Multiplicative Impact of Adverse Social Determinants of Health on Outcomes in Lupus Nephritis: A Meta-analysis and Systematic Review.

BACKGROUND: Social determinants of health (SDoH) likely contribute to outcome disparities in lupus nephritis (LN). Understanding the overall burden and contribution of each domain could guide future health-equity focused interventions to improve outcomes and reduce disparities in LN. Objectives of this meta-analysis were to: 1) determine the association of overall SDoH and specific SDoH domains on LN outcomes, and 2) develop a framework for the multidimensional impact of SDoH on LN outcomes. METHODS: We performed a comprehensive search of studies measuring associations between SDoH and LN outcomes. We examined pooled odds of poor LN outcomes including mortality, end-stage kidney disease, or cardiovascular disease in patients with and without adverse SDoH. Additionally, we calculated the pooled odds ratios of outcomes by four SDoH domains: individual (e.g., insurance), healthcare (e.g., fragmented care), community (e.g., neighborhood socioeconomic status), and health behaviors (e.g., smoking). RESULTS: Among 531 screened studies, 31 met inclusion and 13 studies with raw data were included in meta-analysis. Pooled odds of poor outcomes, were 1.47-fold higher in patients with any adverse SDoH. Patients with adverse SDoH in individual and healthcare domains had 1.64-fold and 1.77-fold higher odds of poor outcomes. We found a multiplicative impact of having ≥2 adverse SDoH on LN outcomes. Patients of Black Race with public insurance and fragmented care had 12-fold higher odds of poor LN outcomes. CONCLUSION: Adverse SDoH is associated with poor LN outcomes. Having ≥2 adverse SDoH, specifically in different SDoH domains, had a multiplicative impact leading to worse LN outcomes, widening disparities.

Distinct transcriptomes and autocrine cytokines underpin maturation and survival of antibody-secreting cells in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple autoantibody types, some of which are produced by long-lived plasma cells (LLPC). Active SLE generates increased circulating antibody-secreting cells (ASC). Here, we examine the phenotypic, molecular, structural, and functional features of ASC in SLE. Relative to post-vaccination ASC in healthy controls, circulating blood ASC from patients with active SLE are enriched with newly generated mature CD19-CD138+ ASC, similar to bone marrow LLPC. ASC from patients with SLE displayed morphological features of premature maturation and a transcriptome epigenetically initiated in SLE B cells. ASC from patients with SLE exhibited elevated protein levels of CXCR4, CXCR3 and CD138, along with molecular programs that promote survival. Furthermore, they demonstrate autocrine production of APRIL and IL-10, which contributed to their prolonged in vitro survival. Our work provides insight into the mechanisms of generation, expansion, maturation and survival of SLE ASC.

Efficacy and Safety of Inebilizumab in IgG4-Related Disease: Protocol for a Randomized Controlled Trial.

INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is a debilitating multiorgan disease characterized by recurring flares leading to organ dysfunction, decreased quality of life, and mortality. Glucocorticoids, the standard of care for IgG4-RD, are associated with substantial treatment-related toxicity. Inebilizumab, an antibody directed against CD19, mediates the rapid and durable depletion of CD19+ B cells thought to be involved in IgG4-RD pathogenesis. We describe the first international, prospective, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-cell depletion for flare prevention in IgG4-RD (MITIGATE). METHODS: The study was designed by an international panel of physicians with expertise in IgG4-RD. Critical trial design decisions included the selection of participants, definition of clinically meaningful primary and secondary endpoints, accommodation of standard of care, and development of flare diagnostic criteria. The study is approved for conduct in 22 countries. PLANNED OUTCOMES: The primary efficacy endpoint is time from randomization to the occurrence of the first centrally adjudicated and investigator-treated disease flare during the 1-year randomized controlled period. A set of novel, organ-specific flare diagnostic criteria were developed specifically for this trial, incorporating symptoms and signs, laboratory findings, imaging study results, and pathology data. MITIGATE aims to accrue 39 flares for the primary endpoint, which provides sufficient power to detect a relative risk reduction of 65% in the inebilizumab group. It is anticipated that enrollment of 160 participants will achieve this goal. Additional endpoints include safety, annualized flare rate, flare-free complete remission, quality-of-life measures, and cumulative glucocorticoid use. MITIGATE represents the first randomized, double-blind, placebo-controlled trial of any treatment strategy conducted in IgG4-RD. Data from this study will provide insights into the natural history and pathophysiology of IgG4-RD and the efficacy and safety of B-cell depletion as a therapeutic avenue. TRIAL REGISTRATION: NCT04540497.

