BackgroundIgG4-related disease (IgG4-RD) is a multi-organ immune-mediated condition of uncertain etiology characterised by substantial organ-specific morbidity if not diagnosed and treated promptly. Identifying IgG4-RD subgroups based on the distribution of organ involvement may influence the understanding of pathogenesis and guide clinical management.ObjectivesTo identify phenotypic clusters of IgG4-RD that may differentiate clinically meaningful subgroups using an unbiased method.MethodsThe study cohort consisted of 493 IgG4-RD subjects diagnosed by 76 IgG4-RD specialists from North America, South America, Europe, and Asia. For each case, investigators included details regarding age at disease onset and diagnosis, race/ethnicity, organ involvement, biopsy findings, and lab results. We performed latent class analysis (LCA) using SAS procedure PROC LCA to identify subgroups representing distinct patterns of organ involvement by IgG4-RD (figure 1). We fitted LCA models with 2–5 subgroups and chose the best model based on Akaike information criteria and adjusted Bayesian information criterion. The posterior probability of subgroup (cluster) membership for all cases was determined and cases were assigned to the cluster in which they had the highest probability of membership. We compared the distribution of organ involvement and other baseline features between clusters using Chi square tests and analysis of variance, where appropriate.ResultsOf the 493 IgG4-RD subjects, 65% were male, 40% were Caucasian, 45% were Asian, and 12% were Hispanic. The mean age at diagnosis was 59.5 (±14.0) years. Using LCA, we identified four clusters of IgG4-RD (table 1), each of which accounted for between 19% and 32% of the cohort. Cluster 1 (‘Hepatobiliary’) included 158 (32%) patients characterised by hepatobiliary involvement. Cluster 2 (‘Orbital’) included 88 (19%) patients characterised by orbital and/or sinus disease. Cluster 3 (‘Mikulicz’) included 109 (22%) patients who had features of classic Mikulicz (dacryoadenitis plus major salivary gland involvement), often accompanied by renal and lung disease. Cluster 4 (‘Retroperitoneal Fibrosis (RPF)’) included 138 (28%) patients with RPF and/or aortic involvement. The clusters differed significantly with regard to age at symptom onset (p<0.001), gender and race distribution (p<0.001), serum IgG4 concentration (p=0.02), and presence of hypocomplementemia (p<0.001). In contrast to the other clusters, cluster 2 (‘Orbital’) included a majority of female patients who tended to be younger. Cluster 3 (‘Mikulicz’) was characterised by the highest serum IgG4 concentrations and cluster 4 (‘RPF’) by the lowest. Hypocomplementemia, which occurred in only a minority of patients overall (9%), tended to segregate in cluster 3 (‘Mikulicz’), a group in which renal disease was common.Abstract OP0081 – Table 1ConclusionsUsing an unbiased method, we identified four phenotypic clusters of IgG4-RD patients. In addition to the differences in organ involvement, clusters were distinguished by age at diagnosis...

Background Elevated plasma uric acid has been inconsistently associated with a increased risk of total stroke; however, data are sparse among women. We examined the association between plasma uric acid concentrations and ischemic stroke among women and evaluate effect modification by key cardiovascular risk factors. Methods A nested case-control design with matching by age, race/ethnicity, smoking status, menopausal status, postmenopausal hormone therapy use, date of blood draw and fasting status was utilized among female participants of the Nurses' Health Study who provided blood samples between 1989-1990. Plasma uric acid was measured on stored blood samples. The National Survey of Stroke criteria were utilized to confirm 460 incident cases of ischemic stroke by medical records from 1990-2006. Multivariable conditional logistic regression models were estimated. Results In matched analysis, risk of ischemic stroke increased by 15% for each 1 mg/dL increase in plasma uric acid (95% CI: 3%-28%), but was no longer significant after adjustment for cardiovascular risk factors, particularly history of hypertension. The highest quartile of uric acid was significantly associated with greater risk of ischemic stroke (OR=1.56; 95% CI: 1.06-2.29, extreme quartiles) in matched analysis, but estimates were no longer significant after adjustment for cardiovascular risk factors (OR=1.43; 95% CI: 0.93-2.18). Significant effect modification by key cardiovascular risk factors was not observed. Conclusions Plasma uric acid levels were not independently associated with increased risk of ischemic stroke in this cohort of women. While plasma uric acid was associated with stroke risk factors, it was not independently associated with stroke risk.

The effect of HT042, a blend of three herbal extracts, on longitudinal bone growth was investigated in short- and long-term rat models. In the short-term model, we divided female Sprague-Dawley rats (3 weeks old) into six groups, according to treatment: vehicle, HT042 (100 mg/kg), Phlomis umbrosa (100 mg/kg), Astragalus membranaceus (100 mg/kg), and Eleutherococcus senticosus (100 mg/kg) were administered twice daily, and recombinant human growth hormone (rhGH) (1 IU) was subcutaneously injected once daily. Treatments were maintained for 4 days in each case. On day 3, tetracycline (20 mg/kg) was injected intraperitoneally (20 mg/kg) to form the fluorescent band on the growth plates. On days 2-4, 5-bromo-2'-deoxyuridine (BrdU) (50 mg/kg) was injected intraperitoneally to label proliferating cells. On day 5, the tibias were dissected and fixed in 30% sucrose. Dehydrated bone was sectioned at a thickness of 40 μm and observed. The bone growth in groups administered HT042 and rhGH was significantly increased to 433.50 ± 21.61 and 434.49 ± 15.21 μm/day, respectively, from 410.03 ± 17.4 μm/day (control). The height of the growth plates in the HT042 and rhGH groups was also significantly increased to 556.5 ± 21.1 and 544.2 ± 21.1 μm (P < .05), respectively, from 518.1 ± 4.1 μm (normal). The number of BrdU-positive cells in chondrocytes of the HT042 and rhGH groups was increased to 389 ± 36 and 627 ± 39 cells/mm² (P < .001), respectively, from 264 ± 17 cells/mm² (control). Insulin-like growth factor-1 and bone morphogenetic protein-2 in the HT042 group were highly expressed in the growth plate. In the long-term rat model, the body weight, nose-tail length, and nose-anus length were measured by microknemometry for 4 weeks. The body weight of the rhGH group was significantly increased. The nose-anus length of the HT042 and rhGH groups was significantly greater at 18.5 ± 0.3 and 18.7 ± 0.3 cm compared to 18.2 ± 0.2 cm (control).

