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Objective: In the randomized Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, myeloablation, followed by hematopoietic stem cell transplantation (HSCT), led to the normalization of systemic sclerosis (SSc) peripheral blood cell (PBC) gene expression signature at the 26-month visit. Herein, we examined long-term molecular changes ensuing 54 months after randomization for individuals receiving an HSCT or 12 months of intravenous cyclophosphamide (CYC)., Methods: Global PBC transcript studies were performed in study participants at pretreatment baseline and at 38 months and 54 months after randomization, as well as in healthy controls using Illumina HT-12 arrays., Results: Thirty (HSCT = 19 and CYC = 11) participants had 38-month samples available, and 26 (HSCT = 16 and CYC = 11) had 54-month samples available. In the paired comparison to baseline, a significant down-regulation of interferon modules and an up-regulation of cytotoxic/natural killer module were observed at the 38-month and 54-month visits in the HSCT arm, indicating a long-term normalization of baseline SSc gene expression signature. No differentially expressed modules were detected in the CYC arm. In comparison to samples from healthy controls, 38-month visit samples in the HSCT arm showed an up-regulation of B cell and plasmablast modules and a down-regulation of myeloid and inflammation modules. Importantly, 54-month HSCT samples did not show any differentially expressed modules compared to healthy control samples, suggesting completion of immune reconstitution. Participants in the CYC arm continued to show an SSc transcript signature in comparison to controls at both time points., Conclusion: Paralleling the observed clinical benefit, HSCT leads to durable long-term normalization of the molecular signature in SSc, with completion of immune resetting to 54 months after HSCT., (© 2024 American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Mycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy., Methods: This multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed., Findings: Between Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 [90%] of 50 participants) and the withdrawal group (46 [88%] of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 [64%]) compared with the withdrawal group (24 [46%])., Interpretations: Mycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE., Funding: The National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases., Competing Interests: Declaration of interests AS received consulting fees from AstraZeneca, AbbVie, GSK, Kezar Life Sciences, Eli Lilly, Bristol Myers Squibb and lecture fees from Astra Zeneca, Rheumatologic Dermatology Society, and Lupus Therapeutics. GC was a member of independent data monitoring boards of clinical trials by Roche and VERA therapeutics. BHR received consulting payments from Roche/Genentech, Aurinia, Novartis, Alexion, GSK, Kyverna, Kezar, HI-Bio, and Tome and served on the Board of Directors for NephroNet and the Scientific or Medical Advisory Board for the Lupus Foundation of America and Lupus Accelerating Breakthroughs Consortium/Lupus Research Alliance. RJL received support for the present manuscript as part of the Autoimmunity Centers of Excellence grant. DE received grants or contracts from the American College of Rheumatology and European Alliance of Associations for Rheumatology, NIH, GSK, and Exagen; royalties or licenses from UptoDate; consulting fees from Chugai, AbbVie, and Argenx; and lecture fees from GSK and Aurinia. JM is an employee of DAIT/NIAID, the sponsor and funding agency of this trial. CA received a grant or contract from GSK; consulting fees from GSK, AstraZeneca, Bristol Myers Squibb, and AbbVie; and served on a data safety monitoring or advisory board for Alumis. LKE serves as a consultant for Rho Federal Division. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: Results from the SCOT (Scleroderma: Cyclophosphamide Or Transplantation) clinical trial demonstrated significant benefits of haematopoietic stem cell transplant (HSCT) versus cyclophosphamide (CTX) in patients with systemic sclerosis. The objective of this study was to test the hypothesis that transplantation stabilises the autoantibody repertoire in patients with favourable clinical outcomes., Methods: We used a bead-based array containing 221 protein antigens to profile serum IgG autoantibodies in participants of the SCOT trial., Results: Comparison of autoantibody profiles at month 26 (n=23 HSCT; n=22 CTX) revealed antibodies against two viral antigens and six self-proteins (SSB/La, CX3CL1, glycyl-tRNA synthetase (EJ), parietal cell antigen, bactericidal permeability-increasing protein and epidermal growth factor receptor (EGFR)) that were significantly different between treatment groups. Linear mixed model analysis identified temporal increases in antibody levels for hepatitis B surface antigen, CCL3 and EGFR in HSCT-treated patients. Eight of 32 HSCT-treated participants and one of 31 CTX-treated participants had temporally varying serum antibody profiles for one or more of 14 antigens. Baseline autoantibody levels against 20 unique antigens, including 9 secreted proteins (interleukins, IL-18, IL-22, IL-23 and IL-27), interferon-α2A, stem cell factor, transforming growth factor-β, macrophage colony-stimulating factor and macrophage migration inhibitory factor were significantly higher in patients who survived event-free to month 54., Conclusions: Our results suggest that HSCT favourably alters the autoantibody repertoire, which remains virtually unchanged in CTX-treated patients. Although antibodies recognising secreted proteins are generally thought to be pathogenic, our results suggest a subset could potentially modulate HSCT in scleroderma., Competing Interests: Competing interests: LC serves on the advisory board or received consulting fees from Mitsubishi Tanabe, Jannsen, Genentech, Kyverna, and Eicos Sciences., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Myeloablative autologous haematopoietic stem cell transplant (HSCT) was recently demonstrated to provide significant benefit over cyclophosphamide (CYC) in the treatment of diffuse cutaneous systemic sclerosis (dcSSc) in the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial. As dysregulation of the B cell compartment has previously been described in dcSSc, we sought to gain insight into the effects of myeloablative autologous HSCT as compared with CYC., Methods: We sequenced the peripheral blood immunoglobulin heavy chain (IGH) repertoires in patients with dcSSc enrolled in the SCOT trial., Results: Myeloablative autologous HSCT was associated with a sustained increase in IgM isotype antibodies bearing a low mutation rate. Clonal expression was reduced in IGH repertoires following myeloablative autologous HSCT. Additionally, we identified a underusage of immunoglobulin heavy chain V gene 5-51 in patients with dcSSc, and usage normalised following myeloablative autologous HSCT but not CYC treatment., Conclusions: Together, these findings suggest that myeloablative autologous HSCT resets the IGH repertoire to a more naïve state characterised by IgM-expressing B cells, providing a possible mechanism for the elimination of pathogenic B cells that may contribute to the benefit of HSCT over CYC in the treatment of dcSSc., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objective: Among individuals with systemic sclerosis (SSc) randomized to cyclophosphamide (CYC) (n = 34) or hematopoietic stem cell transplantation (HSCT) (n = 33), we examined longitudinal trends of clinical, pulmonary function, and quality of life measures while accounting for the influence of early failures on treatment comparisons., Methods: Assuming that data were missing at random, mixed-effects regression models were used to estimate longitudinal trends for clinical measures when comparing treatment groups. Results were compared to observed means and to longitudinal trends estimated from shared parameter models, assuming that data were missing not at random. Longitudinal trends for SSc intrinsic molecular subsets defined by baseline gene expression signatures (normal-like, inflammatory, and fibroproliferative signatures) were also studied., Results: Available observed means for pulmonary function tests appeared to improve over time in both arms. However, after accounting for participant loss, forced vital capacity in HSCT recipients increased by 0.77 percentage points/year but worsened by -3.70/year for CYC (P = 0.004). Similar results were found for diffusing capacity for carbon monoxide and quality of life indicators. Results for both analytic models were consistent. HSCT recipients in the inflammatory (n = 20) and fibroproliferative (n = 20) subsets had superior long-term trends compared to CYC for pulmonary and quality of life measures. HSCT was also superior for modified Rodnan skin thickness scores in the fibroproliferative subset. For the normal-like subset (n = 22), superiority of HSCT was less apparent., Conclusion: Longitudinal trends estimated from 2 statistical models affirm the efficacy of HSCT over CYC in severe SSc. Failure to account for early loss of participants may distort estimated clinical trends over the long term., (© 2021 American College of Rheumatology.)

