate an induction cycle (two infusions). We varied these parameters in sensitivity analyses and assessed the impact of infusion rates and formulation (biosimilar vs. subcutaneous) on capacity before and after assuming a fixed budget. Results: The base‐case cost was $19 452; more than 90% was due to drug cost. In sensitivity analyses, varying projected biosimilar cost led to the greatest cost savings ($8,988 per cycle). Faster infusion rates and subcutaneous rituximab increased annual capacity (300% and 800%, respectively). With a fixed budget, subcutaneous rituximab led to a relative increase in capacity over biosimilar rituximab except when biosimilar cost savings relative to originator rituximab exceeded 40%; faster biosimilar infusion rates did not meaningfully affect these findings. Conclusion: Using TDABC, we demonstrate that rituximab cost is the primary driver of treatment cost, but capacity is largely driven by treatment time. Subcutaneous rituximab leads to higher capacity than biosimilar rituximab across a range of plausible costs; its use in rheumatology should be studied. [ABSTRACT FROM AUTHOR]

Objective: Four autoantigens have been described recently in IgG4‐related disease (IgG4‐RD): prohibitin, annexin A11, laminin 511‐E8, and galectin‐3. However, no external validation has been performed, and the possibility that some individuals break tolerance to more than 1 autoantigen has not been explored. We undertook this study to evaluate the relative frequencies of antibody responses against these autoantigens in order to explore the role of adaptive immune response in IgG4‐RD. Methods: Autoantibody responses against prohibitin, annexin A11, and laminin 511‐E8 were measured among a clinically diverse cohort of IgG4‐RD patients (n = 100) using enzyme‐linked immunosorbent assays. Autoantibody responses were correlated with disease severity and organ distribution. Results: The frequencies of IgG4 autoantibody responses against prohibitin (10%), annexin A11 (12%), and laminin 511‐E8 (7%) were not significantly different from those of controls. A portion of the cohort (n = 86) had been analyzed previously at our center for anti–galectin‐3 antibody responses, with 25 patients (29%) having IgG4 anti–galectin‐3 antibodies. Of these 86 patients, 32 (37%) had IgG4 antibodies to ≥1 of the 4 autoantigens and 12 (14%) showed reactivity with ≥2 of the tested antigens. The subset of patients with ≥2 autoantibodies had higher total levels of IgG1, IgG2, IgG4, and C‐reactive protein, were more commonly hypocomplementemic, and were more likely to have visceral organ involvement. Conclusion: Antibodies against prohibitin, annexin A11, and laminin 511‐E8 were found in only a small portion of patients with IgG4‐RD. A subset of IgG4‐RD patients, however, had IgG4 antibodies against ≥2 autoantigens. These patients presented with robust IgG subclass elevations, complement consumption, and visceral organ involvement. This broader break in immunologic tolerance in IgG4‐RD was associated with more severe disease. [ABSTRACT FROM AUTHOR]

Objective: To assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)–Associated Vasculitis (RAVE) trial and identify novel potential risk factors. Methods: VTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA‐associated vasculitis (AAV). Results: VTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0–2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247–134.842]; P = 0.006), positive proteinase 3 (PR3)–ANCA (HR 7.731 [95% CI 1.021–58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448–10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491–69.854]; P < 0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566–185.805]; P = 0.005), PR3‐ANCA (HR 9.12 [95% CI 1.158–71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453–10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607–75.075]; P < 0.001) remained. Conclusion: Patients diagnosed as having AAV with pulmonary hemorrhage, positive PR3‐ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Objective: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to evaluate glucocorticoid dosages and serologic findings in patients with giant cell arteritis (GCA) flares. Methods: Patients with GCA were randomly assigned to receive double‐blind dosing with either subcutaneous tocilizumab (TCZ) 162 mg weekly plus 26‐week prednisone taper (TCZ‐QW + Pred‐26), every‐other‐week TCZ plus 26‐week prednisone taper (TCZ‐Q2W + Pred‐26), placebo plus 26‐week prednisone taper (PBO + Pred‐26), or placebo plus 52‐week prednisone taper (PBO + Pred‐52). Outcome measures were prednisone dosage, C‐reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) at the time of flare. Results: One hundred patients received TCZ‐QW + Pred‐26, 49 received TCZ‐Q2W + Pred‐26, 50 received PBO + Pred‐26, and 51 received PBO + Pred‐52. Of the 149 TCZ‐treated patients, 36 (24%) experienced flare, 23 (64%) of whom were still receiving prednisone (median dosage 2.0 mg/day). Among 101 PBO + Pred–treated patients, 59 (58%) experienced flare, 45 (76%) of whom were receiving prednisone (median dosage 5.0 mg/day). Many flares occurred while patients were taking >10 mg/day prednisone: 9 (25%) in the TCZ groups and 13 (22%) in the placebo groups. Thirty‐three flares (92%) in TCZ‐treated groups and 20 (34%) in PBO + Pred–treated groups occurred with normal CRP levels. More than half of the PBO + Pred–treated patients had elevated CRP levels without flares. Benefits of the TCZ and prednisone combination over prednisone alone for remission induction were apparent by 8 weeks. Conclusion: Most GCA flares occurred while patients were still receiving prednisone. Acute‐phase reactant levels were not reliable indicators of flare in patients treated with TCZ plus prednisone or with prednisone alone. The addition of TCZ to prednisone facilitates earlier GCA control. [ABSTRACT FROM AUTHOR]

