Explore the vast range of titles available.

Correspondence to Dr Keisuke Maeshima, Rheumatology, Faculty of Medicine Graduate School of Medicine, Oita University, Yufu 879-5593, Japan; maeshima@oita-u.ac.jp The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is crucial for the autocrine loop of type I interferons (IFNs) and is located upstream of important systemic lupus erythematosus (SLE)-associated pathogenic proinflammatory cytokines and chemokines. Along with the relapse of serum markers and proteinuria, chilblain lupus erythematosus and diffuse hair loss developed. Because the reinitiation of tacrolimus had no beneficial effect, the PSL dose was increased to 17.5 mg/day and mycophenolate mofetil 1500 mg/day was initiated. Since promising outcomes of treatment with the JAK inhibitors tofacitinib, ruxolitinib and baricitinib for alopecia areata unrelated to SLE have been reported,4 we introduced baricitinib (4 mg/day) along with combination therapy with PSL, mycophenolate mofetil and hydroxychloroquine.

Epigenetics contributes to the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA). Here we show the first comprehensive epigenomic characterization of RA fibroblast-like synoviocytes (FLS), including histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, and H3K9me3), open chromatin, RNA expression and whole-genome DNA methylation. To address complex multidimensional relationship and reveal epigenetic regulation of RA, we perform integrative analyses using a novel unbiased method to identify genomic regions with similar profiles. Epigenomically similar regions exist in RA cells and are associated with active enhancers and promoters and specific transcription factor binding motifs. Differentially marked genes are enriched for immunological and unexpected pathways, with “Huntington’s Disease Signaling” identified as particularly prominent. We validate the relevance of this pathway to RA by showing that Huntingtin-interacting protein-1 regulates FLS invasion into matrix. This work establishes a high-resolution epigenomic landscape of RA and demonstrates the potential for integrative analyses to identify unanticipated therapeutic targets. Fibroblast-like synoviocytes (FLS) in the intimal layer of the synovium can become invasive and destroy cartilage in patients with rheumatoid arthritis (RA). Here the authors integrate a variety of epigenomic data to map the epigenome of FLS in RA and identify potential therapeutic targets.

Abstract We report a 16-year-old female case of intractable adult-onset Still's disease accompanied by macrophage activation syndrome, who went into full remission after switching from infliximab to etanercept. Although the disease promptly relapsed when etanercept was discontinued, she again responded fully upon the reintroduction of etanercept. Furthermore, the effect of etanercept was apparently enhanced by combining it with a sufficient dose of methotrexate. This combination therapy should be considered as one of treatment options for the disease.

We report a 16-year-old female case of intractable adult-onset Still’s disease accompanied by macrophage activation syndrome, who went into full remission after switching from infliximab to etanercept. Although the disease promptly relapsed when etanercept was discontinued, she again responded fully upon the reintroduction of etanercept. Furthermore, the effect of etanercept was apparently enhanced by combining it with a sufficient dose of methotrexate. This combination therapy should be considered as one of treatment options for the disease.

We report a 16-year-old female case of intractable adult-onset Still's disease accompanied by macrophage activation syndrome, who went into full remission after switching from infliximab to etanercept. Although the disease promptly relapsed when etanercept was discontinued, she again responded fully upon the reintroduction of etanercept. Furthermore, the effect of etanercept was apparently enhanced by combining it with a sufficient dose of methotrexate. This combination therapy should be considered as one of treatment options for the disease.

Identification of genetic alterations through next‐generation sequencing (NGS) can guide treatment decision‐making by providing information on diagnosis, therapy selection, and prognostic stratification in patients with hematological malignancies. Although the utility of NGS‐based genomic profiling assays was investigated in hematological malignancies, no assays sufficiently cover driver mutations, including recently discovered ones, as well as fusions and/or pathogenic germline variants. To address these issues, here we have devised an integrated DNA/RNA profiling assay to detect various types of somatic alterations and germline variants at once. Particularly, our assay can successfully identify copy number alterations and structural variations, including immunoglobulin heavy chain translocations, IKZF1 intragenic deletions, and rare fusions. Using this assay, we conducted a prospective study to investigate the feasibility and clinical usefulness of comprehensive genomic profiling for 452 recurrently altered genes in hematological malignancies. In total, 176 patients (with 188 specimens) were analyzed, in which at least one alteration was detected in 171 (97%) patients, with a median number of total alterations of 7 (0–55). Among them, 145 (82%), 86 (49%), and 102 (58%) patients harbored at least one clinically relevant alteration for diagnosis, treatment, and prognosis, respectively. The proportion of patients with clinically relevant alterations was the highest in acute myeloid leukemia, whereas this assay was less informative in T/natural killer‐cell lymphoma. These results suggest the clinical utility of NGS‐based genomic profiling, particularly for their diagnosis and prognostic prediction, thereby highlighting the promise of precision medicine in hematological malignancies. We have developed an integrated DNA/RNA profiling assay for detecting germline variants and somatic alterations, including structural variations and fusions, recurrently found in hematological malignancies. We performed a prospective hospital‐based cohort study to demonstrate that our assay is feasible and useful for identifying clinically relevant alterations, particularly for diagnosis and prognostic prediction. These results suggest the clinical utility of our assay, thereby highlighting the promise of precision medicine in hematological malignancies.

