Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases.

Genetic studies have revealed many variant loci that are associated with immune-mediated diseases. To elucidate the disease pathogenesis, it is essential to understand the function of these variants, especially under disease-associated conditions. Here, we performed a large-scale immune cell gene-expression analysis, together with whole-genome sequence analysis. Our dataset consists of 28 distinct immune cell subsets from 337 patients diagnosed with 10 categories of immune-mediated diseases and 79 healthy volunteers. Our dataset captured distinctive gene-expression profiles across immune cell types and diseases. Expression quantitative trait loci (eQTL) analysis revealed dynamic variations of eQTL effects in the context of immunological conditions, as well as cell types. These cell-type-specific and context-dependent eQTLs showed significant enrichment in immune disease-associated genetic variants, and they implicated the disease-relevant cell types, genes, and environment. This atlas deepens our understanding of the immunogenetic functions of disease-associated variants under in vivo disease conditions.

Organ Damage and Quality of Life in Takayasu Arteritis　- Evidence From a National Registry Analysis.

BACKGROUND: Takayasu arteritis, affecting primarily young women, damages large arteries and organs. We examined the impact of disease duration and sex on organ damage and quality of life using Japan's Intractable Disease Registry.Methods and Results: After refining data, 2,013 of 2,795 patients were included in the study. Longer disease duration was related to a lower prevalence of disease activity symptoms, a higher prevalence of organ damage, and a higher proportion of patients requiring nursing care. Compared with men, women tended to have an earlier onset age, exhibiting longer disease duration. A higher proportion of women had aortic regurgitation and required nursing care. The proportion of female patients in employment was lower than that of the general female population, whereas no difference was observed between male patients and the general male population. Logistic regression analysis revealed that age at surveillance, brain ischemia, visual impairment/loss, and ischemic heart disease were significant factors associated with high nursing care needs (Level ≥2, with daily activity limitations). CONCLUSIONS: Early diagnosis and effective treatment, particularly to prevent brain ischemia, visual impairment, and ischemic heart disease, may improve the quality of life of patients with Takayasu arteritis, especially women.

Validation of the Diagnostic Criteria for IgG4-Related Periaortitis/Periarteritis and Retroperitoneal Fibrosis (IgG4PA/RPF) 2018, and Proposal of a Revised 2023 Version for IgG4-Related Cardiovascular/Retroperitoneal Disease.

BACKGROUND: In 2018, diagnostic criteria were introduced for IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis (PA/RPF). This study assessed the existing criteria and formulated an improved version.Methods and Results: Between August 2022 and January 2023, we retrospectively analyzed 110 Japanese patients diagnosed with IgG4-related disease (IgG4-RD) involving cardiovascular and/or retroperitoneal manifestations, along with 73 non-IgG4-RD patients ("mimickers") identified by experts. Patients were stratified into derivation (n=88) and validation (n=95) groups. Classification as IgG4-RD or non-IgG4-RD was based on the 2018 diagnostic criteria and various revised versions. Sensitivity and specificity were calculated using experts' diagnosis as the gold standard for the diagnosis of true IgG4-RD and mimickers. In the derivation group, the 2018 criteria showed 58.5% sensitivity and 100% specificity. The revised version, incorporating "radiologic findings of pericarditis", "eosinophilic infiltration or lymphoid follicles", and "probable diagnosis of extra-PA/-RPF lesions", improved sensitivity to 69.8% while maintaining 100% specificity. In the validation group, the original and revised criteria had sensitivities of 68.4% and 77.2%, respectively, and specificities of 97.4% and 94.7%, respectively. CONCLUSIONS: Proposed 2023 revised IgG4-related cardiovascular/retroperitoneal disease criteria show significantly enhanced sensitivity while preserving high specificity, achieved through the inclusion of new items in radiologic, pathological, and extra-cardiovascular/retroperitoneal organ categories.

Similarity and difference between systemic lupus erythematosus and NZB/W F1 mice by multi-omics analysis.