Understanding natural soil redistribution processes is essential for measuring the anthropogenic impact on landscapes. Although meteoric beryllium‐10 (10Be) has been used to determine erosion processes within the Pleistocene and Holocene, fewer studies have used the isotope to investigate the transport and accumulation of the resulting sediment. Here we use meteoric 10Be in hilltop and valley site soil profiles to determine sediment erosion and deposition processes in the Christina River Basin (Pennsylvania, USA). The data indicate natural erosion rates of 14 to 21 mm 10−3 yr and soil ages of 26 000 to 57 000 years in hilltop sites. Furthermore, valley sites indicate an alteration in sediment supply due to climate change (from the Pleistocene to the Holocene) within the last 60 000 years and sediment deposition of at least 0.5–2 m during the Wisconsinan glaciation. The change in soil erosion rate was most likely induced by changes in geomorphic processes; probably solifluction and slope wash during the cold period, when ice advanced into the mid latitudes of North America. This study shows the value of using meteoric 10Be to determine sediment accumulation within the Quaternary and quantifies major soil redistribution occurred under natural conditions in this region. © 2018 John Wiley & Sons, Ltd. This study uses meteoric 10Be distribution with depth in soil profiles to not only determine the soil residence times and erosion rates in hilltop areas, but also to study sediment depositional processes in valley wall areas in the Christina River Basin (PA, USA). [ABSTRACT FROM AUTHOR]

Objective: To examine temporal trends in mortality rates in a large nationwide cohort of patients with end-stage renal disease (ESRD) due to granulomatosis with polyangiitis (Wegener's) (GPA-ESRD).Methods: We identified cases of GPA-ESRD reported in the US Renal Data System between 1995 and 2014, using coding by nephrologists for the cause of ESRD. The cohort was divided into four 5-year subcohorts based on the year of onset of ESRD (1995-1999, 2000-2004, 2005-2009, and 2010-2014) to assess trends in mortality rates and hazard ratios (HRs) for overall death and cause-specific death, adjusting for potential confounders.Results: Between 1995 and 2014, there were 5,929 incident cases of GPA-ESRD. The mortality rate (incidence per 100 patient-years) declined from 19.0 in 1995-1999 to 15.3 in 2010-2014 (P for trend = 0.01). The multivariable-adjusted HR for mortality in the 2010-2014 cohort was 0.77 (95% confidence interval [95% CI] 0.66-0.90) (P for trend < 0.001 versus the 1995-1999 cohort). The corresponding cause-specific HRs for mortality, after accounting for competing risk, were 0.61 (95% CI 0.47-0.80) for CVD-related death and 0.42 (95% CI 0.28-0.63) for death due to infection (P for trend < 0.001).Conclusion: In this study of nearly all patients in whom GPA-ESRD developed in the US over 2 decades, we observed significant improvements in mortality among GPA-ESRD patients. The number of cause-specific deaths due to CVD and the number due to infections declined significantly during the study period. These findings are encouraging and likely reflect improved management of both GPA and ESRD. [ABSTRACT FROM AUTHOR]

