Urinary biomarkers associated with pathogenic pathways reflecting histological findings in lupus nephritis.

OBJECTIVE: There is a pressing need to understand the pathogenesis of histological findings and identify the biomarkers for predicting the histological severity in lupus nephritis (LN). This study aimed to identify the pathogenic signal pathway and elucidate urinary biomarkers for predicting the presence or severity of histological findings in LN. METHODS: Urine samples from patients with biopsy-proven active LN were screened for 1305 proteins using an aptamer-based proteomic assay. The diversity and expansion of individual renal histological features in LN were quantified to identify the urinary proteins associated with the histological findings found in each score. Candidate urinary proteins were validated in a validation cohort. Immunohistochemical staining of the renal tissues was performed to clarify the localisation of the candidate proteins. RESULTS: Cluster analysis extracted five histological subgroups according to their correlations with each histological finding in LN. Protein groups which correlated with each histological subgroup revealed a distinct pathogenesis in LN using pathway analyses. Enzyme-linked immunosorbent assay validation revealed that urinary calgranulin B (S100A9), MCP-1, and IGFBP-5 levels could specifically predict the presence and severity of active glomerular lesions, interstitial inflammation, and interstitial fibrosis, respectively. Immunohistochemical staining revealed the localisation of these proteins in each lesion. CONCLUSIONS: Renal histological findings may reflect the different pathogeneses involved in each lesion, and estimating the urinary calgranulin B, MCP-1, and IGFBP-5 levels may be useful in predicting the presence and severity of histological findings in LN.

Tense blisters and hemorrhagic bullae as the first manifestation of eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) poses a significant diagnostic challenge due to its varied clinical presentation. Here, we present a case of a 59-year-old female with a history of asthma and sinusitis, who manifested with an extremely rare presentation of drastic tense blisters and hemorrhagic bullae alongside purpuric lesions and peripheral neuropathy. Examinations revealed eosinophilia, positive anti-neutrophil cytoplasmic antibody, and characteristic pathological findings with small vessel vasculitis in the purpura. Treatment with glucocorticoids and cyclophosphamide led to rapid improvement in peripheral eosinophilia, skin manifestations and motor neuron deficits. Although rare, our case underscores that bullous skin lesions should be recognized as a potential cutaneous hallmark of EGPA to aid timely diagnosis, since prompt treatment initiation is crucial given the potential irreversible organ damage and poor prognosis of EGPA.

Longitudinal analysis at pre- and post-flare of T peripheral helper and T follicular helper subsets in patients with systemic lupus erythematosus.

OBJECTIVE: We focused to analyze the time-course changes at pre- and post-flare of T peripheral helper (Tph) cells and circulating T follicular helper (Tfh) cells in the blood of patients with systemic lupus erythematosus (SLE) with lupus low disease activity state (LLDAS) before flare. METHODS: This study included inactive (n = 29) and active (n = 55) patients with SLE. Tph subsets, Tfh subsets, CD11chi B cells, and plasma cells in the blood were determined by flow cytometry. The blood levels of cytokines including interferons (IFNs) were measured by electrochemiluminescence assay or cytokine beads array. RESULTS: Active SLE patients exhibited the increased frequency of Tph1, Tph2, Tfh1, and Tfh2 subsets when compared to inactive patients, but no clear changes in the other subsets. During the treatment with medications, Tph1, Tph2, and Tfh2 subsets were significantly reduced along with disease activity and Tph1 and Tph2 subsets were positively correlated with SLE disease activity index (SLEDAI). The time course analysis of patients at pre- and post-flare revealed that in the patients at LLDAS before flare, Tph subsets and Tfh subsets were relatively low levels. At the flare, Tph cells, particularly Tph1 and Tph2 subsets, were increased and correlated with SLEDAI. Furthermore, the blood levels of IFN-α2a, IFN-γ, and IFN-λ1 were low in the patients with LLDAS before flare but these IFNs, particularly IFN-λ1, were increased along with flare. CONCLUSION: Increased frequency of Tph1 and Tph2 subsets and elevated levels of serum IFN-λ1 are presumably critical for triggering of flare in SLE.

Systematic review and meta-analysis for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis.