Objectives: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial compared hematopoietic stem cell transplant to CYC treatment in patients with early SSc with progressive skin and lung or kidney involvement. Here we describe lymphocyte phenotype abnormalities at study entry and the relation to prior DMARD therapy., Methods: Lymphocyte subsets (n = 26) measured by flow cytometry were compared in 123 heathy controls and 71 SCOT participants, including those given (n = 57) or not given (n = 14) DMARDs within 12 months of randomization., Results: Compared with healthy controls, individuals with SSc showed significant reductions in central memory CD8 T cells, activated total and CD4 T cells, γ/δ T cells, memory B cells, myeloid and plasmacytoid dendritic cells and FOXP3+CD25+ Treg cells and increases in naïve CD4 T cells, effector memory CD4 T cells and effector CD8 T cells. A greater bias towards a IL-4+ Th2/T cytotoxic 2 (Tc2) phenotype based on the Th2:Th1 CD4 ratio and Tc2:Tc1 CD8 T cells was also found. Notably, no difference in any lymphocyte subset was observed between those given or not given prior DMARDs., Conclusions: In patients with early, severe SSc, significant lymphocyte subset abnormalities were observed. Prior treatment with immunosuppressive therapy did not impact the immunophenotype, suggesting that lymphocyte disturbances in scleroderma appeared to be due to the disease itself., Trial Registration: ClinicalTrials.gov (https://clinicaltrials.gov), NCT00114530., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: B cells can become activated in germinal center (GC) reactions in secondary lymphoid tissue and in ectopic GCs in rheumatoid arthritis (RA) synovium that may be tumor necrosis factor (TNF) and lymphotoxin (LT) dependent. This study was undertaken to characterize the peripheral B cell compartment longitudinally during anti-TNF therapy in RA., Methods: Participants were randomized in a 2:1 ratio to receive standard dosing regimens of etanercept (n = 43) or adalimumab (n = 20) for 24 weeks. Eligible participants met the American College of Rheumatology 1987 criteria for RA, had clinically active disease (Disease Activity Score in 28 joints >4.4), and were receiving stable doses of methotrexate. The primary mechanistic end point was the change in switched memory B cell fraction from baseline to week 12 in each treatment group., Results: B cell subsets remained surprisingly stable over the course of the study regardless of treatment group, with no significant change in memory B cells. Blockade of TNF and LT with etanercept compared to blockade of TNF alone with adalimumab did not translate into significant differences in clinical response. The frequencies of multiple activated B cell populations, including CD21- double-negative memory and activated naive B cells, were higher in RA nonresponders at all time points, and CD95+ activated B cell frequencies were increased in patients receiving anti-TNF treatment in the nonresponder group. In contrast, frequencies of transitional B cells-a putative regulatory subset-were lower in the nonresponders., Conclusion: Overall, our results support the notion that peripheral blood B cell subsets are remarkably stable in RA and not differentially impacted by dual blockade of TNF and LT with etanercept or single blockade of TNF with adalimumab. Activated B cells do associate with a less robust response., (© 2021, American College of Rheumatology.)

