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ObjectiveRegulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential.AimWe aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases.MethodsWe performed a prospective, open-label, phase I–IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet’s disease, granulomatosis with polyangiitis, Takayasu’s disease, Crohn’s disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation.Resultsld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed.ConclusionThe dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases.Trial registration numberNCT01988506.

The association between psoriatic arthritis (PsA) and psoriasis is well known, but some have suggested that other musculoskeletal (MSK) conditions might also be more common in patients with skin psoriasis compared with the general population. The aim of our study was to describe the prevalence of a large panel of MSK conditions, in consecutive patients with psoriasis according to skin phenotype. This was a cross-sectional study. We consecutively included 148 patients, consulting for their skin psoriasis, in the dermatology department of a tertiary hospital, Hospital Cochin in Paris, France. After the scheduled consultation with a dermatologist, a rheumatologist conducted a dedicated face-to-face interview to collected data, included demographics, comorbidities, information about the psoriasis, the MSK conditions and their treatments. Of the 148 patients, 122 (82%) had at least one MSK condition. The most common condition was mechanical back pain, present in 98 (66%) patients. Nineteen (13%) patients had spondyloarthritis (SpA), of which 95% had PsA. For all MSK conditions, the dominant psoriasis phenotype was psoriasis vulgaris. The prevalence of the other phenotypes of psoriasis differed by disease. In SpA patients, the three predominant psoriasis phenotypes were: psoriasis vulgaris (82%), scalp involvement (76%) and inverse psoriasis (65%). For all MSK diseases, the prevalence was higher than expected in the general population. Our data suggest that skin psoriasis is associated with different MSK diseases, and not only PsA.

Objective : Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential. Aim : We aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases. Methods : We performed a prospective, open-label, phase I–IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet’s disease, granulomatosis with polyangiitis, Takayasu’s disease, Crohn’s disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation. Results : ld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed. Conclusion : The dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases.

Background: Subacute cutaneous lupus erythematosus (SCLE) can be induced by numerous drugs. We report 3 cases of SCLE induced by proton pump inhibitors (PPIs). Objective: To highlight a rare cutaneous side effect induced by a frequently prescribed drug such as a PPI. Case Reports: Case 1 was a 30-year-old man who developed multiple annular plaques over the trunk and lower limbs 1 month after the initiation of pantoprazole. Antinuclear antibodies (ANA) were positive with anti-Ro/SSA and anti-La/SSB antibodies, and histology confirmed the diagnosis. Clinical improvement was achieved 8 weeks after the discontinuation of pantoprazole and the introduction of a treatment combining topical steroids and hydroxychloroquine. Lesions relapsed when pantoprazole was accidentally rechallenged. The second case was a 31-year-old woman, 28 weeks pregnant, who presented erythematous annular plaques over the trunk 7 weeks after starting esomeprazole. ANA and anti-Ro/SSA antibodies were positive, and the histology was compatible with SCLE. Fetal ultrasound was normal. She was treated with topical and oral steroids and hydroxychloroquine. Clinical improvement was achieved 4 weeks after the discontinuation of esomeprazole. The third case was a 57-year-old woman with systemic erythematosus lupus presenting annular and psoriasiform lesions on the trunk for 15 months. She was treated successively with hydroxychloroquine, azathioprine, mycophenolate mofetil and methotrexate with prednisone. A review of her drug history revealed the introduction of omeprazole a few weeks before the first appearance of skin lesions and omeprazole was contraindicated. Conclusion: SCLE should systematically be suspected in case of eruption after the introduction of PPI. The risk of fetal cardiac complications is important in pregnant women.