OBJECTIVES: To update evidence on the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) and provide information to the taskforce for the 2024 update of the Japan College of Rheumatology (JCR) clinical practice guidelines (CPG) for the management of rheumatoid arthritis (RA). METHODS: We searched various databases for randomised controlled trials on RA published until June 2022, with no language restriction. For each of the 15 clinical questions, 2 independent reviewers screened the articles, evaluated the core outcomes, and performed meta-analyses. RESULTS: Subcutaneous injection of methotrexate (MTX) showed similar efficacy to oral MTX in MTX-naïve RA patients. Ozoralizumab combined with MTX improved drug efficacy compared to the placebo in RA patients with inadequate response (IR) to csDMARD. Rituximab with and without concomitant csDMARDs showed similar efficacy to other bDMARDs in bDMARD-IR RA patients. Combined Janus kinase inhibitors and MTX achieved similar clinical responses and equal safety during a 4-year period compared to tumour necrosis factor inhibitors in MTX-IR RA patients. Biosimilars showed efficacy equivalent to that of the original bDMARDs in csDMARD-IR and bDMARD-IR RA patients. CONCLUSION: This systematic review provides latest evidence for the 2024 update of the JCR CPG for RA management.

Successful high-dose glucocorticoid therapy for anti-mitochondrial antibody-positive myocarditis arising during tocilizumab and low-dose glucocorticoid therapy for rheumatoid arthritis.

Anti-mitochondrial antibody (AMA)-positive myopathy, a recently identified condition with significant cardiac involvement, poses a serious challenge in treatment consensus due to its extreme rarity. While several studies demonstrate the efficacy of high-dose prednisolone in managing this disease, the current literature lacks substantial evidence regarding the effectiveness of biologic therapy or low-dose prednisolone for remission induction. Here, we present a case of AMA-positive myocarditis that emerged during rheumatoid arthritis treatment with tocilizumab (TCZ) and low-dose prednisolone (PSL). Successfully, intensive immunosuppressive therapy with high-dose PSL proved effective in stabilizing this condition. Our case highlights the necessity of a robust immunosuppressive approach, favoring high-dose PSL over the combination of low-dose PSL and TCZ in this disease.

Cytotoxic Tph subset with low B-cell helper functions and its involvement in systemic lupus erythematosus.

T peripheral helper (Tph) cells are thought to contribute to extra-follicular B cell activation and play a pathogenic role in autoimmune diseases. However, the role of Tph subsets is not fully elucidated. Here, we investigate the immunological functions of Tph subsets and their involvement in systemic lupus erythematosus (SLE). We have defined four Tph subsets (Tph1: CXCR3+CCR6-, Tph2: CXCR3-CCR6-, Tph17: CXCR3-CCR6+, and Tph1-17: CXCR3+CCR6+) and performed RNA sequencing after cell sorting. Tph1 and Tph17 subsets express substantial levels of IL21, indicating B cell helper functions. However, Tph2 and Tph1-17 subsets express low IL21. Interestingly, we have found Tph2 subset express high levels of CX3CR1, GZMB, PRF1, GLNY, S1PR5, TBX21, EOMES, ZNF863, and RUNX3, indicating a feature of CD4+ cytotoxic T lymphocytes. In SLE patients, the frequency of Tph1 and Tph2 subsets are significantly increased and positively correlated with SLE disease activity indexes. Tph1 cells expansion has been observed in patients with cutaneous and musculoskeletal manifestations. On the other hand, Tph2 cell expansion has been found in patients with lupus nephritis in addition to the above manifestations. Our findings imply that Tph1 and Tph2 subsets exert distinct immunological functions and are contributed to the complexity of clinical manifestations in SLE.

A Case of Successful Immunosuppressive Therapy for Interstitial Lung Disease Associated with Sjögren's Syndrome With Double-positive Anti-SS-A and Anti-centromere Antibodies.

Sjögren's syndrome (SS) can present with extraglandular organs, such as interstitial lung disease (ILD). Anti-SS-A antibody is frequently found in SS cases, whereas anti-centromere antibody (ACA) is detected in some SS cases. Notably, the anti-SS-A and ACA double-positive cases exhibited distinct features with a higher prevalence of ILD. However, there have so far been no reports on the treatment of ILD in anti-SS-A and ACA double-positive cases. We herein present a case of ILD with anti-SS-A and ACA double-positive SS that was successfully treated with immunosuppressive therapy. Our case suggests the potential efficacy of immunosuppressive therapy for this poorly understood condition.

