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.)

Background In 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 Objectives To investigate the association of IL-6 with baseline clinical features and to examine its longitudinal changes in the treatment arms of the SCOT trials. Methods The 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. Results Serum 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). Conclusions The 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 Interest None declared

BACKGROUND:Pemphigus vulgaris (PV) is a blistering disease and tumour necrosis factor-α has a role in its pathogenesis.OBJECTIVES:To evaluate the safety of infliximab (IFX) with prednisone compared with prednisone alone in the treatment of PV. In addition, treatment response was assessed and mechanistic studies were performed.METHODS:Subjects with PV who had ongoing disease activity while being maintained on prednisone were randomized to receive either IFX or placebo in addition to prednisone. Response status and immunoglobulin (Ig) G anti-desmoglein (Dsg)1 and Dsg3 antibodies were assessed at 18 and 26 weeks.RESULTS:Ten subjects were randomized to each group. There were no safety signals during the course of the study. At week 18, one subject in each group had responded. At week 26, three IFX-treated subjects vs. none in the placebo group had responded (P = 0·21). At weeks 18 and 26, the median IgG anti-Dsg1 and anti-Dsg3 levels were lower in the IFX-treated patients [IgG anti-Dsg-1 (week 18, P = 0·035; week 26, P = 0·022); IgG anti-Dsg3 (week 18, P = 0·035; week, 26 P = 0·05)].CONCLUSIONS:This study is limited by the relatively small sample size. There was no significant difference between study arms in the proportion of subjects with treatment-related adverse events > grade 3. IFX therapy was not shown to be effective for the treatment of patients with PV in this randomized, placebo-controlled trial, although IFX treatment may be associated with a decrease in anti-Dsg1 and Dsg3 antibodies.