Abstract: Walker Connor's extensive writings on nationalism covered a wide range of issues and an even wider range of societies, from North America to Western Europe, from the countries of the Communist bloc to the evolving forms of identity and affiliation throughout the postcolonial, developing world. No theme in his work is perhaps more salient than his critical distinction between state and nation, one that was so often blurred by a loose terminology that saw political units and forms of ethnic identity as synonymous. For Connor, this sin was perpetrated by both academic scholars and general writers and led to a lack of appreciation of one of the foremost forces – what he called ethno‐nationalism – shaping the contemporary world. [ABSTRACT FROM AUTHOR]

Objective: An unconventional population of CD4+ signaling lymphocytic activation molecule family member 7–positive (SLAMF7+) cytotoxic effector memory T (TEM) cells (CD4+ cytotoxic T lymphocytes [CTLs]) has been linked causally to IgG4‐related disease (IgG4‐RD). Glucocorticoids represent the first‐line therapeutic approach in patients with IgG4‐RD, but their mechanism of action in this specific condition remains unknown. We undertook this study to determine the impact of glucocorticoids on CD4+ CTLs in IgG4‐RD. Methods: Expression of CD8α, granzyme A, perforin, and SLAMF7 within the effector memory compartment of CD45RO+ (TEM) and CD45RA+ effector memory T (TEMRA) CD4+ cells was quantified by flow cytometry in 18 patients with active IgG4‐RD, both at baseline and after 6 months of glucocorticoid treatment. Eighteen healthy subjects were studied as controls. Next‐generation sequencing of the T cell receptor α‐ and β‐chain gene was performed on circulating CD4+ CTLs from patients with IgG4‐RD before and after treatment and in affected tissues. Results: Circulating CD4+ TEM and TEMRA cells were not expanded in IgG4‐RD patients compared to healthy controls. CD4+SLAMF7+ TEM cells (but not TEMRA cells) were significantly increased among IgG4‐RD patients. Within CD4+SLAMF7+ TEM cells, CD8α− cells but not CD8αlow cells were elevated in IgG4‐RD patients. The same dominant clones of CD8α−CD4+SLAMF7+ TEM cells found in peripheral blood were also identified in affected tissue. CD8α− and CD8αlowCD4+SLAMF7+ TEM cells both expressed cytolytic molecules. Clonally expanded CD8α− but not CD8αlowCD4+SLAMF7+ TEM cells decreased following glucocorticoid‐induced disease remission. Conclusion: A subset of CD8α−CD4+SLAMF7+ cytotoxic TEM cells is oligoclonally expanded in patients with active IgG4‐RD. This TEM cell population contracts following glucocorticoid‐induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Objective: To evaluate circulating cytokine profiles in patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV), classified by antineutrophil cytoplasmic antibody (ANCA) specificity (proteinase 3 ANCA [PR3‐ANCA] versus myeloperoxidase ANCA [MPO‐ANCA]) or by clinical diagnosis (granulomatosis with polyangiitis [GPA] versus microscopic polyangiitis [MPA]). Methods: A panel of 29 cytokines was tested in 186 patients with active AAV at inclusion into the Rituximab in AAV trial. Cytokine concentrations were compared between groups within each classification system. Multivariable analyses adjusted for age, sex, and renal insufficiency were performed, with each biomarker as a dependent variable and ANCA specificity and clinical diagnosis as explanatory variables of interest. Results: Levels of 9 circulating cytokines (interleukin‐6 [IL‐6], granulocyte–macrophage colony‐stimulating factor [GM‐CSF], IL‐15, IL‐18, CXCL8/IL‐8, CCL‐17/thymus and activation–regulated chemokine [TARC], IL‐18 binding protein [IL‐18 BP], soluble IL‐2 receptor α [sIL‐2Rα], and nerve growth factor β [NGFβ]) were significantly higher in PR3‐AAV than MPO‐AAV, 4 cytokines (sIL6R, soluble tumor necrosis factor receptor type II [sTNFRII], neutrophil gelatinase–associated lipocalin [NGAL], and soluble intercellular adhesion molecule 1 [sICAM‐1]) were higher in MPO‐AAV than in PR3‐AAV, 6 cytokines (IL‐6, GM‐CSF, IL‐15, IL‐18, sIL‐2Rα, and NGFβ) were higher in GPA than in MPA, and 3 cytokines (osteopontin, sTNFRII, and NGAL) were higher in MPA than in GPA (all P < 0.05). For nearly all cytokines, the difference between PR3‐AAV and MPO‐AAV was larger than that between GPA and MPA. The multivariate analysis showed that 8 cytokines (IL‐15, IL‐8, IL‐18 BP, NGF‐β, sICAM‐1, TARC, osteopontin, and kidney injury molecule 1 (P < 0.05) distinguished patients with AAV better (lower P values and larger effect sizes) when grouped by ANCA specificity than by clinical diagnosis. Conclusion: Distinct cytokine profiles were identified for PR3‐AAV versus MPO‐AAV and for GPA versus MPA. Differences in these circulating immune mediators are more strongly associated with ANCA specificity than with clinical diagnosis, suggesting that heterogeneity in the AAV subtypes extends beyond clinical phenotypes. [ABSTRACT FROM AUTHOR]