Cohesin complexes mediate sister-chromatid cohesion in dividing cells but may also contribute to gene regulation in postmitotic cells. How cohesin regulates gene expression is not known. Here we describe cohesin-binding sites in the human genome and show that most of these are associated with the CCCTC-binding factor (CTCF), a zinc-finger protein required for transcriptional insulation. CTCF is dispensable for cohesin loading onto DNA, but is needed to enrich cohesin at specific binding sites. Cohesin enables CTCF to insulate promoters from distant enhancers and controls transcription at the H19 / IGF2 (insulin-like growth factor 2) locus. This role of cohesin seems to be independent of its role in cohesion. We propose that cohesin functions as a transcriptional insulator, and speculate that subtle deficiencies in this function contribute to ‘cohesinopathies’ such as Cornelia de Lange syndrome. The other face of cohesin A study of the distribution of cohesin binding sites in the human genome shows that they co-locate with sites for the transcription insulator protein CTCF. Cohesin is well known as a protein that acts as a 'chromosome glue', promoting sister chromatid cohesion during chromosome segregation. This new finding has uncovered a second and independent role for cohesin, facilitating CTCF function by acting as a transcription insulator. The discovery could be of medical relevance as a pointer to pathways that could be involved in 'cohesinopathies' such as Roberts syndrome and Cornelia de Lange syndrome.

A 62-year-old female was referred to our hospital because of left pleural effusion. She had a history of primary large B-cell lymphoma (LBCL) of the CNS (PCNSL), which was treated with chemoradiotherapy 14 years ago. Imaging studies revealed no other lesions. Pathologically, large atypical lymphoid cells were present in the pleural fluid and positive for CD20 and CD79a, while EBV and HHV-8 were negative. She was diagnosed with HHV8-negative effusion-based lymphoma (EBL) and achieved complete response after two cycles of rituximab monotherapy. We performed targeted-capture sequencing of lymphoma-associated genes using tumor samples from EBL and PCNSL, and detected the identical mutations in eight genes including MYD88 and CD79B . Identical arm-level copy number changes and focal deletions involving HLA-B , HLA-C , and CDKN2A , were also observed, suggesting clonal association between EBL and PCNSL. On the other hand, there were several lymphoma subtype-specific alterations, such as CARD11 and KMT2D mutations in PCNSL as well as PIM1 and PRDM1 mutations in EBL. LBCLs involving specific extranodal sites, such as CNS, testis, and adrenal gland, tend to recur in CNS, and harbors characteristic driver alterations, such as mutations in MYD88 and CD79B , similar to the MCD subtype of diffuse large B-cell lymphoma. Our genetic analysis suggests that in this case (i) PCNSL recurred as EBL or (ii) EBL developed from a common founder clone with PCNSL after long-term remission, providing insights into genetic basis underlying extranodal LBCL with CNS tropism.

Patients with recurrent peripheral T-cell lymphoma (PTCL) after allogeneic hematopoietic cell transplantation (HCT) have dismal outcomes. Nodal PTCL with the T follicular helper phenotype (PTCL-TFH) is uniquely sensitive to histone deacetylase inhibitors compared to non-TFH phenotypes. We report the case of a 19-year-old man who experienced recurrence of PTCL-TFH shortly after allogeneic HCT and subsequently achieved durable remission with romidepsin. Before HCT, the patient had refractory disease after CHOP and ESHAP chemotherapies but achieved a partial response after two cycles of romidepsin as salvage treatment. HLA-haploidentical peripheral blood stem cell transplantation was performed using conditioning with fludarabine 180 mg/sqm, melphalan 80 mg/sqm, and total body irradiation 2 Gy, and graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide. One month after HCT, disease progression was observed in the lung. Romidepsin was readministered every 2 weeks at a reduced dose of 12 mg/sqm. After two cycles of romidepsin, the patient achieved a complete metabolic response without severe GVHD or other non-hematological toxicities. Romidepsin was discontinued after seven treatment cycles due to prolonged lymphopenia. The patient remains in complete remission 30 months after the last dose of romidepsin. Our experience suggests that romidepsin could be safely administered soon after allogeneic transplantation.