BackgroundIL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients.MethodsWe conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6-17 years).ResultsThere was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.ConclusionTocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.Trial RegistrationClinicalTrials.gov NCT02293837.FundingNIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.

Rationale: Systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH) is one of the most prevalent and deadly forms of PAH. B cells may contribute to SSc pathogenesis. Objectives: We investigated the safety and efficacy of B-cell depletion for SSc-PAH. Methods: In an NIH-sponsored, multicenter, double-blinded, randomized, placebo-controlled, proof-of-concept trial, 57 patients with SSc-PAH on stable-dose standard medical therapy received two infusions of 1,000 mg rituximab or placebo administered 2 weeks apart. The primary outcome measure was the change in 6-minute-walk distance (6MWD) at 24 weeks. Secondary endpoints included safety and invasive hemodynamics. We applied a machine learning approach to predict drug responsiveness. Measurements and Main Results: We randomized 57 subjects from 2010 to 2018. In the primary analysis, using data through Week 24, the adjusted mean change in 6MWD at 24 weeks favored the treatment arm but did not reach statistical significance (23.6 ± 11.1 m vs. 0.5 ± 9.7 m; P  = 0.12). Although a negative study, when data through Week 48 were also considered, the estimated change in 6MWD at Week 24 was 25.5 ± 8.8 m for rituximab and 0.4 ± 7.4 m for placebo ( P  = 0.03). Rituximab treatment appeared to be safe and well tolerated. Low levels of RF (rheumatoid factor), IL-12, and IL-17 were sensitive and specific as favorable predictors of a rituximab response as measured by an improved 6MWD (receiver operating characteristic area under the curve, 0.88-0.95). Conclusions: B-cell depletion therapy is a potentially effective and safe adjuvant treatment for SSc-PAH. Future studies in these patients can confirm whether the identified biomarkers predict rituximab responsiveness. Clinical trial registered with www.clinicaltrails.gov (NCT01086540).

Objective: To provide a large-scale assessment of serum protein dysregulation in diffuse cutaneous systemic sclerosis (dcSSc) and to investigate serum protein correlates of SSc fibrotic features., Methods: We investigated serum protein profiles of 66 participants with dcSSc at baseline who were enrolled in the Scleroderma: Cyclophosphamide or Transplant Trial and 66 age- and sex-matched healthy control subjects. A panel of 230 proteins, including several cytokines and chemokines, was investigated. Whole blood gene expression profiling in concomitantly collected samples was performed., Results: Among the participants with dcSSc, the mean disease duration was 2.3 years. All had interstitial lung disease (ILD), and none were being treated with immunosuppressive agents at baseline. Ninety proteins were differentially expressed in participants with dcSSc compared to healthy control subjects. Similar to previous global skin transcript results, hepatic fibrosis, granulocyte and agranulocyte adhesion, and diapedesis were the top overrepresented pathways. Eighteen proteins correlated with the modified Rodnan skin thickness score (MRSS). Soluble epidermal growth factor receptor was significantly down-regulated in dcSSc and showed the strongest negative correlation with the MRSS, being predictive of the score's course over time, whereas α 1 -antichymotrypsin was significantly up-regulated in dcSSc and showed the strongest positive correlation with the MRSS. Furthermore, higher levels of cancer antigen 15-3 correlated with more severe ILD, based on findings of reduced forced vital capacity and higher scores of disease activity on high-resolution computed tomography. Only 14 genes showed significant differential expression in the same direction in serum protein and whole blood RNA gene expression analyses., Conclusion: Diffuse cutaneous SSc has a distinct serum protein profile with prominent dysregulation of proteins related to fibrosis and immune cell adhesion/diapedesis. The differential expression for most serum proteins in SSc is likely to originate outside the peripheral blood cells., (© 2021, American College of Rheumatology.)

