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 characterised 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 diarrhoea and hospitalised 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+ plasmacyte infiltration into mucosa of the small intestine and ischaemic change secondarily caused by chronic inflammation. Random biopsies from the mucosa of stomach, duodenum, ileum, and colon also revealed diffuse and massive IgG4+ plasmacyte 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.

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.

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.

Synergistic enhancement of production of proinflammatory cytokines of human peripheral blood monocytes by anti-Sm and anti-RNP antibodies.

The present study was performed to elucidate the roles of serum anti-Sm antibodies in the pathogenesis of systemic lupus erythematosus (SLE). Highly purified peripheral blood monocytes obtained from healthy donors were cultured in the presence of monoclonal anti-Sm antibody (anti-Sm mAb), monoclonal anti-U1-RNP antibody (anti-RNP mAb) or control murine IgG1 or IgG3. After various periods of incubation, levels of IL-6 and TNF-α in the culture supernatants were measured by ELISA and the expression of mRNA for various molecules in monocytes was determined using RT-PCR. Flow cytometry analysis confirmed the bindings of anti-Sm mAb and anti-RNP mAb on viable human monocytes. Both anti-Sm mAb and anti-RNP mAb significantly increased the production of IL-6 and TNF-α of human monocytes in a dose-dependent manner, although the latter was more potent than the former. Of note, anti-Sm mAb synergistically enhanced the production and mRNA expression of IL-6 and TNF-α of human monocytes in the presence of anti-RNP mAb. Notably, anti-RNP mAb, but not anti-Sm mAb, significantly enhanced the mRNA expression of RelA in human monocytes. Finally, anti-Sm mAb still up-regulated the IL-6 production of monocytes in the presence of anti-RNP mAb under the influence of N-acetyl cysteine or pyrrolidine dithiocarbamate that totally abrogated the IL-6 production provoked by anti-Sm mAb alone in the absence of anti-RNP mAb. These results demonstrate that anti-Sm and anti-RNP antibodies synergistically up-regulate the expression of IL-6 and TNF-α in human monocytes. The data also suggest that the effect of anti-Sm in the synergy with anti-RNP might not involve NFkB activation.

Elevation of serum anti-glucose-regulated protein 78 antibodies in neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: Recent studies have demonstrated that autoantibodies directed against glucose-regulated protein 78 (GRP78) on endothelial cells promote blood-brain barrier (BBB) damages. The present study examined whether serum anti-GRP78 antibodies might be involved in the pathogenesis of neuropsychiatric SLE (NPSLE). METHODS: Serum samples were obtained from 129 patients with SLE (58 patients with diffuse psychiatric/neuropsychological syndromes of NPSLE (diffuse NPSLE), 30 with neurological syndromes (focal NPSLE), 21 with lupus nephritis (LN), 20 without NPSLE or LN (SLE alone)), from 35 patients with non-SLE rheumatic diseases (non-SLE RD) and from 24 healthy controls (HC). Anti-GRP78 levels were measured with an ELISA, using recombinant GRP78 as antigens. Cerebrospinal fluid (CSF) samples were also obtained from 88 patients with NPSLE. The BBB function was evaluated by Q albumin ((CSF albumin/serum albumin)×103). RESULTS: Serum anti-GRP78 levels were significantly elevated in SLE compared with non-SLE RD or HC. There were no significant differences in serum anti-GRP78 levels among NPSLE, LN and SLE alone. Of note, serum anti-GRP78 levels were significantly higher in acute confusional state (ACS) than in non-ACS diffuse NPSLE (p=0.0001) or in focal NPSLE (p=0.0002). Finally, serum anti-GRP78 levels were significantly correlated with Q albumin (r=0.294, p=0.0054) in NPSLE. CONCLUSION: These results indicate that anti-GRP78 antibodies are associated with the development of diffuse NPSLE, especially ACS. Thus, the data suggest that anti-GRP78 antibodies might contribute to the development of ACS through the damages of BBB.

Role of serum autoantibodies in blood brain barrier damages in neuropsychiatric systemic lupus erythematosus.