Poor immunogenicity upon SARS-CoV-2 mRNA vaccinations in autoimmune SLE patients is associated with pronounced EF-mediated responses and anti-BAFF/Belimumab treatment.

Novel mRNA vaccines have resulted in a reduced number of SARS-CoV-2 infections and hospitalizations. Yet, there is a paucity of studies regarding their effectiveness on immunocompromised autoimmune subjects. In this study, we enrolled subjects naïve to SARS-CoV-2 infections from two cohorts of healthy donors (HD, n=56) and systemic lupus erythematosus (SLE, n=69). Serological assessments of their circulating antibodies revealed a significant reduction of potency and breadth of neutralization in the SLE group, only partially rescued by a 3rd booster dose. Immunological memory responses in the SLE cohort were characterized by a reduced magnitude of spike-reactive B and T cell responses that were strongly associated with poor seroconversion. Vaccinated SLE subjects were defined by a distinct expansion and persistence of a DN2 spike-reactive memory B cell pool and a contraction of spike-specific memory cTfh cells, contrasting with the sustained germinal center (GC)-driven activity mediated by mRNA vaccination in the healthy population. Among the SLE-associated factors that dampened the vaccine responses, treatment with the monoclonal antibody anti-BAFF/Belimumab (a lupus FDA-approved B cell targeting agent) profoundly affected the vaccine responsiveness by restricting the de novo B cell responses and promoting stronger extra-follicular (EF)-mediated responses that were associated with poor immunogenicity and impaired immunological memory. In summary, this study interrogates antigen-specific responses and characterized the immune cell landscape associated with mRNA vaccination in SLE. The identification of factors associated with reduced vaccine efficacy illustrates the impact of SLE B cell biology on mRNA vaccine responses and provides guidance for the management of boosters and recall vaccinations in SLE patients according to their disease endotype and modality of treatment.

Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID.

While immunologic correlates of COVID-19 have been widely reported, their associations with post-acute sequelae of COVID-19 (PASC) remain less clear. Due to the wide array of PASC presentations, understanding if specific disease features associate with discrete immune processes and therapeutic opportunities is important. Here we profile patients in the recovery phase of COVID-19 via proteomics screening and machine learning to find signatures of ongoing antiviral B cell development, immune-mediated fibrosis, and markers of cell death in PASC patients but not in controls with uncomplicated recovery. Plasma and immune cell profiling further allow the stratification of PASC into inflammatory and non-inflammatory types. Inflammatory PASC, identifiable through a refined set of 12 blood markers, displays evidence of ongoing neutrophil activity, B cell memory alterations, and building autoreactivity more than a year post COVID-19. Our work thus helps refine PASC categorization to aid in both therapeutic targeting and epidemiological investigation of PASC.

Obexelimab in Systemic Lupus Erythematosus With Exploration of Response Based on Gene Pathway Co-Expression Patterns: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial.

