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Objectives: Late-onset SLE is usually milder and associated with lower frequency of LN and neuropsychiatric manifestations. The diagnosis of NPSLE is especially challenging in older patients because of increased incidence of neurological comorbidities. We performed a systematic review and meta-analysis to evaluate the differences in NPSLE manifestations in early-onset (<50-year-old) vs late-onset (≥50-year-old) SLE patients., Methods: A literature search was performed using the PubMed, Web of Science and Cochrane Library databases. Studies available in English (1959-2022) including a late-onset SLE comparison group and evaluating the frequency of NPSLE were eligible. A forest plot was used to compare odds ratios (95% CI) of incidence and manifestations of NPSLE by age groups. Study heterogeneity was assessed using I2 statistics., Results: A total of 44 studies, including 17 865 early-onset and 2970 late-onset SLE patients, fulfilled our eligibility criteria. CNS involvement was reported in 3326 patients. Cumulative NPSLE frequency was higher in the early-onset group than in the late-onset group (OR: 1.41, 95% CI: 1.24, 1.59, P < 0.0001). In early-onset SLE patients, seizures (OR: 1.68, 95% CI: 1.27, 2.22) and psychosis (OR: 1.72, 95% CI: 1.23, 2.41) were more common than in late-onset SLE patients (P values, 0.0003 and 0.0014, respectively). Peripheral neuropathy was more commonly reported in the late-onset SLE group than in the early-onset SLE group (OR: 0.64, 95% CI: 0.47, 0.86, P = 0.004)., Conclusion: Our meta-analysis revealed that the frequencies of overall NPSLE, seizures, and psychosis were less common in late-onset SLE patients than in early-onset SLE patients. In contrast, peripheral neuropathy was more common in the late-onset SLE group., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Autologous haematopoietic cell transplantation (AHSCT) improves immunologic dysfunction in patients with SLE. However, the curative potential of this therapy remains uncertain. This study reports outcomes in SLE patients receiving a lymphodepleting, reduced intensity regimen for AHSCT in SLE., Methods: Eight patients with SLE refractory to treatment, including i.v. cyclophosphamide (CYC), were enrolled. Five had LN and three CNS involvement as primary indications for transplant. Haematopoietic cell mobilization with CYC, G-CSF and rituximab was followed by collection of CD34+ positively selected cells. The conditioning regimen consisted of concurrent administration of CYC, fludarabine and rituximab. All immunosuppressive medications were discontinued at the start of mobilization and CS were rapidly tapered after the transplant., Results: Five of eight patients achieved a complete response, including a decline in the SLEDAI to zero, which was sustained in four patients for a median of 165 months (range 138-191). One patient achieved a partial response, which was followed by relapse at month 18. Two patients with nephritis and underlying comorbidities in most organs had early deaths from infection and multiorgan failure. AHSCT resulted in profound lymphodepletion, followed by expansion of Treg cells and repopulation of naive T and B cells. Patients with a complete response showed a sustained suppression of the SLE-associated IFN-induced gene signature, marked depletion of memory and plasmablast B cells and resultant sustained elimination of anti-dsDNA antibody., Conclusion: Durable clinical and serologic remissions with suppression in the IFN gene signature can be achieved in refractory SLE following lymphodepleting AHSCT., Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00076752., (Published by Oxford University Press on behalf of the British Society for Rheumatology 2021. This work is written by a US Government employee and is in the public domain in the US.)

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder whose pathology involves multiple immune cell types, including B and T lymphocytes as well as myeloid cells. While it is clear that autoantibody-producing B cells, as well as CD4 + T cell help, are key contributors to disease, little is known regarding the role of innate lymphoid cells such as natural killer (NK) cells in the pathogenesis of SLE. We have characterized the phenotype of NK cells by multi-color flow cytometry in a large cohort of SLE patients. While the overall percentage of NK cells was similar or slightly decreased compared to healthy controls, a subset of patients displayed a high frequency of NK cells expressing the proliferation marker, Ki67, which was not found in healthy donors. Although expression of Ki67 on NK cells correlated with Ki67 on other immune cell subsets, the frequency of Ki67 on NK cells was considerably higher. Increased frequencies of Ki67 + NK cells correlated strongly with clinical severity and active nephritis and was also related to low NK cell numbers, but not overall leukopenia. Proteomic and functional data indicate that the cytokine interleukin-15 promotes the induction of Ki67 on NK cells. These results suggest a role for NK cells in regulating the immune-mediated pathology of SLE as well as reveal a possible target for therapeutic intervention., (© 2019 British Society for Immunology.)

In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to contribute to diverse inflammatory and immune-mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune-mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK-STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead., (©2018 Society for Leukocyte Biology.)