OBJECTIVES: Several animal disease models have been used to understand the mechanisms of systemic lupus erythematosus (SLE); however, the translation of findings from animals to humans has not been sufficiently examined in drug development. To confirm the validity of New Zealand black x New Zealand white (NZB/W) F1 mice as an SLE model, we extensively characterized SLE patients and NZB/W F1 mice by omics analysis. METHODS: Peripheral blood from patients and mice and spleen and lymph node tissue from mice were analysed using cell subset analysis, cytokine panel assays, and transcriptome analysis. RESULTS: CD4+ effector memory T cells, plasmablasts, and plasma cells were increased in both SLE patients and NZB/W F1 mice. Levels of tumor necrosis factor-α, interferon gamma induced protein-10, and B cell activating factor in plasma were significantly higher in SLE patients and NZB/W F1 mice than in their corresponding controls. Transcriptome analysis revealed an upregulation of genes involved in the interferon signalling pathway and T-cell exhaustion signalling pathway in both SLE patients and the mouse model. In contrast, death receptor signalling genes showed changes in the opposite direction between patients and mice. CONCLUSION: NZB/W F1 mice are a generally suitable model of SLE for analysing the pathophysiology and treatment response of T/B cells and monocytes/macrophages and their secreted cytokines.

Establishing clinical remission criteria for giant cell arteritis: Results of a Delphi exercise carried out by an expert panel of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis.

OBJECTIVE: To develop a proposal for giant cell arteritis remission criteria in order to implement a treat-to-target algorithm. METHODS: A task force consisting of 10 rheumatologists, 3 cardiologists, 1 nephrologist, and 1 cardiac surgeon was established in the Large-vessel Vasculitis Group of the Japanese Research Committee of the Ministry of Health, Labour and Welfare for Intractable Vasculitis to conduct a Delphi survey of remission criteria for giant cell arteritis. The survey was circulated among the members over four reiterations with four face-to-face meetings. Items with a mean score of ≥4 were extracted as items for defining remission criteria. RESULTS: An initial literature review yielded a total of 117 candidate items for disease activity domains and treatment/comorbidity domains of remission criteria, of which 35 were extracted as disease activity domains (systematic symptoms, signs and symptoms of cranial and large-vessel area, inflammatory markers, and imaging findings). For the treatment/comorbidity domain, ≤5 mg/day of prednisolone 1 year after starting glucocorticoids was extracted. The definition of achievement of remission was the disappearance of active disease in the disease activity domain, normalization of inflammatory markers, and ≤5 mg/day of prednisolone. CONCLUSION: We developed proposals for remission criteria to guide the implementation of a treat-to-target algorithm for giant cell arteritis.

Risk factors for serious infections and infection-related mortality in patients with microscopic polyangiitis: Multicentre REVEAL cohort study.

OBJECTIVE: Infections are a critical concern for patients with microscopic polyangiitis (MPA). This study aimed to identify the risk factors associated with serious infections (SIs) and infection-related mortality in patients with MPA, as well as the effect of glucocorticoid (GC) dose tapering on these outcomes. METHODS: This multicentre, retrospective, and observational study utilised data from a cohort of patients with MPA in Japan [Registry of Vasculitis Patients to Establish REAL World Evidence (REVEAL) cohort]. Patients were categorised based on the occurrence of SIs or infection-related deaths, and various characteristics were compared among the groups. RESULTS: Among 182 patients, 66 (36.2%) experienced 129 SIs and 27 (14.8%) developed infection-related deaths. Advanced age, elevated C-reactive protein (CRP) levels, and higher ratio of the GC dose at 3 months to the initial dose were identified as independent risk factors for SIs. Older age was also associated with infection-related deaths. Furthermore, the cumulative incidence of infection-related deaths was significantly higher in patients with a higher ratio of the GC dose at 24 months to the initial dose. CONCLUSION: Older age, elevated CRP levels, and slower GC dose tapering predispose patients to SIs and infection-related deaths. Strategies, such as rapid GC dose tapering, are anticipated to mitigate the risk of infections.

Pathogenicity of IgG-Fc desialylation and its association with Th17 cells in an animal model of systemic lupus erythematosus.