OBJECTIVE: Obexelimab is an investigational, bifunctional, noncytolytic monoclonal antibody that binds CD19 and FcyRIIb to inhibit B cells, plasmablasts, and plasma cells. This trial evaluated the efficacy and safety of obexelimab in the treatment of patients with systemic lupus erythematosus (SLE). METHODS: During screening, patients with active, non-organ-threatening SLE received corticosteroid injections to ameliorate symptoms while immunosuppressants were withdrawn (≤10 mg/day prednisone equivalent and ≤400 mg/day hydroxychloroquine allowed). Patients with improved disease activity were randomized 1:1 to obexelimab 5 mg/kg intravenously or placebo once every 2 weeks until week 32 or loss of improvement (LOI). RESULTS: In this study, 104 patients were randomized. Analysis of the primary endpoint, proportion of patients reaching week 32 without LOI, used an efficacy-evaluable (EE) population defined as patients who completed the study or withdrew for flare or treatment-related toxicity. This endpoint did not reach statistical significance: 21 of 50 obexelimab-treated patients (42.0%) versus 12 of 42 patients (28.6%) treated with a placebo (P = 0.183). Time to LOI was increased in obexelimab-treated patients versus patients treated with a placebo in the EE (hazard ratio [HR] 0.53, P = 0.025) and intention-to-treat (HR 0.59, P = 0.062) populations. In obexelimab-treated patients, B cells decreased approximately 50%, and trough concentration and inclusion in baseline gene expression clusters with high B cell pathway modules were associated with increased time to LOI. Obexelimab was associated with infusion reactions but was generally safe and well-tolerated. CONCLUSION: Although the primary endpoint was not reached, secondary analysis showed time to LOI was significantly increased in obexelimab-treated patients, and analysis of patient subsets defined by gene expression patterns at baseline suggests a responding subpopulation.

SLE Antibody-Secreting Cells Are Characterized by Enhanced Peripheral Maturation and Survival Programs.

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by multiple autoantibodies, some of which are present in high titers in a sustained, B cell-independent fashion consistent with their generation from long-lived plasma cells (LLPC). Active SLE displays high numbers of circulating antibody-secreting cells (ASC). Understanding the mechanisms of generation and survival of SLE ASC would contribute important insight into disease pathogenesis and novel targeted therapies. We studied the properties of SLE ASC through a systematic analysis of their phenotypic, molecular, structural, and functional features. Our results indicate that in active SLE, relative to healthy post-immunization responses, blood ASC contain a much larger fraction of newly generated mature CD19- CD138+ ASC similar to bone marrow (BM) LLPC. SLE ASC were characterized by morphological and structural features of premature maturation. Additionally, SLE ASC express high levels of CXCR4 and CD138, and molecular programs consistent with increased longevity based on pro-survival and attenuated pro-apoptotic pathways. Notably, SLE ASC demonstrate autocrine production of APRIL and IL-10 and experience prolonged in vitro survival. Combined, our findings indicate that SLE ASC are endowed with enhanced peripheral maturation, survival and BM homing potential suggesting that these features likely underlie BM expansion of autoreactive PC.

Clinical Characteristics and Classification Criteria Performance in a Single-Center Cohort of 114 Patients With Immunoglobulin G4-Related Disease.

INTRODUCTION/OBJECTIVES: Immunoglobulin G4-related disease (IgG4-RD) is a heterogeneous fibroinflammatory condition. The 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Classification Criteria for IgG4-RD were published to provide unified classification criteria in clinical research. The purpose of this study was to characterize demographics, disease manifestations, and treatments of patients with IgG4-RD and assess performance of the Classification Criteria in a heterogeneous cohort with a large population of Black patients. METHODS: This was a medical records review of all patients referred to a specialized IgG4-RD clinic. Demographics, serology, histopathology, disease manifestations, and treatment information were collected and analyzed. An ACR/EULAR Classification Criteria score for IgG4-RD was calculated to compare performance in definite diagnosis, probable diagnosis, and mimicker groups. RESULTS: A total of 198 patients were evaluated. Eighty-five (43%) were mimickers. Of the remaining 114, 58 (51%) were classified as definite, and 56 (49%) as probable cases by treating clinicians. Pancreatitis was the most common presentation (37%) among 28 different organ manifestations of IgG4-RD. In patients with definite clinical diagnosis of IgG4-RD, 84% met the IgG4-RD Classification Criteria (i.e., score ≥20) with mean score of 29. Only 9% of the probable cases met this threshold with an average score of 8. None of the mimickers met the Classification Criteria. CONCLUSIONS: This study highlights the broad spectrum of IgG4-RD and validates the use of the ACR/EULAR Classification Criteria for IgG4-RD, including a large proportion of Black patients. As shown in this study, IgG4-RD is a heterogeneous disease and continues to represent a diagnostic challenge to clinicians.