Objective: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial demonstrated clinical benefit of haematopoietic stem cell transplant (HSCT) compared with cyclophosphamide (CYC). We mapped PBC (peripheral blood cell) samples from the SCOT clinical trial to scleroderma intrinsic subsets and tested the hypothesis that they predict long-term response to HSCT., Methods: We analysed gene expression from PBCs of SCOT participants to identify differential treatment response. PBC gene expression data were generated from 63 SCOT participants at baseline and follow-up timepoints. Participants who completed treatment protocol were stratified by intrinsic gene expression subsets at baseline, evaluated for event-free survival (EFS) and analysed for differentially expressed genes (DEGs)., Results: Participants from the fibroproliferative subset on HSCT experienced significant improvement in EFS compared with fibroproliferative participants on CYC (p=0.0091). In contrast, EFS did not significantly differ between CYC and HSCT arms for the participants from the normal-like subset (p=0.77) or the inflammatory subset (p=0.1). At each timepoint, we observed considerably more DEGs in HSCT arm compared with CYC arm with HSCT arm showing significant changes in immune response pathways., Conclusions: Participants from the fibroproliferative subset showed the most significant long-term benefit from HSCT compared with CYC. This study suggests that intrinsic subset stratification of patients may be used to identify patients with SSc who receive significant benefit from HSCT., Competing Interests: Competing interests: MLW reports grants and personal fees from Celdara Medical, grants and personal fees from Bristol Myers Squib, personal fees from Acceleron, personal fees from Abbvie, grants and personal fees from Corbus, personal fees from Boehringer Ingelheim, outside the submitted work. MDM reports personal fees from Medtelligence, personal fees from Actelion Pharma, personal fees from Astellas, personal fees from Mitsubishi-Tanabe, grants from Bayer, grants from Reata, grants from Sanofi, grants from Corbus, grants and personal fees from Boehringer-Ingelheim, grants and personal fees from EICOS, grants and personal fees from Galapagos, grants from GSK, outside the submitted work. DEF reports grants from Actelion, grants and personal fees from Amgen, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Galapagos, grants and personal fees from Novartis, grants and personal fees from Pfizer, grants from Sanofi, grants from Roche/Genentech, grants and personal fees from Corbus, grants from GSK, outside the submitted work. All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: 3-hydroxy-3-methylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (statins) are standard treatment for hyperlipidaemia. In addition to lipid-lowering abilities, statins exhibit multiple anti-inflammatory effects. The objectives of this study were to determine whether treatment of patients with RA with lovastatin decreased CRP or reduced disease activity., Methods: We conducted a randomized double-blind placebo-controlled 12 week trial of lovastatin vs placebo in 64 RA patients with mild clinical disease activity but an elevated CRP. The primary efficacy end point was the reduction in mean log CRP. Secondary end points included disease activity, RF and anti-CCP antibody titres. Mechanistic end points included levels of serum cytokines. Safety was assessed; hepatic and muscle toxicities were of particular interest., Results: Baseline features were similar between groups. No significant difference in mean log CRP reduction between the two groups was observed, and disease activity did not change from baseline in either treatment group. Mechanistic analyses did not reveal significant changes in any biomarkers. A post hoc analysis of subjects not using biologic therapy demonstrated a significantly greater proportion achieving ⩾20% reduction in CRP from baseline in the lovastatin group compared with placebo (P-value = 0.007). No difference was observed in subjects receiving biologics. Lovastatin was well tolerated with no serious safety concerns., Conclusion: This study showed no anti-inflammatory or clinical effects on RA disease activity after 12 weeks of treatment with lovastatin. Lovastatin had a modest effect on CRP in subjects not using biologics, suggesting statins may be anti-inflammatory in selected patients., Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00302952., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes., Methods: pSS patients met American-European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ⩾0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200., Results: Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell-attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters., Conclusion: Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study., Methods: Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples., Results: At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score., Conclusion: HSCT contrary to conventional treatment leads to a significant 'correction' in disease-related molecular signatures., Competing Interests: Competing interests: SA reports grants from National Institute of Health, grants from Karen Brown Scleroderma Foundation, grants from Department of Defense, during the conduct of the study; grants and personal fees from Boehringer Ingelheim, personal fees from Integrity Continuing Education, personal fees from Medscape, outside the submitted work. MDM reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Galapagos NV (Pharma), personal fees from Medtelligence, personal fees from Actelion Pharma, personal fees from Astellas, personal fees from Mitsubishi-Tanabe, grants from Bayer, grants from Reata, grants from Sanofi, grants from Corbus, grants from Eicos/ Sciences, outside the submitted work. KMS reports grants from National Institutes of Health, NIAID, during the conduct of the study; personal fees from GlaxoSmith/Kline, grants from Astra Zeneca, grants from Takeda Millennium, personal fees from Magenta, personal fees from Aerotek, personal fees from Kiadis Pharma, from Genentech Roche, outside the submitted work., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess survival and identify predictors of survival in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) who participated in the Scleroderma Lung Studies (SLS) I and II., Methods: SLS I randomised 158 patients with SSc-ILD to 1  year of oral cyclophosphamide (CYC) vs placebo. SLS II randomised 142 patients to 1 year of oral CYC followed by 1 year of placebo vs 2 years of mycophenolate mofetil. Counting process Cox proportional hazard modelling identified variables associated with long-term mortality in SLS I and II. Internal validation was performed using joint modelling., Results: After a median follow-up of 8 years, 42% of SLS I patients died, and when known the cause of death was most often attributable to SSc. There was no significant difference in the time to death between treatment arms in SLS I or II. Higher baseline skin score, older age, and a decline in the forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) over 2 years were independently associated with an increased risk of mortality in SLS I. The Cox model identified the same mortality predictor variables using the SLS II data., Conclusion: In addition to identifying traditional mortality risk factors in SSc (skin score, age), this study demonstrated that a decline in FVC and DLCO over 2 years was a better predictor of mortality than baseline FVC and DLCO. These findings suggest that short-term changes in surrogate measures of SSc-ILD progression may have important effects on long-term outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the clinical efficacy and safety of baminercept, a lymphotoxin β receptor IgG fusion protein (LTβR-Ig), for the treatment of primary Sjögren's syndrome (SS), and to explore the possible mechanisms of action of this treatment., Methods: In this multicenter trial, 52 patients with primary SS were randomized in a 2:1 ratio to receive subcutaneous injections of 100 mg of baminercept every week for 24 weeks or matching placebo. The primary end point was the change between screening and week 24 in the stimulated whole salivary flow (SWSF) rate. Secondary end points included the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI), as well as measurements of select chemokines and cytokines and enumeration of peripheral blood B and T cell subsets., Results: The change from baseline to week 24 in the SWSF rate was not significantly different between the baminercept and placebo treatment groups (baseline-adjusted mean change -0.01 versus 0.07 ml/minute; P = 0.332). The change in the ESSDAI during treatment was also not significantly different between the treatment groups (baseline-adjusted mean change -1.23 versus -0.15; P = 0.104). Although the incidence of adverse events was similar between the treatment groups, baminercept therapy was associated with a higher incidence of liver toxicity, including 2 serious adverse events. Baminercept also produced a significant decrease in plasma levels of CXCL13 and significant changes in the number of circulating B and T cells, consistent with its known inhibitory effects on LTβR signaling., Conclusion: In this trial, treatment with baminercept failed to significantly improve glandular and extraglandular disease in patients with primary SS, despite evidence from mechanistic studies showing that it blocks LTβR signaling., (© 2018, American College of Rheumatology.)