Abstract: Granulomatosis with polyangiitis (GPA; formerly Wegener's) can present with clinical and histopathological features similar to those of immunoglobulin‐G4 related disease (IgG4‐RD), a recently described fibro‐inflammatory condition. The ability of these two distinct entities to mimic each other closely creates significant pitfalls in diagnosis. We present a unique case in which GPA presented as a peri‐aortic fibrotic mass in the retroperitoneum. The patient's other clinical features also overlapped with classic IgG4‐RD disease manifestations, but the histopathology in two organs and the serological data confirmed the diagnosis of GPA. Rigorous histopathological review remains the gold standard for the diagnosis of GPA and the distinction of this entity from IgG4‐RD and other mimickers. [ABSTRACT FROM AUTHOR]

The article discusses IgG4-related disease (IgG4-RD), which is multiorgan disorder, and discusses latest treatment models in rheumatology. Topics include distinguishing autoimmune pancreatitis from other diseases of pancreatic and biliary tract; abundance of IgG4-expressing plasma cells within affected tissues; and use of conventional disease-modifying antirheumatic drugs such as azathioprine, methotrexate, and mycophenolate mofetil in IgG4.

Deglaciation of the Ross Sea following the last ice age provides an important opportunity to examine the stability of marine ice sheets and their susceptibility to changing environmental conditions. Insufficient chronology for Ross Sea deglaciation has helped sustain (i) the theory that this region contributed significantly to Meltwater Pulse 1A (MWP-1A) and (ii) the idea that Ross Sea grounding-line retreat occurred in a 'swinging gate' pattern hinged north of Roosevelt Island. We present deglaciation records from southern Transantarctic Mountain glaciers, which delivered ice to the central Ross Sea. Abrupt thinning of these glaciers 9-8 kyr B.P. coincided with deglaciation of the Scott Coast, ∼800 km to the north, and ended with the Ross Sea grounding line near Shackleton Glacier. This deglaciation removed grounded ice from most of the central and western Ross Sea in less than 2 kyr. The Ross Sea Sector neither contributed nor responded significantly to MWP-1A. [ABSTRACT FROM AUTHOR]

Objective We investigated the relationships between glucocorticoid use, disease activity, and changes in body mass index (BMI) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods We analyzed AAV patients enrolled in the Rituximab in AAV trial. Glucocorticoid use, BMI, and disease activity were measured regularly during the trial period. We performed mixed-effects regressions to examine the associations of time-dependent cumulative average glucocorticoid use and disease activity with changes in BMI over time, while adjusting for potential confounders. Results The mean ± SD baseline BMI of the 197 patients enrolled was 28.8 ± 6.3 kg/m2. Patients with newly diagnosed AAV tended to have a lower mean ± SD BMI than those with relapsing disease (28.0 ± 5.7 kg/m2 versus 29.6 ± 6.8 kg/m2) and higher disease activity (mean ± SD Birmingham Vasculitis Activity Score for Wegener's Granulomatosis 8.7 ± 3.3 versus 7.4 ± 2.7). The most significant change in BMI occurred during the first 6 months of the trial (mean ± SD increase of 1.1 ± 2.2 kg/m2; P < 0.0001). Disease activity improvement, glucocorticoid exposure, and randomization to rituximab were each independently associated with an increase in BMI ( P < 0.001 for all analyses). Conclusion Our findings suggest that changes in BMI, as well as glucocorticoid exposure, are independently associated with improvements in disease activity in AAV. Rituximab may also have effects on BMI independent of its impact on disease activity. [ABSTRACT FROM AUTHOR]

