IgG4-Related Disease Complicated with Diffuse and Chronic Gastrointestinal Inflammation Leading to Small Intestinal Perforation.

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a systemic inflammatory disease characterized by elevated serum IgG4, IgG4+ cell infiltration, storiform fibrosis, and obliterative phlebitis. While IgG4-RD can affect various organs, gastrointestinal tract involvement is less common. Here, we report a 70-year-old female with IgG4-RD complicated with diffuse and chronic gastrointestinal inflammation which led to small intestinal perforation. She had been suffering from anorexia, abdominal pain, vomiting, and diarrhea, and hospitalized due to recurrent ileus. Consequently, she was referred due to small intestinal perforation required for surgical intervention. Pathology revealed acute and chronic inflammation with massive IgG4+ plasmacytes infiltration into mucosa of the small intestine, and ischemic change secondarily caused by chronic inflammation. Random biopsies from the mucosa of stomach, duodenum, ileum, and colon, also revealed diffuse and massive IgG4+ plasmacytes infiltration in stomach, duodenum, small intestine, and colon. She was diagnosed with IgG4-RD based on the pathological findings and elevated serum IgG4 levels. Glucocorticoid rapidly ameliorated the symptoms. IgG4-RD may cause gastrointestinal manifestations and histopathological assessment should be considered, even in the absence of specific characteristics of IgG4-RD.

A case of dupilumab combination therapy for exacerbation of atopic dermatitis in a patient with eosinophilic granulomatosis with polyangiitis treated with mepolizumab.

We report a 60-year-old male with eosinophilic granulomatosis with polyangiitis (EGPA) complicated with atopic dermatitis (AD). The patient was initially treated with prednisolone, cyclosporine A, and mepolizumab (MEPO). Due to worsening skin symptoms after prednisolone tapering, dupilumab (DUP) was added as an adjunctive therapy for AD confirmed by skin biopsy. The combination therapy of MEPO and DUP resulted in rapid improvement of skin symptoms, suggesting it may be an effective therapeutic option for patients with EGPA and AD. This case report emphasises the importance of a multidisciplinary approach in treating complex diseases such as EGPA and AD.

Real-world efficacy of belimumab in achieving remission or low-disease activity in systemic lupus erythematosus: A retrospective study.

OBJECTIVES: We investigated the effect of belimumab (BEL) on achieving low disease activity (LDA) and remission as an additive molecular-targeting agent to standard of care (SoC) in patients with SLE. METHODS: Clinical information was retrospectively collected from patients with SLE who received BEL additive to SoC (BEL+SoC), and from patients treated with SoC alone as a control arm. Disease activity was measured by SLE-disease activity score (SLE-DAS). The proportion of patients in LDA and remission at 12 months was compared after propensity score matching. The factors contributing to LDA and remission achievement was identified by Cox proportional hazard model. RESULTS: BEL+SoC significantly reduced SLE-DAS at 6 months, with a significantly higher proportion of patients achieving LDA and remission at 12 months compared to SoC alone. The presence of arthritis at baseline was significantly associated with achieving LDA and remission. Additionally, both treatment groups experienced a significant reduction in daily glucocorticoid dose. CONCLUSIONS: Adding BEL to SoC was beneficial for patients with arthritis, leading to higher proportion of achieving LDA and remission, while also reducing their glucocorticoid dose. Our results indicate the utility of BEL in a treat-to-target approach for SLE patients in a real-world setting.

Involvement of the complement system in immune thrombocytopenia: review of the literature.

