OBJECTIVE: Previous technical limitations prevented the proof of Fcγ-receptor (FcγR)-activation by soluble immune complexes (sICs) in patients. FcγRIIIa (CD16) is a risk factor in rheumatoid arthritis (RA). We aimed at determining the presence of CD16-activating sICs in RA and control diseases.
METHODS: Sera from an exploratory cohort (n=50 patients with RA) and a validation cohort (n=106 patients with RA, 20 patients with psoriasis arthritis (PsA), 22 patients with systemic lupus erythematosus (SLE) and 31 healthy controls) were analysed using a new reporter cell assay. Additionally, 26 synovial fluid samples were analysed, including paired serum/synovial samples.
RESULTS: For the first time using a reliable and sensitive functional assay, the presence of sICs in RA sera was confirmed. sICs possess an intrinsic capacity to activate CD16 and can be found in both synovial fluid and in blood. In low experimental dilutions, circulating sICs were also detected in a subset of healthy people and in PsA. However, we report a significantly increased frequency of bioactive circulating sICs in RA. While the bioactivity of circulating sICs was low and did not correlate with clinical parameters, synovial sICs were highly bioactive and correlated with serum autoantibody levels. Receiver operator curves indicated that sICs bioactivity in synovial fluid could be used to discriminate immune complex-associated arthritis from non-associated forms. Finally, circulating sICs were more frequently found in SLE than in RA. The degree of CD16 bioactivity showed strong donor-dependent differences, especially in SLE.
CONCLUSIONS: RA is characterised by the presence of circulating and synovial sICs that can engage and activate CD16.

OBJECTIVE: Hypocomplementaemia is common in patients with IgG4-related disease (IgG4-RD). We aimed to determine the IgG4-RD features associated with hypocomplementaemia and investigate mechanisms of complement activation in this disease.
METHODS: We performed a single-centre cross-sectional study of 279 patients who fulfilled the IgG4-RD classification criteria, using unadjusted and multivariable-adjusted logistic regression to identify factors associated with hypocomplementaemia.
RESULTS: Hypocomplementaemia was observed in 90 (32%) patients. In the unadjusted model, the number of organs involved (OR 1.42, 95% CI 1.23 to 1.63) and involvement of the lymph nodes (OR 3.87, 95% CI 2.19 to 6.86), lungs (OR 3.81, 95% CI 2.10 to 6.89), pancreas (OR 1.66, 95% CI 1.001 to 2.76), liver (OR 2.73, 95% CI 1.17 to 6.36) and kidneys (OR 2.48, 95% CI 1.47 to 4.18) were each associated with hypocomplementaemia. After adjusting for age, sex and number of organs involved, only lymph node (OR 2.59, 95% CI 1.36 to 4.91) and lung (OR 2.56, 95% CI 1.35 to 4.89) involvement remained associated with hypocomplementaemia while the association with renal involvement was attenuated (OR 1.6, 95% CI 0.92 to 2.98). Fibrotic disease manifestations (OR 0.43, 95% CI 0.21 to 0.87) and lacrimal gland involvement (OR 0.53, 95% CI 0.28 to 0.999) were inversely associated with hypocomplementaemia in the adjusted analysis. Hypocomplementaemia was associated with higher concentrations of all IgG subclasses and IgE (all p<0.05). After adjusting for serum IgG1 and IgG3, only IgG1 but not IgG4 remained strongly associated with hypocomplementaemia.
CONCLUSIONS: Hypocomplementaemia in IgG4-RD is not unique to patients with renal involvement and may reflect the extent of disease. IgG1 independently correlates with hypocomplementaemia in IgG4-RD, but IgG4 does not. Complement activation is likely involved in IgG4-RD pathophysiology.