Performance of Modified ALMS and BLISS Criteria with Standard of Care Treatment in Two US Health Care Systems.

OBJECTIVE: A retrospective cohort study was undertaken in a predominantly Black population undergoing standard treatment for lupus nephritis (LN) to estimate the incidence of, and risk factors for, complete response (CR) according to modified Aspreva Lupus Management Study (mALMS) and modified Belimumab International Study in Lupus Nephritis (mBLISS) criteria by 12 months. METHODS: Patients with biopsy-proven LN class III or IV ± V, urine protein-to-creatinine ratio of ≥1gm/gm and estimated glomerular filtration rate of >50 ml/minute/1.73 m2 at the time of the incident LN flare were included. The clinical, treatment, and laboratory factors associated with CR were identified using multivariable Cox regression. RESULTS: Of 173 patients, 86.1% were women, 77.5% were Black, and over half (59.5%) had non-commercial insurance. By 12 months, 20.6% (95% confidence interval (95% CI) 14.6-28.6%) achieved mALMS CR and 33.7% (95% CI 26.4-42.4%) achieved mBLISS CR. Factors associated with mBLISS CR were commercial insurance (adjusted CR ratio = 3.5 [95% CI 1.9-6.7]; P < 0.001), albumin (adjusted CR ratio = 1.8 per 1 gm/dl increase in albumin; P = 0.02), and low C4 (adjusted CR ratio = 2.6; P = 0.03). Cumulative incidence of end-stage renal disease (ESRD) at 3 years was 23.1% (95% CI 15.7-31.3%) and 6.1% (95% CI 2.8-11.1%) for death. Patients with non-commercial insurance were more likely to develop ESRD, with cumulative incidence of 30.4% (95% CI 19.6-41.9%) compared to 12.7% (95% CI 5.0-24.2%) for patients with commercial insurance (P = 0.024). CONCLUSION: In a primarily Black, uninsured LN population, despite achieving similar CR rates at 12 months, the incidence of ESRD and death exceeded those observed in controlled clinical trials with placebo arms.

Dysregulated naive B cells and de novo autoreactivity in severe COVID-19.

Severe SARS-CoV-2 infection1 has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic2-5. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential6-10, although their origins and resolution have remained unclear11. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity12,13, as a dominant feature of severe and critical COVID-19 (refs. 14-18). Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-derived, low-mutation IgG1 population of antibody-secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10-15 days after the onset of symptoms. Detailed analysis of the low-selection compartment shows a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway on recovery, re-establishment of tolerance standards and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae.

Outcomes of COVID-19 in a cohort of pediatric patients with rheumatic diseases.