Immune thrombocytopenia (ITP) is a thrombocytopenic condition induced by autoimmune mechanisms and includes secondary ITP with underlying diseases such as connective tissue diseases (CTD). In recent years, it has been elucidated that the subsets of the ITP are associated with complement abnormalities but much remains unclear. To perform a literature review and identify the characteristics of complement abnormalities in ITP. PUBMED was used to collect the literature published up to June 2022 related to ITP and complement abnormalities. Primary and secondary ITP (CTD-related) were examined. Out of the collected articles, 17 were extracted. Eight articles were related to primary ITP (pITP) and 9 to CTD-related ITP. Analysis of the literature revealed that the ITP severity was inversely correlated with serum C3, C4 levels in both ITP subgroups. In pITP, a wide range of complement abnormalities was reported, including abnormalities of initial proteins, complement regulatory proteins, or the end products. In CTD-related ITP, reported complement abnormalities were limited to the initial proteins. Activation of the early complement system, mainly through activation of C3 and its precursor protein C4, was reported for both ITPs. On the other hand, more extensive complement activation has been reported in pITP.

The pathogenic role of lupus-specific autoantibodies and Interleukin-6 on demyelination of the brainstem and spinal cord in systemic lupus erythematosus.

OBJECTIVES: Demyelinating syndromes that result in brainstem and/or spinal cord lesions similar to those observed in neuromyelitis optica spectrum disorder (NMOSD) as neuropsychiatric syndromes in systemic lupus erythematosus (NPSLE) occasionally develop in patients with SLE. Cerebrospinal fluid (CSF) interleukin (IL)-6 is a known biomarker for NMOSD; however, its application in patients with SLE with brainstem and/or spinal cord lesions is unknown. Additionally, the breakdown of blood-brain barrier (BBB) integrity by autoantibodies is another mechanism of NMOSD; however, it is not elucidated in SLE. Therefore, this study was designed to clarify the use of CSF IL-6 and investigate whether autoantibodies contribute to BBB breaches and the development of brainstem and/or spinal cord lesions. METHODS: Data from patients with NPSLE who had NMOSD-like demyelinating lesions in the central nervous system (CNS), including brainstem and/or spinal cord lesions, were retrospectively analyzed. We retrospectively investigated the interval changes in CSF IL-6 and clinical and serological factors related to BBB permeability using CSF/serum albumin ratio (QAlb). RESULTS: Twelve patients with NPSLE who had demyelinating lesions in the brainstem and/or spinal cord were recruited. Before treatment, CSF IL-6 levels were 29.1 pg/mL and significantly decreased to 3.8 pg/mL by treatment (p = 0.008). Before treatment, CSF IL-6 was significantly correlated with the anti-dsDNA antibody titer (p = 0.027). Furthermore, before treatment, QAlb was significantly correlated with the serum anti-Smith antibody titer. In patients with atypical NMOSD who had specific lesions defined in the NMOSD diagnostic criteria but were negative for antiaquaporin four antibody, a significant correlation was observed between the serum anti-Smith antibody titer and CSF IL-6 (p = 0.025) and QAlb (p = 0.033) values before treatment. CONCLUSION: CSF IL-6 could be a surrogating marker for disease activity, and serum anti-Smith antibody permeabilizes the BBB in patients with NPSLE, supporting the development of NMOSD-like CNS lesions.

Neuropilin-1 (NRP1) expression distinguishes self-reactive helper T cells in systemic autoimmune disease.

Pathogenic T helper cells (Th cells) that respond to self-antigen cannot be easily distinguished from beneficial Th cells. These cells can generate systemic autoimmune disease in response to widely expressed self-antigens. In this study, we have identified neuropilin-1 (NRP1) as a cell surface marker of self-reactive Th cells. NRP1+ Th cells, absent in non-regulatory T cell subsets in normal mice, appeared in models of systemic autoimmune disease and strongly correlated with disease symptoms. NRP1+ Th cells were greatly reduced in Nr4a2 cKO mice, which have reduced self-reactive responses but showed normal responses against exogenous antigens. Transfer of NRP1+ Th cells was sufficient to initiate or accelerate systemic autoimmune disease, and targeting NRP1-expressing Th cells therapeutically ameliorated SLE-like autoimmune symptoms in BXSB-Yaa mice. Peripheral NRP1+ Th cells were significantly increased in human SLE patients. Our data suggest that self-reactive Th cells can be phenotypically distinguished within the Th cell pool. These findings offer a novel approach to identify self-reactive Th cells and target them to treat systemic autoimmune disease.