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Eucommia ulmoides is one of the popular tonic herbs for the treatment of low back pain and bone fracture and is used in Korean medicine to reinforce muscles and bones. This study was performed to investigate the effects of E. ulmoides extract on longitudinal bone growth rate, growth plate height, and the expressions of bone morphogenetic protein 2 (BMP-2) and insulin-like growth factor 1 (IGF-1) in adolescent female rats. In two groups, we administered a twice-daily dosage of E. ulmoides extract (at 30 and 100 mg/kg, respectively) per os over 4 days, and in a control group, we administered vehicle only under the same conditions. Longitudinal bone growth rate in newly synthesized bone was observed using tetracycline labeling. Chondrocyte proliferation in the growth plate was observed using cresyl violet dye. In addition, we analyzed the expressions of BMP-2 and IGF-1 using immunohistochemistry. Eucommia ulmoides extract significantly increased longitudinal bone growth rate and growth plate height in adolescent female rats. In the immunohistochemical study, E. ulmoides markedly increased BMP-2 and IGF-1 expressions in the proliferative and hypertrophic zones. In conclusion, E. ulmoides increased longitudinal bone growth rate by promoting chondrogenesis in the growth plate and the levels of BMP-2 and IGF-1. Eucommia ulmoides could be helpful for increasing bone growth in children who have growth retardation.

Background: CD4 T cells help B cells produce antibodies following antigen challenge. This response classically occurs in germinal centers (GC) located in B-cell follicles of secondary lymphoid organs (SLO), a site of immunoglobulin isotype switching and affinity maturation. GC formation requires specialized CD4 T cells, T-follicular helper (Tfh) cells, which localize to follicles and provide B cells with survival and differentiation signals that are essential for B-cell maturation into memory and long-lived plasma cells. Pathogenic autoantibodies in human and murine lupus arise in a like manner. Although Tfh cells are critical for GC development, their genesis in humans, role in promotion of autoimmunity, and potential as therapeutic targets in SLE are incompletely understood. To address these issues, we dissected Tfh cell development and function, defining their transcriptional regulation, migration, and function in vivo in normal and lupus-prone mice and ex vivo in normal humans and patients with SLE. Methods: We used a combination of approaches-flow cytometry, confocal microscopy, microarrays, quantitative chromatin immunoprecipitation and DNA sequencing (ChIP-seq), retroviral overexpression, and T-cell-B-cell helper assays-to characterize Tfh cells in normal mice and in lupus-prone strains, and from the tonsils of normal humans and the blood of patients with SLE. Results: We found that the transcription factor Bcl6 (B-cell CLL/lymphoma 6) is necessary and sufficient for Tfh development and function, via genetic control of Tfh proteins that are essential for their migration to B-cell follicles and GC and subsequent B-cell maturation. We dissected steps in Tfh development within SLO, beginning with their genesis in the T-cell zone followed by emigration to sites of B-cell interaction outside the B-cell follicle, where we have shown that B cells serve to provide signals for continued Tfh expansion and follicular migration. We have now begun to tease apart the factors that mediate T-cell-B-cell collaboration in the follicle; these represent therapeutic targets in SLE. Finally, we have shown that patients with SLE have expansion of Tfh cells in the blood, a finding that highlights their potential role in the pathogenesis of SLE and as likely therapeutic targets. Conclusion: These studies help define the developmental pathways for Tfh cells, and the steps that enable these cells to function in the B-cell follicle to promote immunoglobulin and autoantibody production. They have also helped define markers of Tfh cells in normals and autoimmune individuals, and suggest that they are a promising therapeutic target in patients.

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HT042 is a new herbal prescription consisting of Astragalus membranaceus, Phlomis umbrosa and Eleutherococcus senticosus, which are used in Korean medicine to stimulate growth in children. We investigated the effects of HT042 on the body weight, longitudinal bone growth, and bone length in spontaneous dwarf rats (SDR). Male and female SDRs were divided into three groups: the control group (DW, 10 mL/kg/day), the recombinant human GH group (rhGH; 500 µg/kg/day), and the HT042 (100 mg/kg/day) group. Each group received the respective treatments for 10 days. Body weight was measured on day 10 of treatment. On day 8, tetracycline (20 mg/kg) was injected intraperitoneally into all individuals to form a fluorescent band on the newly synthesized bone. On day 10, femur and tibia lengths were measured using PIXImus. Body weight, longitudinal bone growth, and bone length were not affected in the HT042 group. In contrast, the rhGH group showed significantly increased body weight, longitudinal bone growth, and bone length. In conclusion, HT042 does not act through a GH-like effect to promote longitudinal bone growth.