Risk of disease flares after SARS-CoV-2 mRNA vaccination in patients with systemic lupus erythematosus.

This study aims to elucidate the effectiveness and safety of SARS-CoV-2 mRNA vaccination in patients with systemic lupus erythematosus (SLE). We enrolled uninfected SLE patients who received two vaccine doses (BNT162b2 or mRNA-1273) and historical unvaccinated patients. Neutralizing antibodies, adverse reactions, and disease flares were evaluated 4 weeks after the second vaccination. Ninety patients were enrolled in each group. Among the vaccinated patients, SLE Disease Activity Index (SLEDAI), and prednisolone doses before vaccination were 2, and 5 mg/d, respectively. After the second vaccination, 19 (21.1%) had no neutralizing antibodies. Adverse reactions occurred in 88.9% within 3 d. Negative antibodies were associated with anemia and mycophenolate mofetil administration. SLEDAI increased modestly but significantly after vaccination, with 13 (14.4%) experiencing flares and 4 (4.4%) severe flares (nephritis in three and vasculitis in one). The flare rate was higher in vaccinated patients than unvaccinated controls. The mean duration between the second vaccination and flares was 35 d, and flares occurred at least 8 days after vaccination. Multivariable analysis showed that high SLEDAI and anti-dsDNA antibodies were associated with flares. The vaccine type, neutralizing antibody titer, and adverse reaction frequency did not affect flares. Therefore, residual disease activity before vaccination increases flare risk.

Re-emphasising the importance of catheter-based angiography to differentiate polyarteritis nodosa from cutaneous arteritis: Two case reports.

Polyarteritis nodosa (PAN) is a systemic necrotising vasculitis with a poor prognosis, characterised by inflammation and necrosis of medium-sized arteries. PAN patients can present with a wide range of systemic manifestations, whereas cutaneous arteritis (CA) is a restricted manifestation to skin of the disease with a more favourable prognosis. Thus, differentiation between PAN and CA is crucial. Here, we present two cases that were initially diagnosed as CA due to the limited presence of systemic symptoms, but were finally diagnosed as PAN through catheter-based angiography. Although contrast-enhanced computed tomography and computed tomographic angiography are increasingly used to diagnose PAN, neither case had any abnormal findings on these examinations. Our cases therefore underscore that catheter-based angiography is critical for differentiation between PAN and CA, even in cases with limited systemic symptoms.

Effectiveness and safety of rituximab in special types of rheumatoid arthritis.

OBJECTIVES: To elucidate the efficacy and safety of rituximab in special types of rheumatoid arthritis. METHODS: We retrospectively reviewed all patients with rheumatoid arthritis with lymphoproliferative disorder or vasculitis treated with rituximab between April 2010 and June 2022 at Keio University Hospital. We assessed the effectiveness of rituximab using the Disease Activity Score for 28 joints-erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), and safety of rituximab during the disease course. We also assessed the glucocorticoid-sparing effects of rituximab. RESULTS: We included eight patients with a history of lymphoproliferative disorder and five patients with rheumatoid vasculitis. They were treated with rituximab without high-dose glucocorticoid. The mean DAS28-ESR and CDAI scores significantly improved 12 months after rituximab administration (DAS28-ESR, 4.7 vs. 2.7, p < .001; CDAI, 16.0 vs. 5.1, p = .006, respectively), and the dose of prednisolone was reduced from a mean of 7.4 mg/day to 4.0 mg/day at 12 months (p = .05) and 3.2 mg/day at the last visit (p = .04). During the mean follow-up period of 52 months, we recorded one recurrence of lymphoproliferative disorder (not B-cell type) in patients with a history of lymphoproliferative disorder and remarkable improvement of skin ulcers in patients with vasculitis. CONCLUSION: B-cell depletion by rituximab may be a useful treatment option for patients with lymphoproliferative disorder and rheumatoid vasculitis.

Deep remission within 12 months prevents renal flare and damage accrual in lupus nephritis.