OBJECTIVE: In addition to various immunosuppressive agents, belimumab and anifrolumab became available in Japan. We aimed to investigate glucocorticoid-free clinical remission in a single-centre retrospective cohort in October 2023.
METHODS: Our cohort included patients with SLE who needed to start or increase glucocorticoids for disease activity and were followed up for more than 1 year. We investigated the rate of achievement of clinical remission off corticosteroids (CR off C), defined as no clinical score on the SLEDAI-2K without glucocorticoids, baseline predictors of CR off C, medications used when CR off C was achieved, and flare rates following CR off C.
RESULTS: Out of the 60 patients followed for an average of 5.4 (±2.6) years, 17 (28.3%) achieved CR off C in 3.6 (±1.2) years after enrolment. Use of belimumab and anifrolumab accounted for eight (47.1%) of the achievers. Among the baseline data, male sex, recent enrolment, high glucocorticoid dose, and detection of immune complex (IC) significantly predicted CR off C, while lupus nephritis (LN) and a low C3 level tended to predict it. In the multivariate analysis, IC detection was the only predictor of CR off C. Clinical flares were observed in 5.9% of the achievers during a median 1.2 years after achievement of CR off C.
CONCLUSIONS: In the era of biologics, CR off C was achieved in 28.3% of the patient cohort requiring the start or increase of glucocorticoids for disease activity, with a relatively low rate of flares, suggesting that glucocorticoid-free clinical remission is an achievable target in SLE. IC disease, represented by male sex or nephritis, is likely to benefit from currently available medications.

A hallmark of rheumatoid arthritis (RA) is the increased levels of autoantibodies preceding the onset and contributing to the classification of the disease. These autoantibodies, mainly anti-citrullinated protein antibody (ACPA) and rheumatoid factor, have been assumed to be pathogenic and many attempts have been made to link them to the development of bone erosion, pain and arthritis. We and others have recently discovered that most cloned ACPA protect against experimental arthritis in the mouse. In addition, we have identified suppressor B cells in healthy individuals, selected in response to collagen type II, and these cells decrease in numbers in RA. These findings provide a new angle on how to explain the development of RA and maybe also other complex autoimmune diseases preceded by an increased autoimmune response.

暂无摘要。

BACKGROUND: NLRP12-associated autoinflammatory disease (NLRP12-AID) is an autosomal dominant autoinflammatory disorder caused by variants of NLRP12 gene. We aimed to report a cohort of Chinese adult patients with NLRP12-AID and summarised phenotypes and genotypes.
METHODS: Twenty patients were diagnosed with NLRP12-AID after performing whole-exome sequencing and were included in our cohort. Demographic information, clinical data and treatment response were collected and evaluated. A literature review of NLRP12-AID was performed, and the clinical features and mutated sites were summarised and compared with our cohort.
RESULTS: Among the 20 NLRP12-AID patients, the main clinical features of NLRP12-AID included fever, cutaneous rash, arthralgia/arthritis, pharyngitis/tonsillitis, lymphadenopathy, myalgia and abdominal pain/diarrhoea. Thirteen NLRP12 variants were detected as F402L, G39V, R1030X, R7G, E24A, Q90X, A218V, A259V, W581X, G729R, R859W, c.-150T>C and c.*126G>C. Glucocorticoids were used in 14 patients, immunosuppressive agents in 13, and tocilizumab in 2. Seventeen patients had good responses to therapy. When compared with 50 NLRP12-AID patients from other countries, Chinese patients had fewer variants in exon 3, higher incidences of cutaneous rash, pharyngitis/tonsillitis and lymphadenopathy. Among all these 70 NLRP12-AID patients, patients carrying non-exon-3 variants had higher frequencies of ocular involvement, pharyngitis/tonsillitis, headache and lymphadenopathy than those with exon-3 variants.
CONCLUSIONS: This is the largest cohort of NLRP12-AID in the world and seven novel variants of NLRP12 were identified. Chinese adult patients of NLRP12-AID had more non-specific symptoms such as pharyngitis/tonsillitis and lymphadenopathy when compared with patients from other countries, for which the less occurrence of exon-3 variants might be one possible reason.

Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease.
Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort.
Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers).
The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

Whereas genetic susceptibility for systemic lupus erythematosus (SLE) has been well explored, the triggers for clinical disease flares remain elusive. To investigate relationships between microbiota community resilience and disease activity, we performed the first longitudinal analyses of lupus gut-microbiota communities.
In an observational study, taxononomic analyses, including multivariate analysis of ß-diversity, assessed time-dependent alterations in faecal communities from patients and healthy controls. From gut blooms, strains were isolated, with genomes and associated glycans analysed.
Multivariate analyses documented that, unlike healthy controls, significant temporal community-wide ecological microbiota instability was common in SLE patients, and transient intestinal growth spikes of several pathogenic species were documented. Expansions of only the anaerobic commensal, Ruminococcus (blautia) gnavus (RG) occurred at times of high-disease activity, and were detected in almost half of patients during lupus nephritis (LN) disease flares. Whole genome sequence analysis of RG strains isolated during these flares documented 34 genes postulated to aid adaptation and expansion within a host with an inflammatory condition. Yet, the most specific feature of strains found during lupus flares was the common expression of a novel type of cell membrane-associated lipoglycan. These lipoglycans share conserved structural features documented by mass spectroscopy, and highly immunogenic repetitive antigenic-determinants, recognised by high-level serum IgG2 antibodies, that spontaneously arose, concurrent with RG blooms and lupus flares.
Our findings rationalise how blooms of the RG pathobiont may be common drivers of clinical flares of often remitting-relapsing lupus disease, and highlight the potential pathogenic properties of specific strains isolated from active LN patients.

IgAV, the most common systemic vasculitis in childhood, is an immunoglobulin A-associated immune complex-mediated disease and its underlying molecular mechanisms are not fully understood. This study attempted to identify differentially expressed genes (DEGs) and find dysregulated immune cell types in IgAV to find the underlying pathogenesis for IgAVN.
GSE102114 datasets were obtained from the Gene Expression Omnibus (GEO) database to identify DEGs. Then, the protein-protein interaction (PPI) network of the DEGs was constructed using the STRING database. And key hub genes were identified by cytoHubba plug-in, performed functional enrichment analyses and followed by verification using PCR based on patient samples. Finally, the abundance of 24 immune cells were detected by Immune Cell Abundance Identifier (ImmuCellAI) to estimate the proportions and dysregulation of immune cell types within IgAVN.
A total of 4200 DEGs were screened in IgAVN patients compared to Health Donor, including 2004 upregulated and 2196 downregulated genes. Of the top 10 hub genes from PPI network, STAT1, TLR4, PTEN, UBB, HSPA8, ATP5B, UBA52, and CDC42 were verified significantly upregulated in more patients. Enrichment analyses indicated that hub genes were primarily enriched in Toll-like receptor (TLR) signaling pathway, nucleotide oligomerization domain (NOD)-like receptor signaling pathway, and Th17 signaling pathways. Moreover, we found a diversity of immune cells in IgAVN, consisting mainly of T cells. Finally, this study suggests that the overdifferentiation of Th2 cells, Th17 cells and Tfh cells may be involved in the occurrence and development of IgAVN.
We screened out the key genes, pathways and maladjusted immune cells and associated with the pathogenesis of IgAVN. The unique characteristics of IgAV-infiltrating immune cell subsets were confirmed, providing new insights for future molecular targeted therapy and a direction for immunological research on IgAVN.

UNASSIGNED: Injection site reactions are defined as skin reactions at the injection site to drugs administered subcutaneously. Pathophysiologically, these reactions are based on different immunological mechanisms. We report the case of a 49-year-old patient with type 1 diabetes mellitus (first diagnosis in 1994 at the age of 23 years). Continuous subcutaneous insulin infusion using an insulin pump has been used for many years. The patient presented to the department of dermatology with progressive symptoms in the area of the insulin injection sites on the lower abdomen, accompanied by pain, burning, erythema, tenderness, and the formation of subcutaneous nodules. Previous attempts to use different insulins and to change the injection sites did not improve his symptoms. Furthermore, the symptoms appeared within hours after the insulin pump was attached, so that the injection site has to be changed as soon as every 48 hours. No anaphylactic shock was reported at any time. Multiple histological specimens were obtained from an older lesion on the abdomen as well as from test sites after standard allergological tests (prick and intradermal tests) of various insulins. Histologically, these biopsies showed the image of an extensive deep-reaching small vessel vasculitis with the aspect of an urticarial vasculitis and confirmed the diagnosis of an injection-site reaction that can be characterized as a type III hypersensitivity reaction.