Pathogenic neuropsychiatric effect of stress-induced microglial interleukin 12/23 axis in systemic lupus erythematosus.

OBJECTIVES: The central nervous system disorder in systemic lupus erythematosus (SLE), called neuropsychiatric lupus (NPSLE), is one of the most severe phenotypes with various clinical symptoms, including mood disorder, psychosis and delirium as diffuse neuropsychological manifestations (dNPSLE). Although stress is one of the aggravating factors for neuropsychiatric symptoms, its role in the pathogenesis of dNPSLE remains to be elucidated. We aimed to investigate stress effects on the neuropsychiatric pathophysiology in SLE using lupus-prone mice and patients' data. METHODS: Sleep disturbance stress (SDS) for 2 weeks was placed on 6-8-week-old female MRL/lpr and control mice. Behavioural phenotyping, histopathological analyses and gene and protein expression analyses were performed to assess SDS-induced neuroimmunological alterations. We also evaluated cytokines of the cerebrospinal fluid and brain regional volumes in patients with dNPSLE and patients with non-dNPSLE. RESULTS: SDS-subjected MRL/lpr mice exhibited less anxiety-like behaviour, whereas stressed control mice showed increased anxiety. Furthermore, stress strongly activated the medial prefrontal cortex (mPFC) in SDS-subjected MRL/lpr. A transcriptome analysis of the PFC revealed the upregulation of microglial activation-related genes, including Il12b. We confirmed that stress-induced microglial activation and the upregulation of interleukin (IL) 12/23p40 proteins and increased dendritic spines in the mPFC of stressed MRL/lpr mice. IL-12/23p40 neutralisation and tyrosine kinase 2 inhibition mitigated the stress-induced neuropsychiatric phenotypes of MRL/lpr mice. We also found a higher level of cerebrospinal fluid IL-12/23p40 and more atrophy in the mPFC of patients with dNPSLE than those with non-dNPSLE. CONCLUSIONS: The microglial IL-12/23 axis in the mPFC might be associated with the pathogenesis and a promising therapeutic target for dNPSLE.

The expanding role of synthetic nucleic acids for diagnosis and treatment.

PURPOSE OF REVIEW: The presence of autoantibodies is a characteristic and diagnostic index of systemic lupus erythematosus (SLE). Antidouble-stranded DNA (antids-DNA) antibodies are the most frequent autoantibodies found in SLE related to the diagnosis and disease activity of SLE, and are measured by established methods like ELISA as a polyclonal autoantibody. However, there is no reliable data on the relationship between the respective reactivity of these polyclonal antids-DNA antibodies against different epitopes generated from the original antigen and the disease phenotype. Of the complications in SLE, neuropsychiatric SLE (NPSLE) is a troublesome and frequent phenotype of the disease but no specific diagnostic autoantibodies in serum have been found. First in this review, the possibility of antids-DNA antibodies for identifying primary NPSLE in patients with SLE based on the reactivity of different synthetic nucleic acids is described as a diagnostic marker. The purpose of this review is to examine diagnostic and therapeutic opportunities to modulate autoimmune in the central nervous system (CNS) developing the CNS inflammatory disorders. RECENT FINDINGS: Khatri et al. investigated antids-DNA antibodies in order to develop a reliable method based on the application of synthetic nucleic acids and protein-based antigen arrays to characterize autoreactive antibodies specially for NPSLE. They found autoantibodies in three particular synthetic double stranded antigens and the antinuclear antibody patterns in ordinary lupus and NPSLE. These discoveries are leading to precision medicine in the CNS inflammatory disorders. SUMMARY: Verifying the similarity of antids-DNA obtained from patients with NPSLE can be useful as a diagnostic marker. mRNA vaccination can locally suppress autoimmunity in the CNS associated with critical steps for the develop of CNS autoinflammation. Synthetic nuclei acids may provide a diagnostic and therapeutic target in patients with autoimmune CNS inflammatory disorders.

