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ObjectivesDetermine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.MethodsSkin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.ResultsSSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.ConclusionsSkin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examinedHLAassociations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominantHLA-DRB1*08:04andHLA-DRB1*11:02alleles were associated with overall SSc risk, and theHLA-DRB1*08:04allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, theHLA-DPB1*13:01andHLA-DRB1*07:01alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance ofHLAin defining autoantibody subtypes. The association of theHLA-DPB1*13:01allele with the ATA+subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence andHLA-DPB1*13:01allele frequency in multiple populations was observed (r= 0.98,P= 3 × 10−6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link betweenHLAalleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.

Background Trials demonstrating the efficacy of biologic therapy for moderate to severe hidradenitis suppurativa (HS) have inspired new multidisciplinary treatment strategies. We present our experience with combined biologic and surgical therapy for recalcitrant HS. Methods Between 2011 and 2014, 21 patients (57 cases) with Hurley Stage III HS underwent radical resection with delayed primary closure alone, or in combination with adjuvant biologic therapy. Demographic data, treatment regimen, outcomes, and complications were retrospectively reviewed for all cases. Results Eleven patients underwent combined surgical and biologic therapy, whereas radical resection alone was performed in 10 patients. The average soft tissue deficit, before closure, for the combined and surgery-only patients was 56 cm2 and 48.5 cm2, respectively (P = 0.66). Biologic agents including infliximab (n = 8) and ustekinumab (n = 3) were initiated 2 to 3 weeks after closure and were continued for an average of 10.5 months. Recurrence was noted in 19% (4/29) and 38.5% (10/26) of previously treated sites for combined and surgery-only patients (P < 0.01). For the combined cohort, the disease-free interval was approximately 1 year longer on average (P < 0.001); however, this difference was reduced to 4.5 months when considering time to recurrence after cessation of biologic therapy (P = 0.09). New disease developed in 18% (2/11) and 50% (5/10) of combined and surgery-only patients, respectively (P < 001). No adverse events were noted among patients who received biologic therapy. Conclusions Lower rates of recurrence and disease progression, as well as a longer disease-free interval may be achieved with the use of adjuvant biologic therapy after radical resection for recalcitrant HS.