Objective: Granulomatosis with polyangiitis (Wegener's) (GPA) is a type of antineutrophil cytoplasmic antibody-associated vasculitis that often entails severe end-organ damage and treatment-related complications that frequently lead to hospitalization and death. Nationwide trends in hospitalizations and in-hospital mortality over the past 2 decades are unknown and were evaluated in this study.Methods: Using the National Inpatient Sample, the largest all-payer inpatient database in the US, trends in hospitalizations with a discharge diagnosis of GPA (formerly Wegener's granulomatosis; International Classification of Disease, Ninth Revision, Clinical Modification code 446.4) between 1993 and 2011 were studied. Analyses were performed using hospital-level sampling weights to obtain US national estimates.Results: From 1993 to 2011, the annual hospitalization rate for patients with a principal diagnosis of GPA increased by 24%, from 5.1 to 6.3 per 1 million US persons (P < 0.0001 for trend); however, in-hospital deaths in this group declined by 73%, from 9.1% to 2.5% (P < 0.0001 for trend), resulting in a 66% net reduction in the annual in-hospital mortality rate. The median length of stay declined by 20%, from 6.9 days in 1993 to 5.5 days in 2011 (P = 0.0002 for trend). Infection was the most common principal discharge diagnosis when GPA was a secondary diagnosis, including among those who died during hospitalization.Conclusion: The findings from these nationally representative, contemporary inpatient data indicate that the in-hospital mortality of GPA has declined substantially over the past 2 decades, while the overall hospitalization rate for GPA increased slightly. Infection remains a common principal hospitalization diagnosis among GPA patients, including hospitalizations resulting in mortality. [ABSTRACT FROM AUTHOR]

Objective S100A8/A9 (calprotectin) has shown promise as a biomarker for predicting relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study was undertaken to investigate serum S100A8/A9 level as a biomarker for predicting future relapse in a large cohort of patients with severe AAV. Methods Serum levels of S100A8/A9 were measured at baseline and months 1, 2, and 6 following treatment initiation in 144 patients in the Rituximab in ANCA-Associated Vasculitis trial (cyclophosphamide/azathioprine versus rituximab [RTX] for induction of remission) in whom complete remission was attained. Results Patients were divided into 4 groups: proteinase 3 (PR3)-ANCA with relapse (n = 37), PR3-ANCA without relapse (n = 56), myeloperoxidase (MPO)-ANCA with relapse (n = 6), and MPO-ANCA without relapse (n = 45). Serum S100A8/A9 level decreased in all groups during the first 6 months of treatment. The percentage reduction from baseline to month 2 was significantly different between patients who experienced a relapse and those who did not in the PR3-ANCA group ( P = 0.046). A significantly higher risk of relapse was associated with an increase in S100A8/A9 level between baseline and month 2 ( P = 0.0043) and baseline and month 6 ( P = 0.0029). Subgroup analysis demonstrated that patients treated with RTX who had increased levels of S100A8/A9 were at greatest risk of future relapse ( P = 0.028). Conclusion An increase in serum S100A8/A9 level by month 2 or 6 compared to baseline identifies a subgroup of PR3-ANCA patients treated with RTX who are at higher risk of relapse by 18 months. Since RTX is increasingly used for remission induction in PR3-ANCA-positive patients experiencing a relapse, S100A8/A9 level may assist in identifying those patients requiring more intensive or prolonged treatment. [ABSTRACT FROM AUTHOR]

Objective 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. Methods 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. Results 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). Conclusion 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. [ABSTRACT FROM AUTHOR]