A patient with Castleman's disease initially manifesting symmetrical synovitis with pitting oedema.

Castleman's disease (CD), especially multicentric CD (MCD) has been known to manifest a variety of clinical features such as fatigue, anaemia, fever, and hypergammaglobulinaemia. Here, we report a 72-year-old female patient who had complicated severe synovitis, as an initial manifestation of the disease, lastly diagnosed as MCD. Initially, she had been diagnosed as remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome because of bilateral leg pitting oedema with significant C-reactive protein and matrix metalloproteinase-3 elevation but no disease-specific autoantibodies. Promptly, corticosteroid and additionally weekly methotrexate were introduced, but her leg oedema and inflammatory findings did not adequately come to be a remission. A lymph node biopsy from the groin region was performed because multiple lymph node swelling in ultrasound examination appeared even after introducing treatments, which revealed mixed-type CD. Multiple lymphadenopathies were observed in the axilla and inguinal region; finally, we diagnosed her as idiopathic MCD and introduced tocilizumab, which significantly improved leg oedema as well as inflammatory findings. As is shown in this case, manifestations included in RS3PE syndrome could be one of the clinical phenotypes in MCD, which should be considered as a differential diagnosis of MCD.

Anti-ribosomal P protein antibodies in patients with systemic lupus erythematosus is associated with hyperferritinemia.

AIM: Anti-ribosomal P protein antibodies (anti-ribo P) have been reported as one of the specific autoantibodies in patients with systemic lupus erythematosus (SLE) and has been demonstrated to bind and activate macrophages in vitro. Clinically, hyperferritinemia has been known to be a biomarker for macrophage activation. The aim of this study is to clarify the relationship of anti-ribo P and clinical characteristics and biomarkers including serum ferritin in patients with SLE. METHODS: Clinical parameters and laboratory data were measured in patients with active SLE (N = 127) in our university hospital. The risk factors affected by anti-ribo P were retrospectively calculated by logistic regression analysis, and the correlation of anti-ribo P and clinical factors was demonstrated. RESULTS: Anti-ribo P was significantly elevated in active SLE compared to non-SLE diseases (P < .0001). Sensitivity and the specificity of anti-ribo P in patients with SLE were 32.0% and 99.3%, respectively. Patients positive for anti-ribo P had the highest risk for elevated serum ferritin (odds ratio: 8.432). Accordingly, anti-ribo P positive patients had significantly elevated serum ferritin compared to negative patients (P = .024). A significant positive correlation was observed between the anti-ribo P titer and the serum ferritin level (r2  = .07, t = 5.22, P = .0081), but not serum interleukin (IL)-6 in SLE patients. CONCLUSION: The presence of anti-ribo P is a risk factor for higher ferritin levels that is independent of systemic inflammation regulated by IL-6. We speculate that anti-ribo P could be directly associated with macrophage activation leading to hyperferritinemia in patients with SLE.

Developmental process in diffuse psychological/neuropsychiatric manifestations of neuropsychiatric systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) involves excessive autoimmune reactions, with pathogenesis characterized by autoantibody production. Although the specific mechanism underlying the development of neuropsychiatric syndromes in SLE (NPSLE) is still unclear, recent studies indicate the involvement of autoimmune pathophysiology. We previously identified the presence of anti-N-methyl-d-aspartate receptor subunit GluN2 antibody (anti-GluN2) as a functional autoantibody which is able to impair neurons and is essential for the diagnosis of diffuse psychiatric/neuropsychological syndromes in NPSLE (dNPSLE). Other autoantibodies like anti-Sm antibodies and anti-glucose-regulated protein 78 antibodies are known to compromise blood brain barrier (BBB) integrity. We demonstrated that high mobility group box-1 protein (HMGB1) decorates synapses on neurons damaged by anti-neuron antibodies, including anti-GluN2, where it behaves as a linker to enhance C1q binding to synapses in a dNPSLE model mouse. This C1q binding via HMGB1 is a critical step for remodeling by activated microglia, which leads to reductions in neuronal complexity and long-term behavioral abnormalities. Suppression of activated microglia can significantly reduce central nervous system (CNS) dysfunction. In this review, we describe the critical steps in the development of dNPSLE in particular, including the phases of BBB breakdown, acute neuronal damage by autoantibodies and neuronal remodeling due to activated microglia.