OBJECTIVES: Decreased sialylation of IgG-Fc glycans has been reported in autoimmune diseases, but its role in systemic lupus erythematosus (SLE) is not fully understood. In this study, we examined the pathogenicity of IgG desialylation and its association with Th17 in SLE using an animal model. METHODS: B6SKG mice, which develop lupus-like systemic autoimmunity due to the ZAP70 mutation, were used to investigate the pathogenicity of IgG desialylation. The proportion of sialylated IgG was compared between B6SKG and wild-type mice with or without ß-glucan treatment-induced Th17 expansion. Anti-interleukin (IL)-23 and anti-IL-17 antibodies were used to examine the role of Th17 cells in IgG glycosylation. Activation-induced cytidine deaminase-specific St6gal1 conditionally knockout (cKO) mice were generated to examine the direct effect of IgG desialylation. RESULTS: The proportions of sialylated IgG were similar between B6SKG and wild-type mice in the steady state. However, IgG desialylation was observed after ß-glucan-induced Th17 expansion, and nephropathy also worsened in B6SKG mice. Anti-IL-23/17 treatment suppressed IgG desialylation and nephropathy. Glomerular atrophy was observed in the cKO mice, suggesting that IgG desialylation is directly involved in disease exacerbation. CONCLUSIONS: IgG desialylation contributes to the progression of nephropathy, which is ameliorated by blocking IL-17A or IL-23 in an SLE mouse model.

Rheumatoid factor recognizes specific domains of the IgG heavy chain complexed with HLA class II molecules.

OBJECTIVE: We previously reported that RF recognized the IgG heavy chain (IgGH)/RA-susceptible HLA class II molecule complex. In the present study, we investigated the molecular mechanisms underlying HLA binding to and the RF recognition of IgGH. METHODS: We synthesized various types of IgGH segments, including VH, CH1, CH2 and CH3, and transfected them with or without HLA class II molecules into the Human Embryonic Kidney 293T cell line. IgGH single domains linked with the HLA-Cw3 peptide, which binds to the binding groove of the HLA class II molecule, were also synthesized. The expression of IgGH domains on the cell surface and their recognition by RF were examined using flow cytometry. RESULTS: Flag-tagged IgGH segments containing CH1 (CH1, VH-CH1, CH1-CH2, VH-CH1-CH2, CH1-CH2-CH3 and VH-CH1-CH2-CH3) were clearly presented on the cell surface by HLA-DR4, while segments without the CH1 domain were expressed at a low level, and the CH3 single domain was only weakly detected on the cell surface, even with HLA-DR4. We then transfected IgGH single domains linked to the Cw3 peptide together with HLA-DR4 and showed that RF-containing sera from RA patients only recognized the CH3 domain and none of the other single domains. When various segments without the Cw3 peptide were transfected with HLA-DR4, only the CH1-CH2-CH3 segment and full-length IgGH were detected by the sera of RA patients. CONCLUSION: The CH1 domain of IgGH binds to the RA-susceptible HLA-DR molecule and is expressed on the cell surface. RF specifically recognizes the CH3 domain of the IgGH/HLA-DR4 complex.

Comparisons of SLE-DAS and SLEDAI-2K and classification of disease activity based on the SLE-DAS with reference to patient-reported outcomes.

OBJECTIVES: Although the SLE Disease Activity Score (SLE-DAS) and its definitions to classify disease activity have been recently developed to overcome the drawbacks of the SLE Disease Activity Index 2000 (SLEDAI-2K), the performance of the SLE-DAS for patient-reported outcomes (PROs) has not been fully examined. We aimed to compare SLE-DAS with SLEDAI-2K and validate the classifications of disease activity based on SLE-DAS in terms of PROs. METHODS: We assessed generic quality of life (QoL) using the Medical Outcome Survey 36-Item Short-Form Health Survey (SF-36), disease-specific QoL using the lupus patient-reported outcome tool (LupusPRO), burden of symptoms using the SLE Symptom Checklist (SSC), patient global assessment (PtGA) and physician global assessment (PhGA). RESULTS: Of the 335 patients with SLE, the magnitudes of the mean absolute error, root mean square error, Akaike information criterion, and Bayesian information criterion were comparable for most PROs between the SLE-DAS and SLEDAI-2K. In contrast, SLEDAI-2K had a higher predictive value for health-related QoL of LupusPRO and PtGA than SLE-DAS. Low disease activity, Boolean and index-based remission and categories of disease activity (remission, mild and moderate/severe activity) were significantly associated with health-related QoL in LupusPRO, SSC and PhGA, but not SF-36 or PtGA. CONCLUSION: No clear differences were identified in the use of the SLE-DAS over the SLEDAI-2K in assessing PROs in patients with SLE. The classification of disease activity based on the SLE-DAS was validated against several PROs. SLE-DAS and its categories of disease activity effectively explain some of the PROs.