Background: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma., Methods: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score., Results: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group., Conclusions: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).

Purpose: In natural history studies, maintenance of higher levels of C-peptide secretion (a measure of endogenous insulin production) correlates with a lower incidence of major hypoglycemic events in patients with type 1 diabetes mellitus (T1D), but it is unclear whether this is also true for drug-induced C-peptide preservation., Methods: We analyzed hypoglycemic events and glycemic control data from the T1DAL (Inducing Remission in New-Onset T1D with Alefacept) study, a trial of alefacept in new-onset T1D, which found significant C-peptide preservation at 1 and 2 years. We performed a post hoc analysis using mixed models of the association between the meal-stimulated 4-hour C-peptide AUC (4-hour AUC) and rates of major hypoglycemia, measures of glycemic control (glycosylated hemoglobin [HbA1c]; mean glucometer readings), and variability (glucometer SDs; highest and lowest readings), and an index of partial remission (insulin dose-adjusted HbA1c[ IDAA1c])., Findings: Data from 49 participants (33 in the alefacept group and 16 in the placebo group) were analyzed at baseline and 12 and 24 months. We found that the 4-hour AUC at baseline and at 1 year was a significant predictor of the number of hypoglycemic events during the ensuing 12-month interval (p = 0.030). There was a strong association between the 4-hour AUC and glucometer SDs (P < 0.001), highest readings (p < 0.001), and lowest readings (p = 0.03), all measures of glycemic variability. There was a strong inverse correlation between the 4-hour AUC and 2 measures of glycemic control: HbA1c and mean glucometer readings (both p < 0.001). There was also a strong inverse correlation between the 4-hour AUC and IDAA1c values (p < 0.001), as well as a strong correlation between IDAA1c values and glucometer SDs (p < 0.001), suggesting that reduced glycemic variability is associated with a trend toward partial remission. None of these analyses found a significant difference between the alefacept and placebo groups., Implications: Measures of glycemic variability and control, including rates of hypoglycemia, are significantly correlated with preservation of C-peptide regardless of whether this is achieved by immune intervention with alefacept or natural variability in patients with new-onset T1D. Thus, preservation of endogenous insulin production by an immunomodulatory drug may confer clinical benefits similar to those seen in patients with higher C-peptide secretion due to slow disease progression., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

Aims/hypothesis: Type 1 diabetes results from T cell mediated destruction of beta cells. We conducted a trial of antithymocyte globulin (ATG) in new-onset type 1 diabetes (the Study of Thymoglobulin to ARrest T1D [START] trial). Our goal was to evaluate the longer-term safety and efficacy of ATG in preserving islet function at 2 years., Methods: A multicentre, randomised, double-blind, placebo-controlled trial of 6.5 mg/kg ATG (Thymoglobulin) vs placebo in patients with new-onset type 1 diabetes was conducted at seven university medical centres and one Children's Hospital in the USA. The site-stratified randomisation scheme was computer generated at the data coordinating centre using permuted-blocks of size 3 or 6. Eligible participants were between the ages of 12 and 35, and enrolled within 100 days from diagnosis. Subjects were randomised to 6.5 mg/kg ATG (thymoglobulin) vs placebo in a 2:1 ratio. Participants were blinded, and the study design included two sequential patient-care teams: an unblinded study-drug administration team (for the first 8 weeks), and a blinded diabetes management team (for the remainder of the study). Endpoints assessed at 24 months included meal-stimulated C-peptide AUC, safety and immunological responses., Results: Fifty-eight patients were enrolled; at 2 years, 35 assigned to ATG and 16 to placebo completed the study. The pre-specified endpoints were not met. In post hoc analyses, older patients (age 22-35 years) in the ATG group had significantly greater C-peptide AUCs at 24 months than placebo patients. Using complete preservation of baseline C-peptide at 24 months as threshold, nine of 35 ATG-treated participants (vs 2/16 placebo participants) were classified as responders; nine of 11 responders (67%) were older. All participants reported at least one adverse event (AE), with 1,148 events in the 38 ATG participants vs 415 in the 20 placebo participants; a comparable number of infections were noted in the ATG and placebo groups, with no opportunistic infections nor difficulty clearing infections in either group. Circulating T cell subsets depleted by ATG partially reconstituted, but regulatory, naive and central memory subsets remained significantly depleted at 24 months. Beta cell autoantibodies did not change over the 24 months in the ATG-treated or placebo participants. At 12 months, ATG-treated participants had similar humoral immune responses to tetanus and HepA vaccines as placebo-treated participants, and no increased infections., Conclusions/interpretation: A brief course of ATG substantially depleted T cell subsets, including regulatory cells, but did not preserve islet function 24 months later in the majority of patients with new-onset type 1 diabetes. ATG preserved C-peptide secretion in older participants, which may warrant further study., Trial Registration: ClinicalTrials.gov NCT00515099 PUBLIC DATA REPOSITORY: START datasets are available in TrialShare www.itntrialshare.org, Funding: National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). The trial was conducted by the Immune Tolerance Network (ITN).