Objective Giant cell arteritis (GCA) and the use of glucocorticoids have both been associated with increased risk of venous thromboembolism (VTE). However, the possibility of confounding by indication has not been investigated. We undertook this study to examine the temporal risk of VTE in GCA patients before and after GCA diagnosis, accounting for confounders including glucocorticoid treatment. Methods We conducted a matched cohort study using an electronic medical record database representative of the UK population (1990-2013). We calculated age-, sex-, and entry time-matched and multivariate relative risks (RRs) of VTE, comparing 6,441 patients with new-onset GCA (defined by corresponding diagnosis codes and prescribed glucocorticoid treatment) to 63,985 controls before and after GCA diagnosis. Analysis before GCA diagnosis was stratified by oral glucocorticoid use to account for confounding. Results There were 27 incident VTE events during the 12 months preceding GCA diagnosis and 195 afterward. Compared to controls, during the 12, 9, 6, and 3 months preceding GCA diagnosis, the age-, sex-, and entry time-matched RRs for VTE among patients with imminent GCA not treated with glucocorticoids were 1.8, 2.2, 2.4, and 3.6, respectively. In the first 3, 6, 12, 24, 48, and 96 months after GCA diagnosis, the corresponding RRs were 9.9, 7.7, 5.9, 4.4, 3.3, and 2.4. Multivariate analyses including several common VTE risk factors showed similar trends. Conclusion The risk of VTE increases shortly before GCA diagnosis, peaks at the time of diagnosis, and then progressively declines thereafter. This risk is apparent in patients with imminent GCA unexposed to oral glucocorticoids, suggesting a role for inflammation-associated thrombosis that is independent of glucocorticoid use. [ABSTRACT FROM AUTHOR]

Objective To 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). Methods We 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). Results Of 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. Conclusion We 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. [ABSTRACT FROM AUTHOR]

Objective IgG4-related disease (IgG4-RD) is a fibroinflammatory disease of unclear etiology. Some studies suggest that IgG4-RD predisposes patients to malignancy or is a forme fruste of cancer, but we have frequently observed IgG4-RD patients who have a history of malignancy preceding the clinical onset of IgG4-RD. This study was undertaken to characterize IgG4-RD in the setting of previous malignancy diagnosis. Methods We identified IgG4-RD patients with a history of invasive malignancy from a well-defined cohort of 125 patients and compared their malignancy history to those of 2 reference groups. First, we calculated a standardized prevalence ratio against general US population estimates from the Surveillance, Epidemiology, and End Results (SEER) database. Second, we identified up to 5 age- and sex-matched controls for each case and calculated the odds of malignancy among those with IgG4-RD compared to controls, using conditional logistic regression. Results The mean ± SD age at IgG4-RD onset was 50.3 ± 14.9 years, and 61% of the patients were male. Twenty (16%) had been diagnosed as having malignancies (total 21 malignancies) before the diagnosis of IgG4-RD. The observed prevalence of malignancy in this cohort was 2.5 times higher (95% confidence interval [95% CI] 1.1-3.6) than expected compared to the SEER database. Compared to matched controls, the frequency of history of malignancy was >3-fold higher in IgG4-RD patients (95% CI 1.6-6.2). Conclusion Our findings suggest that, in a subset of patients with IgG4-RD, malignancy may be associated with subsequent IgG4-RD development. Potential explanations include shared risk factors for both IgG4-RD and cancer, the triggering by cancer of autoantigen expression leading to IgG4-RD, and an increased risk of IgG4-RD resulting from cancer treatment. [ABSTRACT FROM AUTHOR]

Objective Relapse following remission is common in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), particularly with ANCAs directed at proteinase 3 (PR3). This study was undertaken to evaluate the association of an increase in PR3-ANCA level with subsequent relapse. Methods Data from the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial were used. Starting from the time of achieving complete remission, serial measurements by direct and capture enzyme-linked immunosorbent assays (ELISAs) were analyzed in 93 patients with PR3-ANCA, using Cox proportional hazards regression. Results An increase in PR3-ANCA level was identified in 58 of 93 subjects (62.4%) by direct ELISA and in 59 of 93 (63.4%) by capture ELISA. Relapses occurred in 55 of 93 subjects (59.1%), with 25 and 21 occurring within 1 year after an increase by direct ELISA and capture ELISA, respectively. An increase by direct ELISA was associated with subsequent severe relapses (hazard ratio [HR] 4.57; P < 0.001), particularly in patients presenting with renal involvement (HR 7.94; P < 0.001) and alveolar hemorrhage (HR 24.19; P < 0.001). Both assays identified increased risk for severe relapse in the rituximab group (HR 5.80; P = 0.002 for direct ELISA and HR 4.54; P = 0.007 for capture ELISA) but not the cyclophosphamide/azathioprine group ( P = 0.103 and P = 0.197, respectively). Conclusion The association of an increase in PR3-ANCA level with the risk of subsequent relapse is partially affected by the PR3-ANCA detection methodology, disease phenotype, and remission induction treatment. An increase in PR3-ANCA level during complete remission conveys an increased risk of relapse, particularly severe relapse, among patients with renal involvement or alveolar hemorrhage and those treated with rituximab. Serial measurements of PR3-ANCA may be informative in this subset of patients, but the risk of relapse must be weighed carefully against the risks associated with therapy. [ABSTRACT FROM AUTHOR]

