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.)

No abstract

BackgroundIn the randomised Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, myeloablation followed by autologous hematopoietic stem cell transplantation (HSCT) led to improved clinical outcomes compared to monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc).1 Moreover, there is emerging evidence on the role of the Th2 cytokine, interleukin 6 (IL-6) in SSc pathogenesis, and clinical trials targeting the IL-6 pathway have been completed.2 ObjectivesTo investigate the association of IL-6 with baseline clinical features and to examine its longitudinal changes in the treatment arms of the SCOT trials.MethodsThe SCOT trial enrolled 75 subjects with diffuse SSc, 65 (HSCT=31, CYC=34) subjects with a mean disease duration of 2.2 years were analysed; 65 age and gender matched controls were also investigated. All available serum samples at the baseline (n=65), 8- (n=55) and 26- (n=45) month visits were included. IL-6 was determined using ultra-sensitive Simoa assay. For purposes of comparison, prominent, pro-inflammatory Th1 cytokines, Interleukin 1β (IL-1β), interleukin 12 (IL-12), and interferon gamma (IFN-γ) were determined by Rule Based Medicine multiplex assays. The serum IFN-γ levels were in undetectable range in the majority of patient and control samples. Therefore, the comparative analysis focused on IL-1β and IL-12.ResultsSerum IL-6 was higher in SSc patients than controls (fold change=1.62, p<0.001). At the baseline visit, IL-6 positively correlated with hsCRP (rs=0.56, p<0.001) and modified Rodnan Skin Score (rs=0.26, p=0.037) and showed an inverse relationship with disease duration (r=−0.26, p=0.037), while it did not have a significant correlation with forced vital capacity (rs=−0.19, p=0.126). Moreover, no significant correlations were observed with IL-1β and IL-12.A comparison of regression lines revealed a significant decrease in serum IL-6 levels in the HSCT arm relative to CYC (p=0.0004). By 26 months, the HSCT arm no longer showed upregulation of serum IL-6 relative to controls while the CYC arm remained upregulated. In contrast, time trends for IL-1β and IL-12 did not differ significantly between arms (p-values=0.161 and 0.456, respectively). (figure 1).ConclusionsThe Serum IL-6 levels decreased significantly 26 months after HSCT, while the two Th1, proinflammatory cytokines did not show similar changes. This finding supports the notion that this treatment modality normalises specific serum protein imbalances implicated in SSc pathogenesis.References[1] Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, et al. Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. N Engl J Med2018.[2] Khanna D, Denton CP, Jahreis A, van Laar JM, Frech TM, Anderson ME, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet2016.Disclosure of InterestNone declared

No abstract

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 CharacteristicsMaintenance armWithdrawal armTotalRandomized5052102Female, 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, mean1,6121,6681,640SELENA-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 C31, n (%)14 (28)9 (17)23 (23)Low C41, n (%)6 (12)5 (10)11 (11)Figure.Kaplan-Meier Estimates of Flare EndpointsDisclosure 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