Clonal haematopoiesis is increased in early onset in systemic sclerosis.

OBJECTIVES: SSc is an autoimmune disease characterized by fibrosis, microangiopathy and immune dysfunctions including dysregulation of proinflammatory cytokines. Clonal haematopoiesis of indeterminate potential (CHIP) is defined by the acquisition of somatic mutations in haematopoietic stem cells leading to detectable clones in the blood. Recent data have shown a higher risk of cardiovascular disease in patients with CHIP resulting from increased production of proinflammatory cytokines and accelerated atherosclerosis. Eventual links between CHIP and autoimmune diseases are undetermined. The aim of our study was to evaluate the prevalence of CHIP in SSc patients and its association with clinical phenotype. METHODS: Forty-one genes frequently mutated in myeloid malignancies were sequenced in peripheral blood mononuclear cells from 90 SSc patients and 44 healthy donors. RESULTS: A total of 15 somatic variants were detected in 13/90 SSc patients (14%) and four somatic variants in 4/44 (9%) healthy donors (HD) (P = 0.58). The prevalence of CHIP was significantly higher in younger SSc patients than in HD: 25% (6/24) vs 4% (1/26) (P = 0.045) under 50 years and 17% (7/42) vs 3% (1/38) (P = 0.065) under 60 years. The prevalence of CHIP in patients over 70 years was similar in SSc patients and healthy donors. The most common mutations occurred in DNMT3A (seven variants). No major clinical differences were observed between SSc patients with or without CHIP. CONCLUSION: Whether CHIP increases the risk to develop SSc or is a consequence of a SSc-derived modified bone marrow micro-environment remains to be explored.

T cell epitope mapping of secukinumab and ixekizumab in healthy donors.

Secukinumab, a human monoclonal antibody that selectively neutralizes IL-17A, has consistently shown low anti-drug antibody responses in patients with psoriasis, psoriatic arthritis, and ankylosing spondylitis. Secukinumab has also shown lower in vitro immunogenicity potential compared with other monoclonal antibodies used to treat psoriasis and psoriatic arthritis, and a significantly lower in vitro T cell precursor frequency compared with ixekizumab, which targets the same antigen. Here, secukinumab and ixekizumab were further examined regarding their specific T cell epitopes. Secukinumab- or ixekizumab-specific CD4 T cell lines were generated from 31 healthy, treatment-naïve donors via 28-day co-culture with mature monocyte-derived dendritic cells exposed to either antibody. Consistent with previous data, the frequency of preexisting T cells to secukinumab was significantly lower as compared with ixekizumab. Only two T cell lines from two different donors could be derived for secukinumab, but no specific T cell epitope was identified. In contrast, 32 T cell lines from eight donors were obtained for ixekizumab. For 11 of these T cell lines, the specific T cell epitopes could be identified and confirmed by major histocompatibility complex-associated peptide proteomics as being naturally presented peptides. All identified T cell epitopes cluster in four main regions that are overlapping with the complementarity-determining regions HCDR3, LCDR1, LCDR2 and LCDR3. Interestingly, ixekizumab CDRs contain amino acids that are not found in any of the germline family members. These amino acids may be associated with the higher number of T cell epitopes identified for ixekizumab light chain and may contribute to the increased in vitro immunogenicity potential observed for ixekizumab vs. secukinumab.

Spatial and Temporal Variability in the Development and Potential Toxicity of Phormidium Biofilms in the Tarn River, France.

Proliferation of Phormidium biofilms in rivers is becoming a worldwide sanitation problem for humans and animals, due to the ability of these bacteria to produce anatoxins. To better understand the environmental conditions that favor the development of Phormidium biofilms and the production of anatoxins, we monitored the formation of these biofilms and their toxins for two years in the Tarn River, biofilms from which are known to have caused the deaths of multiple dogs. As previously observed in New Zealand, Phormidium biofilm development occurred in riffle areas. The coverage of these biofilms at the bottom of the river exhibited strong spatial and temporal variations, but was positively correlated with water temperature and depth. Anatoxin-a was detected in less than 50% of the biofilms. The concentrations of these toxins in the biofilms exhibited high spatiotemporal variability, with the highest concentrations being recorded at the end of the summer period at the upstream sampling sites. These findings suggest that the maturity of the biofilms, combined with the local environmental conditions, have an impact on the production of anatoxin, making risk assessment for these benthic proliferations challenging.

Author Correction: Secukinumab Demonstrates Significantly Lower Immunogenicity Potential Compared to Ixekizumab.

In the original publication, information regarding "ustekinumab" was incorrectly published under the Methods section. The correct information in the section "Antibodies and Control Protein" should be "(secukinumab, 150 mg/mL; ixekizumab, 90 mg/mL; adalimumab, 50 mg/mL; ustekinumab 90 mg/ml)". Infliximab, which is mentioned in that section, was not used in the study.

Secukinumab Demonstrates Significantly Lower Immunogenicity Potential Compared to Ixekizumab.

INTRODUCTION: Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL-17A, has been shown to have significant efficacy in the treatment of moderate to severe plaque psoriasis (PsO) and psoriatic arthritis (PsA), demonstrating a rapid onset of action and sustained responses with a favorable safety profile. All biotherapeutics, including monoclonal antibodies (mAbs), can be immunogenic, leading to formation of anti-drug antibodies (ADAs) that can result in loss of response and adverse events such as hypersensitivity reactions. Thus, the immunogenicity potential of biotherapeutics is of particular interest for physicians. Of the 2842 patients receiving secukinumab across six phase 3 psoriasis clinical trials, only 0.4% developed treatment-emergent ADAs over 3 years of treatment. Direct comparison of clinical immunogenicity incidence rates is hampered by the nature of clinical immunogenicity assays, differences in study designs, patient populations, and treatment regimens. METHODS: We evaluated side-by-side in the same healthy donors two recently approved IL-17A selective antibodies, secukinumab and ixekizumab, along with adalimumab and ustekinumab, for their capacity to induce anti-drug related T cell responses in vitro and estimated their potential for developing ADAs in patients. RESULTS: We found that healthy donors show both significantly less frequent T cell responses and lower numbers of pre-existing T cells to secukinumab than to ixekizumab and adalimumab. Although there was a tendency for a lower response to ustekinumab, this difference was not significant. CONCLUSION: In summary, this in vitro study confirms the significantly lower immunogenicity potential and provides an explanation for the lower clinical immunogenicity incidence found for secukinumab in comparison to other approved therapeutic antibodies used to treat plaque psoriasis. FUNDING: Novartis Pharmaceuticals AG.