OBJECTIVES: The present study was carried out to elucidate the roles of serum autoantibodies in the development of blood-brain barrier (BBB) damages in neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Paired serum and CSF samples were obtained from 101 SLE patients when they presented active neuropsychiatric manifestations (69 patients with diffuse psychiatric/neuropsychological syndromes [diffuse NPSLE] and 32 patients with neurologic syndromes or peripheral neuropathy [focal NPSLE]). IgG anti-NR2 subunit of NMDA receptor (anti-NR2), anti-Sm, anti-ribosomal P and IgG anti-cardiolipin in sera and albumin in CSF and sera were measured by ELISA. Blood-brain barrier (BBB) function was evaluated by Q albumin (CSF/serum albumin quotient x 1,000). RESULTS: Q albumin was significantly higher in acute confusional state (ACS) than in non-ACS diffuse NPSLE (anxiety disorder, cognitive dysfunction, mood disorder and psychosis) or in focal NPSLE. Anti-Sm, but not anti-NR2, anti-P or anticardiolipin, was significantly elevated in ACS compared with the other 2 groups of NPSLE, although serum anti-NR2 was significantly higher in ACS than that in focal NPSLE. Multiple regression analysis confirmed the significant contribution of anti-Sm (p=0.0040), but not anti-NR2 (p=0.5023), anti-P (p=0.2651), or anti-cardiolipin (p=0.6769) in the elevation of Q albumin. CONCLUSIONS: The data demonstrate that serum anti-Sm antibodies play a most important role in the disruption of BBB in NPSLE.

The expression of mRNA for peptidylarginine deiminase type 2 and type 4 in bone marrow CD34+ cells in rheumatoid arthritis.

OBJECTIVES: Antibodies directed to citrullinated proteins are highly specific for rheumatoid arthritis (RA). Citrullination is catalyzed by peptidylarginine deiminase (PAD) enzymes. The current study examined the mRNA expression of PADI2 and PADI4 in bone marrow (BM) CD34+ cells from RA patients. METHODS: CD34+ cells were purified from BM samples obtained from 48 RA patients and from 30 osteoarthritis (OA) patients during joint operations via aspiration from the iliac crest. The expression of mRNAs for PADI2, PADI4 and Sp1 was examined by quantitative reverse transcription PCR. RESULTS: The expression of mRNA for PADI2 was significantly higher in RA BM CD34+ cells than OA BM CD34+ cells. The expression of mRNAs for PADI4 and Sp1 in RA BM CD34+ cells appeared to be increased compared to OA BM CD34+ cells, although it did not reach the statistical significance. The levels of mRNAs for PADI2, PADI4 and Sp1 were not correlated with serum C-reactive protein or with the administration of methotrexate or oral steroids. Finally, the level of PADI2 mRNA as well as that of PADI4 mRNA was significantly correlated with the level of Sp1 mRNA in RA BM CD34+ cells. CONCLUSIONS: These results indicate that the mRNA expression of PADI2, PADI4 and Sp1 is upregulated in RA BM CD34+ cells independently of the systemic inflammation or treatment regimen. Moreover, the data suggest that the enhanced mRNA expression of PADI2 and PADI4 in BM CD34+ cells might be a result of the enhanced expression of Sp1 gene in RA BM CD34+ cells.

Differential influences of Fc gamma receptor blocking on the effects of certolizumab pegol and infliximab on human monocytes.

OBJECTIVES: To compare the effects of certolizumab pegol (CZP) and infliximab (IFX) on human monocytes. METHODS: Highly purified monocytes from healthy donors were cultured with CZP, IFX, control IgG1, or polyethylene glycol (PEG) at pharmacological attainable concentrations in culture medium with 10% autologous normal human serum (NHS) or with fetal bovine serum (FBS) for 24 h, after which the supernatants were replaced by fresh culture medium containing LPS. After additional 24 h of incubation, the supernatants were assayed for TNF-α and IL-6. In some experiments, the cells were harvested after 1 h of stimulation with LPS for analysis of mRNA for TNF-α by quantitative PCR. RESULTS: Pre-incubation of monocytes with CZP or IFX reduced the production of TNF-α in subsequent cultures stimulated by LPS in a dose-dependent manner. The suppressive effects of IFX on the TNF-α production were significantly diminished, but those of CZP were rather enhanced, in cultures with autologous NHS compared with in cultures with FBS. Addition of IgG, but not IgG F(ab')2 fragments, significantly inhibited the suppressive effects of IFX on the production of TNF-α and IL-6, whereas either IgG or IgG F(ab')2 fragments had no significant influences on the suppressive effects of CZP. Furthermore, pre-incubation with CZP or IFX significantly inhibited the expression of mRNA for TNF-α and IL-6 in monocytes compared with PEG or IgG. CONCLUSION: These results indicate that the mechanism of action of CZP is different from that of IFX. Thus, CZP suppresses the production of proinflammatory cytokines independently of Fc receptors, whereas the suppressive effects of IFX on human monocytes are almost totally dependent on the interaction with Fc receptors.