Promoting awareness of terminology related to unmet medical needs in context of rheumatic diseases in Japan: a systematic review for evaluating unmet medical needs.

To optimize patient prognosis, patient needs, including unmet needs, should be adequately assessed. However, such needs are more challenging to report and, consequently, more likely to go unmet compared with the needs reported by physicians. We aimed to determine the appropriate direction of future research on unmet medical needs in rheumatic diseases in Japan by conducting a literature review. We searched PubMed and Web of Science using 23 terms linked to unmet medical needs for major rheumatic diseases in Japan. Further, we collected articles on health-related quality of life and investigated the scales used for assessment, as well as whether the terms "unmet needs" or "unmet medical needs" were used. We identified 949 papers on 10 diseases, including systemic lupus erythematosus, systemic sclerosis, dermatomyositis, juvenile idiopathic arthritis, adult-onset Still's disease, antiphospholipid syndrome, mixed connective tissue disease, Takayasu arteritis, Sjögren's syndrome, and Behçet's disease; 25 of the 949 papers were selected for full-text review. Fifteen articles on five diseases were related to health-related quality of life. The term "unmet needs" was used in only one article. Six out of 15 studies used the 36-item short form survey, whereas the scales used in other studies differed. The optimal treatment plan determined by a physician may not necessarily align with the best interests of the patient. In clinical research, cross sectional and standardized indicators of health-related quality of life should be employed along with highly discretionary questionnaires to assess and optimize resource allocation in healthcare and simultaneously achieve patient-desired outcomes.

Summary of the current status of clinically diagnosed cases of Schnitzler syndrome in Japan.

BACKGROUND: Schnitzler syndrome is a rare disorder with chronic urticaria, and there is no report summarizing the current status in Japan. METHODS: A nationwide survey of major dermatology departments in Japan was conducted in 2019. We further performed a systematic search of PubMed and Ichushi-Web, using the keywords "Schnitzler syndrome" and "Japan" then contacted the corresponding authors or physicians for further information. RESULTS: Excluding duplicates, a total of 36 clinically diagnosed cases were identified from 1994 through the spring of 2022, with a male to female ratio of 1:1. The median age of onset was 56.5 years. It took 3.3 years from the first symptom, mostly urticaria, to reach the final diagnosis. The current status of 30 cases was ascertained; two patients developed B-cell lymphoma. SchS treatment was generally effective with high doses of corticosteroids, but symptoms sometimes recurred after tapering. Colchicine was administered in 17 cases and was effective in 8, but showed no effect in the others. Tocilizumab, used in six cases, improved laboratory abnormalities and symptoms, but lost its efficacy after several years. Rituximab, used in five cases, was effective in reducing serum IgM levels or lymphoma mass, but not in inflammatory symptoms. Four cases were treated with IL-1 targeting therapy, either anakinra or canakinumab, and achieved complete remission, except one case with diffuse large B-cell lymphoma. CONCLUSIONS: Since Schnitzler syndrome is a rare disease, the continuous collection and long-term follow-up of clinical information is essential for its appropriate treatment and further understanding of its pathophysiology.

Glucocorticoids in the treatment of IgG4-related disease-Prospects for new international treatment guidelines.