Insulin and other growth factors are key regulators of liver gene expression, including in metabolic diseases. Most of the phosphoinositide 3-kinase (PI3K) activity induced by insulin is considered to be dependent on PI3Kα. We used mice lacking p110α, the catalytic subunit of PI3Kα, to investigate its role in the regulation of liver gene expression in health and in metabolic dysfunction-associated steatotic liver disease (MASLD). The absence of hepatocyte PI3Kα reduced maximal insulin-induced PI3K activity and signaling, promoted glucose intolerance in lean mice and significantly regulated liver gene expression, including insulin-sensitive genes, in ad libitum feeding. Some of the defective regulation of gene expression in response to hepatocyte-restricted insulin receptor deletion was related to PI3Kα signaling. In addition, though PI3Kα deletion in hepatocytes promoted insulin resistance, it was protective against steatotic liver disease in diet-induced obesity. In the absence of hepatocyte PI3Kα, the effect of diet-induced obesity on liver gene expression was significantly altered, with changes in rhythmic gene expression in liver. Altogether, this study highlights the specific role of p110α in the control of liver gene expression in physiology and in the metabolic rewiring that occurs during MASLD.

This study revises the taxonomy of Cephalomanes javanicum (Hymenophyllaceae), a filmy fern traditionally considered widespread across the Indomalayan and Australasian regions. Through a comprehensive analysis of the literature, type specimens, and herbarium collections, we clarify the taxonomic status of three recognized varieties: typical C. javanicum, C. javanicum var. sumatranum, and C. javanicum var. asplenioides. Morphological, morphometric, and molecular phylogenetic investigations reveal that these varieties represent distinct species rather than intraspecific variants. Additionally, we reassess C. atrovirens, a species often confused with C. javanicum, and confirm that its two previously recognized subspecies also warrant species status. Based on these findings, we propose the elevation of the C. javanicum varieties and C. atrovirens subspecies to full species rank, providing updated taxonomic treatments, synonymy lists, and new lectotypifications. These revisions contribute to a more accurate understanding of species diversity within Cephalomanes and have broader implications for fern taxonomy, biogeography, and conservation in the tropical Asia, Australasian, and Oceanian regions.

Background: The gut microbiota-intestine-liver relationship is emerging as an important factor in multiple hepatic pathologies, but the hepatic sensors and effectors of microbial signals are not well defined. Results: By comparing publicly available liver transcriptomics data from conventional vs. germ-free mice, we identified pregnane X receptor (PXR, NR1I2) transcriptional activity as strongly affected by the absence of gut microbes. Microbiota depletion using antibiotics in Pxr +/+ vs Pxr-/-C57BL/6J littermate mice followed by hepatic transcriptomics revealed that most microbiota-sensitive genes were PXR-dependent in the liver in males, but not in females. Pathway enrichment analysis suggested that microbiota-PXR interaction controlled fatty acid and xenobiotic metabolism. We confirmed that antibiotic treatment reduced liver triglyceride content and hampered xenobiotic metabolism in the liver from Pxr +/+ but not Pxr-/male mice. Conclusions: These findings identify PXR as a hepatic effector of microbiota-derived signals that regulate the host's sexually dimorphic lipid and xenobiotic metabolisms in the liver. Thus, our results reveal a potential new mechanism for unexpected drug-drug or food-drug interactions.

Insulin and other growth factors are key regulators of liver gene expression, including in metabolic diseases. Most of the phosphoinositide 3-kinase (PI3K) activity induced by insulin is considered to be dependent on PI3K[alpha]. We used mice lacking p110[alpha], the catalytic subunit of PI3K[alpha], to investigate its role in the regulation of liver gene expression in health and in metabolic dysfunction-associated steatotic liver disease (MASLD). The absence of hepatocyte PI3K[alpha] reduced maximal insulin-induced PI3K activity and signaling, promoted glucose intolerance in lean mice and significantly regulated liver gene expression, including insulin-sensitive genes, in ad libitum feeding. Some of the defective regulation of gene expression in response to hepatocyte-restricted insulin receptor deletion was related to PI3K[alpha] signaling. In addition, though PI3K[alpha] deletion in hepatocytes promoted insulin resistance, it was protective against steatotic liver disease in diet-induced obesity. In the absence of hepatocyte PI3K[alpha], the effect of diet-induced obesity on liver gene expression was significantly altered, with changes in rhythmic gene expression in liver. Altogether, this study highlights the specific role of p110[alpha] in the control of liver gene expression in physiology and in the metabolic rewiring that occurs during MASLD.