Background: Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D., Methods: In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses., Results: A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01)., Conclusions: In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy., Trial Registration: https://clinicaltrials.gov/ NCT00965458., Funding: NIH and Astellas.

Objective: Vitamin D modulates the immune response and blocks induction of an interferon (IFN) signature by systemic lupus erythematosus (SLE) sera. This study was undertaken to investigate the effects of vitamin D supplementation on the IFN signature in patients with SLE., Methods: SLE patients (n = 57) with stable, inactive disease, a serum 25-hydroxyvitamin D (25[OH]D) level ≤20 ng/ml, an elevated anti-double-stranded DNA antibody level, and an IFN signature (as determined by measuring the expression levels of 3 IFN response genes) were randomized into a 12-week double-blind, placebo-controlled trial of vitamin D3 at doses of 2,000 IU or 4,000 IU. An IFN signature response was defined as a 50% reduction in the expression of 1 of the 3 genes or a 25% reduction in the expression of 2 of the 3 genes. Disease activity, adverse events, and endocrine effects were assessed., Results: Baseline characteristics of the patients in the 3 treatment groups (placebo, low-dose vitamin D3 , or high-dose vitamin D3 ) were similar. Repletion of 25(OH)D (i.e., levels ≥30 ng/ml) was not observed in any of the patients who were receiving placebo, while repletion was observed in 16 of 33 patients receiving vitamin D3 . The percentage of patients with an IFN signature response did not differ among the treatment groups. Moreover, there was no difference in the percentage of patients with an IFN signature response between those who remained vitamin D deficient and those who demonstrated repletion of vitamin D. Modular microarray analysis of a subset of patients (n = 40) did not reveal changes from baseline in any modules (including the IFN-inducible module) in any of the treatment groups, and no differences in expression were found between patients who demonstrated vitamin D repletion and patients who were persistently vitamin D deficient. Vitamin D3 was well tolerated, and there were no safety concerns., Conclusion: Vitamin D3 supplementation up to 4,000 IU daily was safe and well-tolerated but failed to diminish the IFN signature in vitamin D-deficient SLE patients. Higher 25(OH)D levels sustained for a longer duration may be required to affect immunologic outcomes., (© 2015, American College of Rheumatology.)

Background: Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results., Methods: For this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12-35 years, and with a peak C-peptide of 0.4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6.5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov, number NCT00515099., Findings: Between Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of -0.195 pmol/mL (95% CI -0.292 to -0.098) and those in the placebo group had a mean change of -0.239 pmol/mL (-0.361 to -0.118) in the placebo group (p=0.591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3-4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases., Interpretation: Our findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual β cells in patients newly diagnosed with type 1 diabetes., Methods: The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458., Findings: Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0.015 nmol/L (95% CI -0.080 to 0.110) in the alefacept group and decreased by 0.115 nmol/L (-0.278 to 0.047) in the placebo group, and the difference between groups was not significant (p=0.065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0.015 nmol/L [95% CI -0.076 to 0.106] vs decrease of -0.156 nmol/L [-0.305 to -0.006]; p=0.019), and daily insulin use (0.48 units per kg per day for placebo vs 0.36 units per kg per day for alefacept; p=0.02) and the rate of hypoglycaemic events (mean of 10.9 events per person per year for alefacept vs 17.3 events for placebo; p<0.0001) was significantly lower at 12 months in the alefacept group than in the placebo group. Mean HbA1c concentrations at week 52 were not different between treatment groups (p=0.75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred., Interpretation: Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve β-cell function in patients with new-onset type 1 diabetes., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Trials of immune therapies in new-onset type 1 diabetes (T1D) have shown success, but not all subjects respond, and the duration of response is limited. Our aim was to determine whether two courses of teplizumab, an Fc receptor-nonbinding anti-CD3 monoclonal antibody, reduces the decline in C-peptide levels in patients with T1D 2 years after disease onset. We also set out to identify characteristics of responders. We treated 52 subjects with new-onset T1D with teplizumab for 2 weeks at diagnosis and after 1 year in an open-label, randomized, controlled trial. In the intent to treat analysis of the primary end point, patients treated with teplizumab had a reduced decline in C-peptide at 2 years (mean -0.28 nmol/L [95% CI -0.36 to -0.20]) versus control (mean -0.46 nmol/L [95% CI -0.57 to -0.35]; P = 0.002), a 75% improvement. The most common adverse events were rash, transient upper respiratory infections, headache, and nausea. In a post hoc analysis we characterized clinical responders and found that metabolic (HbA1c and insulin use) and immunologic features distinguished this group from those who did not respond to teplizumab. We conclude that teplizumab treatment preserves insulin production and reduces the use of exogenous insulin in some patients with new-onset T1D. Metabolic and immunologic features at baseline can identify a subgroup with robust responses to immune therapy.