BACKGROUND: There are few reports of COVID-19 in pediatric patients with rheumatic diseases. This study describes the clinical presentation and outcomes of COVID-19 in this population. METHODS: We analyzed a single-center case series of pediatric patients with rheumatic diseases and laboratory-confirmed COVID-19. Demographic, baseline and COVID-19 associated clinical features were compared between ambulatory and hospitalized patients using univariate analysis. RESULTS: Fifty-five cases were identified: 45 (81.8%) in the ambulatory group and 10 (18.2%) hospitalized. African American race (OR 7.78; 95% CI [1.46-55.38]; p = 0.006) and cardiovascular disease (OR 19.40; 95% CI 2.45-254.14; p = 0.001) predominated in hospitalized patients. Active rheumatic disease (OR 11.83; 95% CI 1.43-558.37; p = 0.01), medium/high-dose corticosteroid use (OR 14.12; 95% CI [2.31-106.04]; p = 0.001), mycophenolate use (OR 8.84; 95% CI [1.64-63.88]; p = 0.004), rituximab use (OR 19.40; 95% CI [2.45-254.14]; p = 0.001) and severe immunosuppression (OR 34.80; 95% CI [3.94-1704.26]; p = < 0.001) were associated with increased odds of hospitalization. Fever (OR 7.78; 95% CI [1.46-55.38]; p = 0.006), dyspnea (OR 26.28; 95% CI [2.17-1459.25]; p = 0.003), chest pain (OR 13.20; 95% CI [1.53-175.79]; p = 0.007), and rash (OR 26.28; 95% CI [2.17-1459.25]; p = 0.003) were more commonly observed in hospitalized patients. Rheumatic disease flares were almost exclusive to hospitalized patients (OR 55.95; 95% CI [5.16-3023.74]; p < 0.001).. One patient did not survive. CONCLUSIONS: Medium/high-dose corticosteroid, mycophenolate and rituximab use, and severe immunosuppression were risk factors for hospitalization. Fever, dyspnea, chest pain, and rash were high-risk symptoms for hospitalization. Rheumatic disease activity and flare could contribute to the need for hospitalization.

Pregnancy in patients with systemic lupus erythematosus after cyclophosphamide therapy.

Systemic lupus erythematosus (SLE) often affects females of reproductive age and Cyclophosphamide, an alkylating agent leading to premature ovarian insufficiency (POF) and labelled category D for pregnancy is used as induction therapy for severe manifestations of lupus. There have been multiple case series reflecting variable outcomes of pregnancies after cyclophosphamide use for cancers and autoimmune diseases. With increasing maternal age, we have an increasing population of lupus patients who may wish to conceive after having received cyclophosphamide therapy. The objective of our study was to improve our understanding of the impact of cyclophosphamide exposure on fertility and pregnancy outcomes in patients with SLE.We retrospectively reviewed the charts of all patients who had received intravenous cyclophosphamide at our academic institute in the time period from 2000-2018 and identified 440 patients which included 157 female patients of reproductive age. There were 37 documented pregnancies after the cyclophosphamide infusion, of which 23 patients had successful outcomes; 4 elective abortion and 10 miscarriages. There were 17 patients who developed POF, of which 7 also had end stage renal disease. The average cumulative dose of cyclophosphamide in the patients who had successful pregnancy was 4080.37 mg compared to 2806.25 mg in those who had a miscarriage (p 0.164) and 5526.47 mg in those who developed POF (p 0.046). Using multiple regressions to evaluate risk factors impacting pregnancy outcomes, when taken as a set, the predictors including race, serological profile, exposure to steroids and Mycophenolate mofetil, age at cyclophosphamide infusion, age at pregnancy, and cumulative cyclophosphamide dose accounted for 46.29% of the variance in outcome of pregnancy (p 0.23) and 39.58% of the variance in development of premature ovarian failure (p 0.008). We noted statistical significance in the impact of maternal age at time of pregnancy (p 0.04) and duration of time between the last infusions to subsequent pregnancy (p 0.02) to pregnancy outcome.Our findings suggest that a longer time interval between the last cyclophosphamide infusion and subsequent pregnancy was favorable for a successful outcome and higher cumulative cyclophosphamide dose is more likely to be associated with premature ovarian failure.

Clinical course and outcomes of COVID-19 in rheumatic disease patients: a case cohort study with a diverse population.