Immunoglobulin G4-related disease (IgG4-RD) is a chronic fibro-inflammatory disease that may cause dysfunction in various organs. Worldwide multidisciplinary experts attending the Fourth International Symposium on IgG4-Related Disease in Japan in 2021 discussed treatments for IgG4-RD, especially glucocorticoid (GC) therapy. This review describes the efficacy, safety, and cost of treatments for IgG4-RD based on findings presented at the international symposium. A medium dose of GC was considered appropriate for the initial treatment of IgG4-RD. A randomized controlled trial and an open-label prospective study have shown that long-term maintenance GC therapy (prednisolone ≥ 5 mg/day) could prevent disease relapse. In addition, two open-label randomized controlled trials reported the effects of combinational use of GC and synthetic immunosuppressive agents, mycophenolate mofetil and leflunomide, on relapse prevention. Moreover, an open-label single-arm study showed an excellent rate of clinical response to rituximab. Many observational studies have shown the efficacy of an appropriate GC regimen in patients with IgG4-RD. Synthetic immunosuppressive agents and a molecular-targeted agent can be potent alternatives to GCs, but additional studies are required comparing their efficacy, risk of infection, and costs.

Role of rituximab in the treatment of systemic sclerosis: A literature review.

This literature review aimed to evaluate the effectiveness of rituximab (RTX) in patients with systemic sclerosis (SSc). PubMed was searched for articles, published through 31 March 2022, on any controlled studies using RTX in the treatment of SSc. Of 85 identified articles, 9 were selected by title/abstract screening and full text examination. All nine articles reported outcomes of forced vital capacity (%FVC), and seven reported those of modified Rodnan skin scores (mRSS). The results showed that among the seven controlled studies evaluating skin lesions in patients with SSc, four showed a significant improvement of mRSS by RTX when compared with a control group, whereas three showed no significant effect. Among the nine controlled studies evaluating lung lesions, five showed a significant improvement of %FVC compared with a control group, whereas four showed no significant effect. In conclusion, RTX may be effective in the treatment of skin and lung lesions in patients with SSc. The profiles of SSc patients for whom RTX was indicated were unclear, although patients with diffuse cutaneous SSc and those positive for anti-topoisomerase I antibody were considered potential targets. Additional studies are needed to assess the long-term effectiveness of RTX in the treatment of patients with SSc.

Clinical profile and outcome of large-vessel giant cell arteritis in Japanese patients: A single-centre retrospective cohort study.

OBJECTIVES: Recent advances in imaging revealed that giant cell arteritis (GCA) is frequently associated with large vessel involvement (LVI), but they may also contribute to earlier diagnosis and treatment of LV-GCA. We aimed to compare the clinical characteristics of GCA with or without LVI and evaluate its association with clinical outcomes. METHOD: We retrospectively reviewed the medical records of 36 patients with GCA in Kyoto University Hospital. RESULTS: Eighteen patients each were assigned to the LVI(+) and LVI(-) groups. Five-year survival rates in the LVI(+) group were better than in the LVI(-) group (p = .034), while five-year relapse-free survival rates were similar between the groups (p = .75). The LVI(+) group required lower doses of glucocorticoid at month 6 (p = .036). Disease activity evaluated with the Birmingham Vasculitis Activity Score at disease onset was higher in the LVI(-) group (p = .014), and the Vasculitis Damage Index score examined at the last visit was higher in the LVI(-) group (p = .011). CONCLUSION: GCA without LVI had more active disease, severer vascular damage, and worse survival, possibly because of ophthalmic complications and their greater glucocorticoid requirement. Our results revisit the impact of cranial manifestations on disease severity and morbidity.

Association between the patterns of large-vessel lesions and treatment outcomes in patients with large-vessel giant cell arteritis.