A case of anti-MDA5 antibody-positive dermatomyositis developing reversible cerebral vasospasm syndrome successfully treated by multi-immunosuppressant combination including mycophenolate mofetil.

A 39-year-old woman admitted with multiple joint pain, hand rashes, and shortness of breath was diagnosed with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) with interstitial pneumonia (IP). Because of progressive dyspnoea and hypoxaemia, her IP was considered rapidly progressive interstitial lung disease. Initially, prednisolone 60 mg/day, cyclosporine A (CyA), and intravenous cyclophosphamide (IVCY) were initiated. A few days following the initiation of treatment, she experienced massive thunderclap headache, which was diagnosed as reversible cerebral vasospasm syndrome based on the findings of contraction in cerebral arteries with brain magnetic resonance imaging. Treatment with CyA and IVCY was discontinued, and diltiazem and mycophenolate mofetil (MMF) were initiated as an alternative immunosuppressant. Considering IVCY as the cause of Reversible cerebral vasospasm syndrome based on her clinical course, tacrolimus was commenced, which improved both DM and IP. DM patients who are anti-MDA5 antibody-positive are considered to have poor prognosis and require aggressive immunosuppressive treatments. In patients experiencing adverse events with standard IVCY, MMF with high-dose steroids and alternative calcineurin inhibitor should be considered.

Serological comparison of systemic lupus erythematosus with neuropsychiatric lupus using synthetic nucleic acid antigens.

Neuropsychiatric systemic lupus erythematosus is an autoimmune disorder characterized by an irregular exchange between the central nervous system and the immune system, leading to the outbreak of neurological conditions with possible disabling effects. Although neuropsychiatric systemic lupus erythematosus is the most common expression of lupus condition, it is still poorly understood. In this study, we focus on the development of an advantageous method based on the application of synthetic nucleic acids and protein-based antigen arrays in order to characterize autoreactive antibodies in neuropsychiatric systemic lupus erythematosus. We confirmed the benefits of using synthetic oligonucleotides such as assay reproducibility, elevated affinity and specificity to autoreactive antibodies. We also demonstrated presence of autoantibodies towards three particular synthetic double stranded antigens and verify similarity of antinuclear antibody patterns in ordinary lupus and neuropsychiatric systemic lupus erythematosus.

Haemophilus influenzae Non-type b Infection in an Adult Patient with Systemic Lupus Erythematosus.

A 40-year-old man with systemic lupus erythematosus taking consecutive oral corticosteroids developed a high-grade fever and disorder of consciousness following acute rhinitis. Haemophilus influenzae type f (Hif) was found and isolated from the blood and cerebrospinal fluid by culture, leading to a diagnosis of meningitis. The prevalence of H. influenzae type b (Hib) infections has decreased due to routine immunization. As a result, the prevalence of invasive non-Hib, including Hif infection, is increasing as a common H. influenzae infection in children and adults. Physicians should be aware of non-Hib H. influenzae infection, even though the Hib vaccine is widely used in Japan.

What are the latest clinical findings regarding the association of neurotoxic brain antibodies found in the cerebrospinal fluid in patients with autoimmune disorders?