OBJECTIVE: To determine clinical course and outcomes in rheumatic disease patients with coronavirus disease 2019 (COVID-19) and compare results to uninfected patients. METHODS: We conducted a case cohort study of autoimmune disease patients with COVID-19 (confirmed by severe acute respiratory syndrome coronavirus 2 PCR) from February 1, 2020, to July 31, 2020, and compared them in a 1:3 ratio with uninfected patients who were matched based on race, age, sex, and comorbidity index. Patient demographics, clinical course, and outcomes were compared among these patient groups. RESULTS: A total of 70 rheumatic disease patients with COVID-19 (mean age, 56.6 years; 64% African American) were identified. The 34 (49%) patients who were hospitalized used oral glucocorticoids more frequently than those treated as outpatients (p < 0.01). All 10 patients using anti-TNFα medications were treated as outpatients (p < 0.01). Those hospitalized with COVID-19 more often required ICU admission (17 (50%) vs 27 (26%), p = 0.01) and intubation (10 (29%) vs 6 (6%), p < 0.01) than uninfected patients and had higher mortality rates (6 (18%) vs 3 (3%), p < 0.01). Of the six COVID-19 patients who died, only one was of African ancestry (p = 0.03). CONCLUSION: Rheumatic disease patients infected with COVID-19 were more likely to require ICU admission, ventilation, and died more frequently versus uninfected patients with autoimmune disease. Patients on anti-TNFα medications were hospitalized less frequently, while those on chronic glucocorticoids were hospitalized more frequently. These findings have important implications for medication choice in rheumatic disease patients during the ongoing spread of COVID-19. Key Points • We show that hospitalized rheumatic disease patients with COVID-19 have poorer outcomes including ICU admission, ventilation, and death compared to hospitalized rheumatic disease patients not infected with COVID-19. • This study adds further support regarding protective effects of anti-TNFα medications in COVID-19 disease course, with 0 of 10 of these patients required hospitalization.

The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease.

IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serological, radiological and pathological data is required for diagnosis. This work was undertaken to develop and validate an international set of classification criteria for IgG4-RD. An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises; existing literature; derivation and validation cohorts of 1879 subjects (1086 cases, 793 mimickers); and multicriterion decision analysis to identify, weight and test potential classification criteria. Two independent validation cohorts were included. A three-step classification process was developed. First, it must be demonstrated that a potential IgG4-RD case has involvement of at least one of 11 possible organs in a manner consistent with IgG4-RD. Second, exclusion criteria consisting of a total of 32 clinical, serological, radiological and pathological items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification. Third, eight weighted inclusion criteria domains, addressing clinical findings, serological results, radiological assessments and pathological interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% CI 97.2% to 99.8%) and a sensitivity of 85.5% (95% CI 81.9% to 88.5%). In the second, the specificity was 97.8% (95% CI 93.7% to 99.2%) and the sensitivity was 82.0% (95% CI 77.0% to 86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds. ACR/EULAR classification criteria for IgG4-RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiological and basic science investigations.

The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease.

OBJECTIVE: IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serologic, radiologic, and pathologic data is required for diagnosis. This work was undertaken to develop and validate an international set of classification criteria for IgG4-RD. METHODS: An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises, existing literature, derivation and validation cohorts of 1,879 subjects (1,086 cases, 793 mimickers), and multicriterion decision analysis to identify, weight, and test potential classification criteria. Two independent validation cohorts were included. RESULTS: A 3-step classification process was developed. First, it must be demonstrated that a potential IgG4-RD case has involvement of at least 1 of 11 possible organs in a manner consistent with IgG4-RD. Second, exclusion criteria consisting of a total of 32 clinical, serologic, radiologic, and pathologic items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification. Third, 8 weighted inclusion criteria domains, addressing clinical findings, serologic results, radiology assessments, and pathology interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% confidence interval [95% CI] 97.2-99.8%) and a sensitivity of 85.5% (95% CI 81.9-88.5%). In the second, the specificity was 97.8% (95% CI 93.7-99.2%) and the sensitivity was 82.0% (95% CI 77.0-86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds. CONCLUSION: ACR/EULAR classification criteria for IgG4-RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiologic, and basic science investigations.