Cytokine release syndrome (CRS) is a phenomenon of immune hyperactivation described in the setting of immunotherapy. Unlike other immune-related adverse events, CRS triggered by immune checkpoint inhibitors (ICIs) is not well described. The clinical characteristics and course of 25 patients with ICI-induced CRS from 2 tertiary hospitals were abstracted retrospectively from the medical records and analyzed. CRS events were confirmed by 2 independent reviewers and graded using the Lee et al. scale. The median duration of CRS was 15.0 days (Q1; Q3 6.3; 29.8) and 10 (40.0%) had multiple episodes of CRS flares. Comparing the clinical factors and biomarkers in Grades 1-2 and 3-5 CRS, we found that patients with Grades 3-5 CRS had following: (i) had longer time to fever onset [25.0 days (Q1; Q3 13.0; 136.5) vs. 3.0 days (Q1; Q3 0.0; 18.0), p=0.027]; (ii) more cardiovascular (p=0.002), neurologic (p=0.001), pulmonary (p=0.044) and rheumatic (p=0.037) involvement; (iii) lower platelet count (p=0.041) and higher urea (p=0.041) at presentation compared to patients with Grades 1-2 CRS. 7 patients (28.0%) with Grades 1-2 CRS were rechallenged using ICIs without event. 9 patients (36.0%) were treated with pulse methylprednisolone and 6 patients (24.0%) were treated with tocilizumab. Despite this, 3 patients (50%) who received tocilizumab had fatal (Grade 5) outcomes from ICI-induced CRS. Longer time to fever onset, lower platelet count and higher urea at presentation were associated with Grade 3-5 CRS. These parameters may be used to predict which patients are likely to develop severe CRS.

Patients with systemic lupus erythematosus (SLE) display increased numbers of immature neutrophils in the blood but the exact role of these immature neutrophils has been unclear. Neutrophils that sediment within the peripheral blood mononuclear cell fraction after density centrifugation of blood are generally defined as low‐density neutrophils (LDNs). Far beyond antimicrobial functions, LDNs are emerging as decision‐shapers during innate and adaptive immune responses. Traditionally, neutrophils were viewed as a homogenous population. However, the various LDN populations identified in SLE to date are heterogeneously composed of mixed populations of activated mature neutrophils and immature neutrophils at various stages of differentiation. Controversy also surrounds the role of LDNs in SLE as to whether they are pro‐inflammatory, or if they are polymorphonuclear myeloid‐derived suppressor cells. It is clear that LDNs in SLE can secrete increased levels of type I interferon (IFN) and that they contribute to the cycle of inflammation and tissue damage. They readily form neutrophil extracellular traps, exposing modified autoantigens and oxidized mitochondrial DNA, which contribute to autoantibody production and type I IFN signaling, respectively. Importantly, the ability of LDNs in SLE to perform canonical neutrophil functions is polarized, based on CD10⁺ mature and CD10^‐ immature neutrophils. Although this field is still relatively new, multiomic approaches have advanced our understanding of the diverse origins, phenotype and function of LDNs in SLE. This review updates the literature on the origin and nature of LDNs; their distinctive features; and their biological roles in the immunopathogenesis and end‐organ damage in SLE.

Systemic lupus erythematosus (SLE) is an immune-complex-mediated multi-systemic autoimmune condition of multifactorial etiology, which mainly affects young women. It is currently believed that the onset of SLE and lupus flares are triggered by various environmental factors in genetically susceptible individuals. Various environmental agents and toxicants, such as cigarette smoke, alcohol, occupationally- and non-occupationally-related chemicals, ultraviolet light, infections, sex hormones and certain medications and vaccines, have been implicated to induce SLE onset or flares in a number case series, case-control and population-based cohort studies and very few randomized controlled trials. Here, we will describe some of these recognized environmental lupus triggering and perpetuating factors and explain how these factors potentially bias the immune system towards autoimmunity through their interactions with genetic and epigenetic alterations. Further in-depth exploration of how potentially important environmental factors mechanistically interact with the immune system and the genome, which trigger the onset of SLE and lupus flares, will certainly be one of the plausible steps to prevent the onset and to decelerate the progress of the disease.

The utility of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) utility in predicting immune-related adverse events (irAEs) and survival have not been well studied in the context of treatment with immune checkpoint inhibitors (ICIs). We performed a case-control study of cancer patients who received at least one dose of ICI in a tertiary hospital. We examined NLR and PLR in irAE cases and controls. Logistic and Cox regression models were used to identify independent risk factors for irAEs, progression-free survival (PFS), and overall survival (OS). The study included 91 patients with irAEs and 56 controls. Multiple logistic regression showed that NLR < 3 at baseline was associated with higher occurrence of irAEs. Multivariate Cox regression showed that development of irAEs and reduction in NLR from baseline to week 6 were associated with longer PFS. Higher NLR values at baseline and/or week 6 were independently associated with shorter OS. A reduction in NLR from baseline to week 6 was associated with longer OS. In this study of cancer patients treated with ICIs, NLR has a bidirectional relationship with adverse outcomes. Lower NLR was associated with increased occurrence of irAEs while higher NLR values were associated with worse clinical outcomes.

Cognitive dysfunction (CD) is a common yet often clinically subtle manifestation that considerably impacts the health-related quality of life in patients with systemic lupus erythaematosus (SLE). Given the inconsistencies in CD assessment and challenges in its attribution to SLE, the reported prevalence of CD differs widely, ranging from 3 to 88%. The clinical presentation of CD in SLE is non-specific and may manifest concurrently with overt neuropsychiatric illness such as psychosis or mood disorders or as isolated impairment of attention, working memory, executive dysfunction or processing speed. Despite the lack of standardized and sensitive neuropsychological tests and validated diagnostic biomarkers of CD in SLE, significant progress has been made in identifying pathogenic neural pathways and neuroimaging. Furthermore, several autoantibodies, cytokines, pro-inflammatory mediators and metabolic factors have been implicated in the pathogenesis of CD in SLE. Abrogation of the integrity of the blood-brain barrier (BBB) and ensuing autoantibody-mediated neurotoxicity, complement and microglial activation remains the widely accepted mechanism of SLE-related CD. Although several functional neuroimaging modalities have consistently demonstrated abnormalities that correlate with CD in SLE patients, a consensus remains to be reached as to their clinical utility in diagnosing CD. Given the multifactorial aetiology of CD, a multi-domain interventional approach that addresses the risk factors and disease mechanisms of CD in a concurrent fashion is the favourable therapeutic direction. While cognitive rehabilitation and exercise training remain important, specific pharmacological agents that target microglial activation and maintain the BBB integrity are potential candidates for the treatment of SLE-related CD.

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23–dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.