OBJECTIVES: To evaluate the significance of achieving deep remission by induction therapy in lupus nephritis (LN) patients. METHODS: We assessed consecutive patients undergoing induction therapy for active LN. Achievement of complete renal response (CR) was defined as a urine protein creatinine ratio (UPCR) ≤0.5 g/gCr, and deep remission (DR) was defined as a UPCR ≤0.15 g/gCr with stabilisation of serum creatinine levels assessed every 2-3 months. We compared renal flare and damage accrual rates among patients with CR, CR without DR, and DR at 3, 6, and 12 months and later. RESULTS: Fifty-nine Asian patients were enrolled, and the median observation period was 48.6 months. Of these, 55 patients achieved CR, and 33 achieved DR within 12 months of receiving induction therapy. The patients with DR within 12 months experienced a significantly lower rate of subsequent renal flare (p<0.001) and damage accrual (p=0.046) than those without CR, those with DR after 12 months, and those with no DR but CR within 12 months. In addition, younger age, shorter disease duration, lower urine protein at baseline, and earlier renal response were associated with DR within 12 months. CONCLUSIONS: Achievement of DR within 12 months after induction therapy should be a treatment target for active LN, as it has implications for preventing renal flare and damage accrual.

A severe cerebral infarction associated with giant cell arteritis, which developed during tocilizumab therapy and was successfully treated with intravenous cyclophosphamide.

Giant cell arteritis (GCA) is a large vessel vasculitis that primarily involves aorta and its major branches. Cerebral infarction is a serious complication that can occur secondary to GCA in up to 3% of patients with a mortality rate of over 50%. Due to the rarity of this severe complication, no therapeutic strategies are currently available. Furthermore, despite the recent progress in molecular-targeted therapy for GCA, it remains unknown whether tocilizumab is effective for severe ischemic complications such as cerebral infarction. The accumulation of individual cases in which this fatal complication could be treated is apparently required to build a better management of the disease. We present our case of GCA that developed severe cerebral infarction during high-dose glucocorticoid and tocilizumab therapy, and its symptoms and image findings were improved by switching to intravenous cyclophosphamide. Our case suggests that an intensive immunosuppressive therapy, including cyclophosphamide, may be necessary to stabilise this fatal complication of GCA.

Differences in the strength of inhibition of interleukin-6 signalling by subcutaneous sarilumab and tocilizumab in rheumatoid arthritis patients.

OBJECTIVES: To assess differences in the strength of inhibition of IL-6/STAT3 signalling induced by subcutaneously (sc) administered tocilizumab (TCZ) and sarilumab (SAR). METHODS: Data were collected on patients with rheumatoid arthritis (RA) who achieved low disease activity (Clinical Disease Activity Index [CDAI]≤10) following treatment with weekly or bi-weekly administration of 162 mg sc of TCZ (TCZ qw group, n=8; TCZ q2w group, n=8), bi-weekly doses of 200 mg sc of SAR (SAR q2w group, n=7), or MTX (n=8) as a control. The clinical characteristics of each group were collected, and the serum concentrations of IL-6 and soluble IL-6 receptor (sIL-6R) were measured using ELISA. Whole blood samples from each group were stimulated with 100 ng/ml of IL-6. The proportion of phosphorylated (p)STAT3-positive CD4+ T cells was measured using phosflow cytometric analysis. RESULTS: The proportion of pSTAT3-positive CD4+ T cells following stimulation with 100 ng/ml of recombinant human IL-6 was significantly different among the groups (median 1.8% [0.9-3.0] vs. 7.7% [2.9-8.0] vs. 12.5% [11.4-16.6] vs. 71.5% [68.0-78.5] for the TCZ qw, SAR q2w, TCZ q2w, and MTX control groups, respectively; p<0.01 for all comparisons). CONCLUSIONS: SAR 200 mg q2w showed significantly stronger inhibition of IL-6/STAT3 signalling than TCZ sc q2w but weaker inhibition than TCZ sc qw. The results of this study may be useful for adjusting the IL-6 blockade treatment for patients with RA.

Detection of Osteoarthritis from Multimodal Hand Data.

Osteoarthritis (OA) describes a degenerative joint disorder that is prevalent among older people and typically results in swollen and inflamed joints. The aim of this paper is to develop a method using images, videos and thermal data of 100 patients taken at Keio University Hospital to detect OA in hands. By using hand pose estimation on the video data, joint angles can be calculated and subsequently transformed into feature vectors. For the thermal and RGB images, hand keypoint detectors were trained to identify and crop the appropriate joints within the images. The resulting extracted features are combined and further trained on Support Vector Machines and Convolutional Neural Networks to obtain the final binary classification for each joint. While the proposed method generally shows favorable accuracy and F1-scores on the Proximal (PIP) and Distal Interphalangeal (DIP) joints, the performance on the Metacarpophalangeal (MCP) joints is limited by the low occurrence of affected joints in the dataset. We further compare the different modalities and found that, apart from the combined approach, using video data provides the best results. Clinical Relevance- The proposed method shows promising first results for the usage of visual and thermal data in combination with machine learning in order to detect OA.