Objective: To describe the prevalence and clinical correlates of endoscopic gastric antral vascular ectasia (GAVE; "watermelon stomach") in early diffuse systemic sclerosis (SSc)., Methods: Subjects with early, diffuse SSc and evidence of specific internal organ involvement were considered for the Scleroderma: Cyclophosphamide Or Transplant (SCOT) trial. In the screening procedures, all patients underwent upper gastrointestinal endoscopy. Patients were then categorized into those with or without endoscopic evidence of GAVE. Demographic data, clinical disease characteristics, and autoantibody data were compared using Pearson chi-square or Student t tests., Results: Twenty-three of 103 (22.3%) individuals were found to have GAVE on endoscopy. Although not statistically significant, anti-topoisomerase I (anti-Scl70) was detected less frequently among those with GAVE (18.8% vs 44.7%; p = 0.071). Similarly, anti-RNP antibodies (anti-U1 RNP) showed a trend to a negative association with GAVE (0 vs 18.4%; p = 0.066). There was no association between anti-RNA polymerase III and GAVE. Patients with GAVE had significantly more erythema or vascular ectasias in other parts of the stomach (26.1% vs 5.0%; p = 0.003)., Conclusion: Endoscopic GAVE was present on screening in almost one-fourth of these highly selected patients with early and severe diffuse SSc. While anti-Scl70 and anti-U1 RNP trended toward a negative association with GAVE, there was no correlation between anti-RNA Pol III and GAVE. Patients with GAVE had a higher frequency of other gastric vascular ectasias outside the antrum, suggesting that GAVE may represent part of the spectrum of the vasculopathy in SSc.

Recipients of hematopoietic cell transplantation may be at risk for developing acute kidney injury (AKI), and this risk may be increased in patients who undergo transplantation for severe systemic sclerosis (SSc) due to underlying scleroderma renal disease. AKI after transplantation can increase treatment-related mortality. To better define these risks, we analyzed 91 patients with SSc who were enrolled in 3 clinical trials in the United States of autologous or allogeneic hematopoietic cell transplantation (HCT). Eleven (12%) of the 91 patients with SSc in these studies (8 undergoing autologous HCT, 1 undergoing allogeneic HCT, 1 pretransplantation, 1 given i.v. cyclophosphamide on a transplantation trial) experienced AKI, of whom 8 required dialysis and/or therapeutic plasma exchange. AKI injury in the 9 HCT recipients developed a median of 35 days (range, 0-90 days) after transplantation. Ten of 11 patients with AKI received angiotensin-converting enzyme inhibitor (ACE-I) therapy. The etiology of AKI was attributed to scleroderma renal crisis in 6 patients (including 2 with normotensive renal crisis), to AKI of uncertain etiology in 2 patients, and to AKI superimposed on scleroderma kidney disease in 3 patients. Eight of the 11 patients died, one each because of progression of SSc, multiorgan failure, gastrointestinal and pulmonary bleeding, pericardial tamponade and pulmonary complications, diffuse alveolar hemorrhage, pulmonary embolism, graft-versus-host disease, and malignancy. Limiting nephrotoxins, cautious use of corticosteroids, renal shielding during total body irradiation, strict control of blood pressure, and aggressive use of ACE-Is may be of importance in preventing renal complications after HCT for SSc., (Copyright © 2011 American Society for Blood and Marrow Transplantation. All rights reserved.)

Background: Physicians are encouraged to provide counseling regarding parental discipline. Quality counseling requires knowledge of disciplinary practices and factors that affect these practices., Methods: One hundred and eighty two parents of 12- to 19-month-old children from general pediatric clinics in North Carolina and Alabama were interviewed regarding discipline using the Discipline Survey. Measures of contextual factors were analyzed to see which predicted disciplinary practices., Results: Ninety-two percent of the participants were mothers; 6% were fathers; participation rate: 78%. Monitoring was the most common type of discipline used and time out was the least common. Parent, child, and family characteristics were all importantly associated with a broad array of disciplinary practices and modes of administration. However, the situation in which discipline occurred was found to be significant for most disciplinary practices even after controlling for other factors. Our study found that the specific misbehavior was most likely, and the presence of the other parent was least likely, to affect the type of discipline which was utilized., Conclusions: When counseling families about discipline, practitioners should incorporate the fact that misbehavior happens in various contexts.