OBJECTIVES: We aimed to identify associations between patterns of large-vessel lesions of large-vessel giant cell arteritis (LV-GCA) and treatment outcomes. METHODS: We extracted data on 68 newly diagnosed patients with LV-GCA from a retrospective, multi-centric, nationwide registry of GCA patients treated with glucocorticoids between 2007 and 2014. Patients with aortic lesions were identified based on the findings from contrast-enhanced computed tomography, magnetic resonance imaging, or positron emission tomography-computed tomography (Group 2, n = 49). Patients without aortic lesions were subdivided into LV-GCA with or without subclavian lesions defined as Group 1 (n = 9) or Group 3 (n = 10), respectively. The primary outcome evaluation was failure to achieve clinical remission by Week 24 and/or relapse within 104 weeks. RESULTS: The mean age and proportion of patients with cranial lesions and polymyalgia rheumatica in Group 2 were numerically lower than in the other two groups. Large-vessel lesions in Group 3 included carotid, pulmonary, renal, hepatic, or mesenteric lesions. The cumulative rate of poor treatment outcomes >2 years was 11.1%, 55.3%, and 88.0% in Groups 1, 2, and 3, respectively (by Kaplan-Meier analysis). The mean time to poor outcome was significantly different between the groups. CONCLUSIONS: Classification by subclavian and aortic lesions may be useful to determine treatment strategy.

Factors associated with osteoporosis and fractures in patients with systemic lupus erythematosus: Kyoto Lupus Cohort.

OBJECTIVES: Osteoporosis and compression fractures of the lumbar spine are some of the major adverse effects of glucocorticoid therapy in patients with systemic lupus erythematosus (SLE). This study examined the association between bone mineral density, bone turnover markers, presence of vertebral fractures, and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in SLE patients. METHODS: This was a cross-sectional study of 246 outpatients with SLE at the Kyoto University Hospital. Lumbar and femoral bone mineral density was measured with dual-energy X-ray absorptiometry, and the presence of vertebral fractures was determined using X-ray, computed tomography, or magnetic resonance imaging. RESULTS: On multiple regression analysis, both high lumbar and femoral T-scores were associated with the concomitant use of hydroxychloroquine (P = .018 and P = .037, respectively), no use of bisphosphonate or denosumab (P = .004 and P = .038, respectively), high body mass index (P < .001), and low bone-specific alkaline phosphatase level (P = .014 and P = .002, respectively). Vertebral fractures showed a significant association with Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index score (P < .001) and femoral T-score (P < .001). CONCLUSION: Vertebral fracture was associated with SLE-associated organ damage, and serum bone-specific alkaline phosphatase level is a potentially useful marker for osteoporosis monitoring in SLE patients.

Autoantibody profiles associated with morbidity and mortality in scleroderma renal crisis.

OBJECTIVE: The aim of this study was to investigate association of autoantibodies with scleroderma renal crisis (SRC) among Japanese patients. METHODS: The clinical characteristics and mortality of 330 patients with sytemic screlosis (SSc) at Kyoto University Hospital were retrospectively analysed, focusing on possible association with anti-topoisomerase I (anti-topo I), anti-centromere (ACA), anti-RNA polymerase III (RNAPIII) and/or anti-U1-RNP. Logistic regression analyses were performed to reveal any association of these autoantibodies with the development and mortality of SRC. RESULTS: SRC was observed in 24 out of 330 SSc patients, including patients with anti-topo I (n = 12/24, 50%), anti-RNAPIII (n = 7/24, 29%), anti-U1-RNP (n = 5/24, 21%) and ACA (n = 3/24, 13%). Anti-U1-RNP [odds ratio (95% CI), 3.63 (1.11, 10.2)], anti-topo I [3.22 (1.37, 7.57)] and anti-RNAPIII (3.29 [1.16, 8.70]) were associated with the development of SRC. Furthermore, anti-topo I [6.00 (1.11, 41.1)] was associated with 1-year mortality of SRC. The 1-year survival rate after the onset of SRC among all patients and among those positive for anti-topo I was 54% and 33%, respectively. In contrast, the survival rate in patients negative for anti-topo I was 75%, of which the survival rate of patients positive for anti-RNAPIII and ACA was 83% and 100%, respectively. CONCLUSION: Specific SSc-related autoantibodies were associated with the morbidity and mortality of SRC.

Detecting immunoglobulin G4-related intracranial arteriopathy with magnetic resonance vessel wall imaging: a preliminary experience in two cases.

