Choi, Hyon K.

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.

ObjectivePatients 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.MethodsLipid 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.ResultsOf 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.ConclusionLipid 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.

ObjectiveIgG4‐related disease (IgG4‐RD) can cause fibroinflammatory lesions in nearly any organ, leading to organ dysfunction and failure. The IgG4‐RD Responder Index (RI) was developed to help investigators assess the efficacy of treatment in a structured manner. The aim of this study was to validate the RI in a multinational investigation.MethodsThe RI guides investigators through assessments of disease activity and damage in 25 domains, incorporating higher weights for disease manifestations that require urgent treatment or that worsen despite treatment. After a training exercise, investigators reviewed 12 written IgG4‐RD vignettes based on real patients. Investigators calculated both an RI score as well as a physician's global assessment (PhGA) score for each vignette. In a longitudinal assessment, 3 investigators used the RI in 15 patients with newly active disease who were followed up over serial visits after treatment. We assessed interrater and intrarater reliability, precision, validity, and responsiveness.ResultsThe 26 physician investigators included representatives from 6 specialties and 9 countries. The interrater and intrarater reliability of the RI was strong (0.89 and 0.69, respectively). Correlations (construct validity) between the RI and PhGA were high (Spearman's r = 0.9, P < 0.0001). The RI was sensitive to change (discriminant validity). Following treatment, there was significant improvement in the RI score (mean change 10.5 [95% confidence interval (95% CI) 5.4–12], P < 0.001), which correlated with the change in the PhGA. Urgent disease and damage were captured effectively.DiscussionIn this international, multispecialty study, we observed that the RI is a valid and reliable disease activity assessment tool that can be used to measure response to therapy.

ObjectiveWe investigated the relationships between glucocorticoid use, disease activity, and changes in body mass index (BMI) in patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV).MethodsWe 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.ResultsThe 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).ConclusionOur 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.

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

Objective Existing criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was undertaken to develop new classification criteria for gout. Methods An international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multicriterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set. Results The entry criterion for the new classification criteria requires the occurrence of at least 1 episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (i.e., synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU‐negative synovial fluid aspirate), and imaging (double‐contour sign on ultrasound or urate on dual‐energy computed tomography, radiographic gout‐related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively). Conclusion The new classification criteria, developed using a data‐driven and decision analytic approach, have excellent performance characteristics and incorporate current state‐of‐the‐art evidence regarding gout.