ObjectiveIn 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).MethodsGlobal 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.ResultsThirty (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.ConclusionParalleling 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.image

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.

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.

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.

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.

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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.

RATIONALE Systemic sclerosis-pulmonary arterial hypertension (SSc-PAH) is one of the most prevalent and deadly forms of PAH. B cells may contribute to SSc pathogenesis. OBJECTIVE We investigated the safety and efficacy of B-cell depletion for SSc-PAH. METHODS AND MEASUREMENTS In an NIH-sponsored, multi-center, double-blinded, randomized, placebo-controlled, proof-of-concept trial, 57 SSc-PAH patients on stable-dose standard medical therapy received two infusions of 1000 mg of rituximab or placebo administered two weeks apart. The primary outcome measure was the change in six-minute walk distance (6MWD) at 24 weeks. Secondary endpoints included safety and invasive hemodynamics. We applied a machine learning approach to predict drug-responsiveness. MAIN RESULTS We randomized 57 subjects from 2010-2018. 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±11.1m vs. 0.5±9.7m, p=0.12). While a negative study, when data through week 48 were also considered, the estimated change in 6MWD at week 24 was 25.5±8.8m for rituximab and 0.4±7.4m for placebo (p=0.03). Rituximab treatment appeared to be safe and well tolerated. Low levels of rheumatoid factor (RF), IL-12, and IL-17 were sensitive and specific as favorable predictors of a rituximab response as measured by an improved 6MWD (ROC AUC 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 registration available at www.clinicaltrials.gov, ID: NCT01086540.

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.

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.

OBJECTIVETo address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes.METHODSpSS 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.RESULTSTranscriptional 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.CONCLUSIONMolecular 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.

Background: Trials and clinical observations have demonstrated the efficacy of mycophenolate mofetil (MMF) for SLE treatment. Long-term use of MMF is associated with adverse events, pregnancy risks, drug monitoring, and increased cost. Current management continues therapy indefinitely. Whether immunosuppression may be safely withdrawn or whether risks of withdrawal outweigh the benefits of continuation is unknown. Objectives: To compare rates of clinically significant disease reactivation (CSDR), major flares, and all flares in patients with quiescent SLE on stable MMF randomized to maintain or withdraw MMF. The goal is to provide guidance for clinicians and patients on the risks of MMF withdrawal. Methods: Adults with quiescent SLE (SELENA-SLEDAI without serologies <4) receiving MMF for ≥2 years for nephritis or ≥ 1 year for non-nephritis were randomized 1:1 to unblinded MMF (maintenance arm, MA) or to a 12-week taper off MMF (withdrawal arm, WA) and followed through 60 weeks. Subjects were on stable hydroxychloroquine; steroids limited to ≤ 10 mg. CSDR, defined as a SLEDAI flare requiring immunosuppression, BILAG flares and adverse events were assessed. Event rates and time to flare were compared using Kaplan-Meier. Results: 102 subjects were randomized (50 MA, 52 WA); 1 subject in each arm was ineligible and 10 terminated early (7 MA, 3 WA). Mean disease duration was 13 years; 76% had a history of nephritis; mean baseline SLEDAI was 2.2. 5 MA subjects (10%) had CSDR, compared to 9 WA (17%). Median time to CDSR was 38 weeks in both arms. BILAG A flares occurred in 1MA subject (pancreatitis) vs. 4 WA (cranial neuropathy, panniculitis, 2 nephritis). Kaplan-Meier curves overlapped for CDSR, BILAG A flares, and all SLEDAI flares (Figure). Based on these data, we are 86% confident that the increased risk of CDSR with MMF withdrawal is less than 15% over 60 weeks. AEs were similar between groups; infections occurred more commonly in MA (63 vs. 49). Conclusion: In this cohort of subjects with quiescent SLE on long term MMF serious flares occurred infrequently in subjects continuing or withdrawing MMF without differences in time to flare. MMF withdrawal may be considered in subjects with prolonged quiescent disease. Table 1. Baseline and Demographic Characteristics Maintenance arm Withdrawal arm Total Randomized 50 52 102 Female, n (%) 39 (78) 47 (90) 86 (84) White, n (%) 25 (50) 19 (37) 44 (43) Black, n (%) 19 (38) 22 (42) 41 (40) Hispanic/Latino, n (%) 10 (20) 12 (23) 22 (22) Age, Years, mean (SD) 42.4 (12.9) 41.6 (12.5) 42.0 (12.6) Disease Duration, Years, mean (SD) 13.6 (8.2) 12.2 (7.9) 12.9 (8.0) H/O Lupus Nephritis, n (%) 40 (80) 38 (73) 78 (76.5) On Baseline Steroids, n (%) 18 (36) 23 (44) 41 (40) Prednisone Dose, mg, mean (SD) 4.8 (2.7) 3.3 (1.7) 4.0 (2.3) MMF Duration, Years, mean (SD) 6.8 (4.3) 6.4 (4.3) 6.6 (4.3) Baseline MMF Dose, mg, mean 1,612 1,668 1,640 SELENA-SLEDAI*, mean (SD) 2.4 (1.76) 1.9 (1.76) 2.2 (1.77) Positive DsDNA, n (%) 35 (70) 27 (52) 62 (61) Low C3 1 , n (%) 14 (28) 9 (17) 23 (23) Low C4 1 , n (%) 6 (12) 5 (10) 11 (11) Figure. Kaplan-Meier Estimates of Flare Endpoints Disclosure of Interests: Eliza Chakravarty: None declared, Tammy Utset: None declared, Diane L Kamen Consultant of: Consulted on SLE survey development for Lilly and consulted on SLE trial protocol development for EMD Serono in 2019, Gabriel Contreras Grant/research support from: Genentech, Merck, Consultant of: Genentech, Merck, William Joseph McCune: None declared, Kenneth C Kalunian: None declared, Cynthia Aranow: None declared, Megan Clowse Grant/research support from: GSK, Pfizer, Consultant of: UCB, Astra-Zeneca, Speakers bureau: UCB, Ellen Goldmuntz: None declared, Jessica Springer: None declared, Lynette Keyes-Elstein: None declared, Bill Barry: None declared, Ashley Pinckney: None declared, Judith James: None declared

To gauge the relative efficacy of treatments, authors of review articles and commentary might attempt to compare results across clinical trials, but failure to recognize inherent differences across studies or apply proper statistical principles could yield flawed conclusions. Several approaches can mitigate the risks in these cross-trial comparisons.

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.