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare, autosomal dominant condition caused by mutations of TREX1 (3-prime repair exonuclease-1). The phenotypic expressions range from isolated retinal involvement to varying degrees of retinopathy, cerebral infarction with calcium depositions, nephropathy, and hepatopathy. We report a case of RVCL caused by a novel TREX1 mutation. This patient's multisystem presentation, retinal involvement interpreted as "retinal vasculitis," and improvement of neuroimaging abnormalities with dexamethasone led to the accepted diagnosis of a rheumatologic disorder resembling Behçet disease. Clinicians should consider RVCL in any patient with retinal capillary obliterations associated with tumefactive brain lesions or nephropathy. [ABSTRACT FROM AUTHOR]

Objective. IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect nearly any organ. Prior studies have focused on individual cases of IgG4-RD or small case series. This study was undertaken to report detailed clinical and laboratory findings in a larger group of patients with IgG4-RD whose diagnosis was established by strict clinicopathologic correlation. Methods. The baseline features of 125 patients with biopsy-proven IgG4-RD were reviewed. The diagnosis was confirmed by pathologists' review, based on consensus diagnostic criteria and correlation with clinicopathologic features. Disease activity and damage were assessed using the IgG4-RD Responder Index (RI). Flow cytometry was used to assess levels of circulating plasmablasts. Results. Of the 125 patients, 107 had active disease and 86 were not receiving treatment for IgG4-RD. Only 51% of the patients with active disease had elevated serum IgG4 concentrations. However, patients with active disease and elevated serum IgG4 concentrations were older, had a higher IgG4-RD RI score, a greater number of organs involved, lower complement levels, higher absolute eosinophil counts, and higher IgE levels compared to those with active disease but normal serum IgG4 concentrations (P < 0.01 for all comparisons). The correlation between IgG41 plasmablast levels and the IgG4-RD RI of disease activity (Spearman's r50.45, P50.003) was stronger than the correlation between total plasmablast levels and the IgG4-RD RI. Seventy-six (61%) of the patients were male, but no significant differences according to sex were observed with regard to disease severity, organ involvement, or serum IgG4 concentrations. Treatment with glucocorticoids failed to produce sustained remission in 77% of patients. Conclusion. Nearly 50% of this patient cohort with biopsy-proven, clinically active IgG4-RD had normal serum IgG4 concentrations. Elevations in the serum IgG4 concentration appeared to identify a subset of patients with a more severe disease phenotype. In addition, the levels of IgG41 plasmablasts correlated well with the extent of disease activity. [ABSTRACT FROM AUTHOR]

Objective To discover biomarkers involved in the pathophysiology of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to determine whether low-density granulocytes (LDGs) contribute to gene expression signatures in AAV. Methods The source of clinical data and linked biologic specimens was a randomized controlled treatment trial in AAV. RNA sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit and during remission 6 months later. Gene expression was compared between patients who met versus those who did not meet the primary trial outcome of clinical remission at 6 months (responders versus nonresponders). Measurement of neutrophil-related gene expression was confirmed in peripheral blood mononuclear cells (PBMCs) to validate the findings in whole blood. A negative-selection strategy isolated LDGs from PBMC fractions. Results Differential expression between responders (n = 77) and nonresponders (n = 35) was detected in 2,346 transcripts at the baseline visit ( P < 0.05). Unsupervised hierarchical clustering demonstrated a cluster of granulocyte-related genes, including myeloperoxidase (MPO) and proteinase 3 (PR3). A granulocyte multigene composite score was significantly higher in nonresponders than in responders ( P < 0.01) and during active disease than during remission ( P < 0.01). This signature strongly overlapped an LDG signature identified previously in lupus (false discovery rate by gene set enrichment analysis <0.01). Transcription of PR3 measured in PBMCs was associated with active disease and treatment response ( P < 0.01). LDGs isolated from patients with AAV spontaneously formed neutrophil extracellular traps containing PR3 and MPO. Conclusion In AAV, increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV. [ABSTRACT FROM AUTHOR]