Objective: To examine the effectiveness of an intervention that combined continuing medical education with process improvement methods to implement "office systems" to improve the delivery of preventive care to children., Design: Randomised trial in primary care practices., Setting: Private paediatric and family practices in two areas of North Carolina., Participants: Random sample of 44 practices allocated to intervention and control groups., Intervention: Practice based continuing medical education in which project staff coached practice staff in reviewing performance and identifying, testing, and implementing new care processes (such as chart screening) to improve delivery of preventive care., Main Outcome Measure: Change over time in the proportion of children aged 24-30 months who received age appropriate care for four preventive services (immunisations, and screening for tuberculosis, anaemia, and lead)., Results: The proportion of children per practice with age appropriate delivery of all four preventive services changed, after a one year period of implementation, from 7% to 34% in intervention practices and from 9% to 10% in control practices. After adjustment for baseline differences in the groups, the change in the prevalence of all four services between the beginning and the end of the study was 4.6-fold greater (95% confidence interval 1.6 to 13.2) in intervention practices. Thirty months after baseline, the proportion of children who were up to date with preventive services was higher in intervention than in control practices; results for screening for tuberculosis (54% v 32%), lead (68% v 30%), and anaemia (79% v 71%) were statistically significant (P < 0.05)., Conclusion: Continuing education combined with process improvement methods is effective in increasing rates of delivery of preventive care to children.

Objective: To improve health outcomes of children, the US Maternal and Child Health Bureau has recommended more effective organization of preventive services within primary care practices and more coordination between practices and community-based agencies. However, applying these recommendations in communities is challenging because they require both more complex systems of care delivery within organizations and more complex interactions between them. To improve the way that preventive health care services are organized and delivered in 1 community, we designed, implemented, and assessed the impact of a health care system-level approach, which involved addressing multiple care delivery processes, at multiple levels in the community, the practice, and the family. Our objective was to improve the processes of preventive services delivery to all children in a defined geographic community, with particular attention to health outcomes for low-income mothers and infants., Design: Observational intervention study in 1 North Carolina county (population 182 000) involving low- income pregnant mothers and their infants, primary care practices, and departments of health and mental health. An interrupted time-series design was used to assess rates of preventive services in office practices before and after the intervention, and a historical cohort design was used to compare maternal and child health outcomes for women enrolled in an intensive home visiting program with women who sought prenatal care during the 9 months before the program's initiation. Outcomes were assessed when the infants reached 12 months of age., Interventions: Our primary objective was to achieve changes in the process of care delivery at the level of the clinical interaction between care providers and patients that would lead to improved health and developmental outcomes for families. We selected interventions that were directed toward major risk factors (eg, poverty, ineffective care systems for preventive care in office practices) and for which there was existing evidence of efficacy. The interventions involved community-, practice-, and family-level strategies to improve processes of care delivery to families and children. The objectives of the community-level intervention were: 1) to achieve policy level changes that would result in changes in resources available at the level of clinical care, 2) to engage multiple practice organizations in the intervention to achieve an effect on most, if not all, families in the community, and 3) to enhance communication between, among, and within public and private practice organizations to improve coordination and avoid duplication of services. The objective of the practice-level interventions was to overcome specific barriers in the process of care delivery so that preventive services could be effectively delivered. To assist the health department in implementing the family-level intervention, we provided assistance in hiring and training staff and ongoing consultation on staff supervision, including the use of structured protocols for care delivery, and regular feedback data about implementation of the program. Interventions with primary care practices focused on the design of the delivery system within the office and the use of teamwork and data in an "office systems" approach to improving clinical preventive care. All practices (N = 8) that enrolled at least 5 infants/month received help in assessing performance and developing systems (eg, preventive services flow sheets) for preventive services delivery. Family-level interventions addressed the process of care delivery to high-risk pregnant women (<100% poverty) and their infants. Mothers were recruited for the home visiting intervention when they first sought prenatal care at the community health center, the county's largest provider of prenatal care to underserved women. The home visiting intervention involved teams of nurses and educators and involved 2 to 4 visits per month through the infant's first year of life to provide parental education on fetal and infant health and development, enhance parents' informal support systems, and link parents with needed health and human services. We included training in injury prevention and discipline, and home visitors assisted mothers in obtaining care from one of the primary care offices., Results: There were high levels of participation, changes in the organization of the delivery system, and improvements in preventive health outcomes. Agencies cooperated in joint contracting, staff training, and defining program eligibility. All 8 eligible practices agreed to participate and 7/8 implemented at least 1 new office system element. Of eligible women, 89% agreed to participate, and outcome data were available on 80% (180/225). After adjusting for differences in baseline characteristics, intervention group women were significantly more likely than comparison group women to use contraceptives (69% vs 47%), not smoke tobacco (27% vs 54%) and have a safe and stimulating home environment for their children. Intervention group children were more likely to have had an appropriate number of well-child care visits (57% vs 37%) and less likely to be injured (2% vs 7%). Intervention mothers also received Aid to Families with Dependent Children for fewer months after the birth of their child (7.7 months vs 11.3 months)., Conclusions: We observed a number of positive effects at all 3 levels of intervention. Policy-level changes at the state and community led to lasting changes in the organization and financing of care, which enabled changes in clinical services to take place. These changes have now been expanded beyond this community to other communities in the state. We were also able to engage multiple practice organizations, reduce duplication, and improve the coordination of care. Changes in the process of preventive services delivery were noted in participating practices. Finally, the outcomes of the family-level intervention were comparable in direction and magnitude to the outcomes of previous randomized trials of the intervention. All the changes were achieved over a relatively brief 3-year study period, and many have been sustained since the project was completed. Tiered, interrelated interventions directed at an entire population of mothers and children hold promise to improve the effectiveness and outcomes of health care for families and children.