PURPOSE OF REVIEW: Recently, experiments show that the autoantibodies with direct access to neurons following blood brain barrier (BBB) disruption destroy neurons and lead to remodeling in damaged neurons. These are critical steps in autoantibody-mediated central nervous system disorder called neuropsychiatric syndromes in systemic lupus erythematosus (NPSLE). The purpose of this review is to examine therapeutic opportunities to repress neuronal remodeling by microglia after acute neuronal injury by autoantibodies. RECENT FINDINGS: Recent studies have demonstrated that BBB disruption is a critical step for developing NPSLE, and serum anti-Sm antibodies have been significantly associated with BBB breakdown. In addition, it has been reported that antiglucose regulated protein-78 in patients with SLE also disrupt the BBB. Experiments with anti-N-methyl-D-aspartate antibodies show that HMGB1 and C1q were essential to activate microglia which, in turn, remodel damaged neurons in vivo. Interestingly treatment with angiotensin-converting enzyme inhibitor inactivated microglia and blunted neuronal remodeling as well as positively affected behavioral abnormalities. SUMMARY: BBB disruption, acute neuronal damage and neuronal remodeling by activated microglia are all critical steps for NPSLE development, and each step will afford novel therapeutic targets.

Anti-ribosomal P protein antibodies influence mortality of patients with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematous involving a severe form of the disease.

Objectives: The aim of this study is to clarify the effect of various autoantibodies on overall mortality in patients with diffuse psychiatric/neuropsychological syndromes in SLE (diffuse NPSLE). Methods: Fifty-five patients with diffuse NPSLE admitted from 1992 to 2017 had met inclusion criteria and were recruited for this study. The relationship of various serum autoantibodies with mortality was retrospectively analyzed based on the medical charts. Results: Of 55 patients, 14 patients [25.5%] had died during the observation period (2728 [22-8842] days (median [range])). The 5-year, 10-year, 15-year and 20-year mortality rates were 18.8%, 21.9%, 36.9% and 47.4%, respectively. Among various serum autoantibodies at the onset of diffuse NPSLE, only the presence of anti-ribosomal P protein antibodies (anti-ribo P) significantly increased the risk for death (relative risk 2.262, 95% confidence interval 1.276-4.417, p = 0.005). Of 14 fatal patients, 10 patients had died within 1 y after the onset of diffuse NPSLE. Remarkably, 7 of 10 patients with positive anti-ribo P had died of the severe complication primarily attributed to SLE except for one patient. Conclusions: The presence of anti-ribo P is a significant risk factor for overall poor prognosis in patients with diffuse NPSLE, involving a fatal complication by SLE.

Clinical significance of anti-DNA/N-methyl-D-aspartate receptor 2 antibodies in de novo and post-steroid cases with neuropsychiatric systemic lupus erythematosus.

BACKGROUND: Anti-DNA/N-methyl-D-aspartate receptor 2 (NR2) antibodies (anti-DNA/NR2 antibodies) are a subset of anti-DNA autoantibodies that cross-react with the extracellular domain of the GluN2A/GluN2B subunits of NR2. These antibodies induce apoptosis of hippocampus neurons and psychiatric disorder in mice and humans. Neuropsychiatric system lupus erythematosus (NPSLE) can develop after initiation of corticosteroids (post-steroid neuropsychiatric manifestation: PSNP) or before treatment (de novo NPSLE); however, pathophysiological differences between these subtypes remain unclear. The objective of this study was to clarify the prevalence of anti-DNA/NR2 antibodies in patients with NPSLE. METHODS: This study involved a cohort of patients with NPSLE admitted to our hospital. NPSLE patients were classified into two groups, de novo NPSLE and PSNP-SLE. Serum anti-DNA antibodies and anti-DNA/NR2 antibodies were measured by enzyme-linked immunosorbent assays. RESULTS: Serum samples were obtained from 24 patients with de novo NPSLE, 25 with PSNP-SLE and 76 healthy controls (HC). The level of anti-DNA/NR2 antibodies in patients with de novo NPSLE and PSNP-SLE were also higher than those in HC. Positive correlation between anti-DNA antibodies and anti-DNA/NR2 antibodies were found in PSNP-SLE, but was not significant in de novo NPSLE. CONCLUSION: The levels of anti-DNA/NR2 antibodies in PSNP-SLE were similar to those in de novo NPSLE. Anti-DNA/NR2 antibodies in PSNP-SLE were suggested as a dominant subset of anti-DNA antibodies, indicating that anti-DNA/NR2 antibodies may be a predictive factor in PSNP-SLE.