BACKGROUND: Detecting immunoglobulin G4 (IgG4)-related intracranial arteriopathy, a rare neurovascular complication of IgG4-related disease, is challenging. While magnetic resonance (MR) vessel wall imaging (VWI) can visualize various neurovascular pathologies, its application to this arteriopathy has not been reported as of this writing. CASE PRESENTATION: A 74-year-old male and a 65-year-old female manifested multiple cranial nerve palsy and neck pain, respectively. Both cases exhibited multiorgan masses with markedly elevated serum IgG4 levels and were clinically diagnosed with IgG4-related disease. Three-dimensional T1-weighted black blood VWI with and without contrast agent identified intracranial vascular lesions characterized as nearly-circumferential mural thickening with homogeneous contrast enhancement in the internal carotid and vertebral arteries; some of the lesions had been unrecognized with screening MR angiography due to expansive remodeling. The former patient underwent corticosteroid therapy, and VWI after treatment revealed decreased mural thickening and enhancement. CONCLUSION: Further studies to elucidate characteristic findings of VWI might contribute to early detection of this treatable pathology.

Neutrophil count reduction 1 month after initiating tocilizumab can predict clinical remission within 1 year in rheumatoid arthritis patients.

Neutropenia is a common adverse event of tocilizumab (TCZ) in rheumatoid arthritis (RA) patients; however, the association between the decrease in neutrophil counts and the TCZ clinical efficacy remains inconclusive. This study aimed to examine whether TCZ-induced neutrophil decrease at 1 month predicts clinical remission within 1 year. We reviewed medical records of RA patients initiating TCZ between May 2011 and September 2019 in our hospital. The Clinical Disease Activity Index (CDAI) was evaluated at baseline (before initiating TCZ) and 1, 3, 6, and 12 months after administration. Clinical remission was defined when CDAI decreased ≤ 2.8. The ratio of neutrophil counts 1 month after initiating TCZ to those at baseline (neutrophil ratio) was also calculated. Among 255 TCZ-treated patients, 169 with valid CDAI and neutrophil counts were enrolled (with median age of 60 years and 79% females). Rheumatoid factor and anti-cyclic citrullinated peptide antibody were positive in 75% and 83%, respectively, and 56% of the patients had concomitant methotrexate (median dose: 8 mg/week). Multivariate logistic regression analysis suggested baseline CDAI (odds ratio (OR) 0.96, p = 0.045), concomitant PSL (OR 0.42, p = 0.030), and the neutrophil ratio (OR 0.19, p = 0.011) as predictors of CDAI remission. Neutrophil ratio ≤ 0.8 was associated with achieving remission (Fisher's exact test, p = 0.02) with no apparent increase of severe infection. More than 20% reduction of neutrophil count 1 month after initiating TCZ predicts clinical remission within 1 year at an early treatment phase.

Phenotypic landscape of systemic lupus erythematosus: An analysis of the Kyoto Lupus Cohort.

OBJECTIVES: The present study aimed to clarify comprehensive relationships among the clinical variables of systemic lupus erythematosus (SLE). METHODS: We retrospectively surveyed 32 clinical variables in 581 patients and conducted comprehensive association studies among SLE clinical phenotypes. A univariate analysis of all possible combinations was performed, and the results of phenotypic correlations were reduced into two dimensions. We also created a regression formula using L1 regularisation (LASSO) to calculate the probability of exhibiting each phenotype. RESULTS: The univariate analysis identified 26 correlations, including multiple phenotypes with low complement. Some unpredicted correlations were identified, including fever and the anti-Sm antibody (odds ratio; OR = 2.3, p = 1.6 × 10-5) or thrombocytopenia and psychosis (OR = 3.7, p = 3.2 × 10-5). The multivariate analysis accurately estimated the probability of exhibiting each phenotype (area under the curve > 0.7) in 10 out of 20 phenotypes. CONCLUSIONS: The present results show the phenotypic architecture of SLE and represent a model for estimating the probability of exhibiting each phenotype. They also offer insights into the pathology of SLE and estimating the probability of the onset of new phenotypes in clinical practice.