A Collaborative Study on the Classification of Silicone Oil Droplets and Protein Particles Using Flow Imaging Method.

In this study, we conducted a collaborative study on the classification between silicone oil droplets and protein particles detected using the flow imaging (FI) method toward proposing a standardized classifier/model. We compared four approaches, including a classification filter composed of particle characteristic parameters, principal component analysis, decision tree, and convolutional neural network in the performance of the developed classifier/model. Finally, the points to be considered were summarized for measurement using the FI method, and for establishing the classifier/model using machine learning to differentiate silicone oil droplets and protein particles.

Role of interferons (IFNs) in the differentiation of T peripheral helper (Tph) cells.

Interleukin (IL)-21-producing T peripheral helper (Tph) cells are thought to contribute to extra-follicular B cell activation and play a pathogenic role in autoimmune diseases. In this study, we investigated the relationship between Tph cells and interferons (IFNs) in several autoimmune diseases because our previous study demonstrated that type I IFNs promote the differentiation of IL-21-producing Tph-like cells. The frequency of Tph cells in the blood as well as serum IFN-α2a and IFN-λ1 were markedly elevated in patients with active systemic lupus erythematosus (SLE) compared to other autoimmune diseases or healthy controls. Notably, the frequency of Tph cells was positively correlated with the SLE disease activity index, serum IFN-α and serum IFN-λ1 in SLE patients. Additionally, we found that type III IFNs (IFN-λ1, IFN-λ2 and IFN-λ3) promote the differentiation of programmed cell death-1 (PD-1)+ CXCR5 -CD4+ T cells and enhance the secretion of IL-21, IFN-γ and CXCL13. IFN-λ1, like IFN-α, up-regulated the mRNA expression of IL21, IFNG, CXCL13, CD244, SLAMF7, GZMB, PRF1, CCR5 and PRDM1, whereas it down-regulated that of CXCR5 and BCL6, reflecting a Tph-related gene expression pattern. IFN-α in combination with IFN-λ1, IFN-λ2 or IFN-λ3 significantly increased the differentiation of PD-1+CXCR5- Tph-like cells and the secretion of Tph-related cytokines as compared with each IFN alone, suggesting a cooperative interaction. From these findings, it is highly probable that type III IFNs in addition to type I IFNs play a key role in the differentiation of Tph cells and that high levels of IFN-α and IFN-λ1 trigger the differentiation and expansion of Tph cells in SLE.

Decreased chronic kidney disease in rheumatoid arthritis in the era of biologic disease-modifying anti-rheumatic drugs.

Background: We investigated the incidence of chronic kidney disease (CKD) progression and its factors relevant to patients with stable rheumatoid arthritis (RA). Methods: We enrolled consecutive patients with RA who had initiated treatment with a biologic disease-modifying anti-rheumatic drug (bDMARD) at our institution and continued the same drug for >5 years between 2001 and 2016. Patients with CKD at bDMARD initiation were excluded. C-reactive protein (CRP) level, Clinical Disease Activity Index (CDAI) score and estimated glomerular filtration rate were measured every 6 months. Results: We included 423 patients, with 196 on tumour necrosis factor inhibitors, 190 on tocilizumab and 37 on abatacept. Among these patients, 34 (8.0%) progressed to CKD within 5 years. The mean CRP level and CDAI score over 5 years were significantly lower in patients without CKD progression than in those with CKD progression (P < .001 and P = .008, respectively). Multivariable analysis revealed that age at bDMARD initiation [odds ratio (OR) 1.05, P = .002], non-steroidal anti-inflammatory drug use (OR 3.47, P = .004) and mean CRP >0.14 mg/dL (OR 5.89, P = .015) were independently associated with CKD progression, while tocilizumab use was associated with a decreased risk of CKD progression (OR 0.31, P = .027). Conclusions: Controlling inflammation contributes to the inhibition of CKD progression in RA patients.