Prognostic improvement and treatment of COVID-19 in patients with rheumatic diseases until December 2022: Analysis of the JCR COVID-19 registry in Japan.

OBJECTIVES: The aim is to evaluate the treatment and prognosis of coronavirus disease 2019 (COVID-19) according to the time of onset and dominant strain in patients with rheumatic diseases. METHODS: This study analysed a nationwide COVID-19 registry of Japanese patients with rheumatic diseases compiled between June 2020 and December 2022. The primary endpoints of the study were hypoxaemia incidence and mortality. Multivariate logistic regression analysis was performed to assess differences according to the period of onset. RESULTS: A total of 760 patients were compared across four periods. Hypoxaemia rates were 34.9, 27.2, 13.8, and 6.1% and mortality rates were 5.6, 3.5, 1.8, and 0% until June 2021, between July and December 2021, January and June 2022, and July and December 2022, respectively. History of vaccination (odds ratio, 0.39; 95% confidence interval, 0.18-0.84) and onset during the July to December 2022 Omicron BA.5-dominant period (odds ratio, 0.17; 95% confidence interval, 0.07-0.41) were negatively associated with hypoxaemia in the multivariate model, adjusting for age, sex, obesity, glucocorticoid dose, and comorbidities. Over the Omicron-dominant period, antiviral treatment was administered in 30.5% of patients with a low probability of hypoxaemia. CONCLUSIONS: COVID-19 prognosis improved over time in patients with rheumatic diseases, especially in the Omicron BA.5-dominant period. In the future, treatment of mild cases should be optimised.

Physician approval for pregnancy in patients with systemic lupus erythematosus showing only serological activity: A vignette survey study.

OBJECTIVE: The European League Against Rheumatism recommends that the disease activity of systemic lupus erythematosus should be stable before pregnancy because complications and disease flares increase if pregnancy occurs while disease activity is high. However, some patients have ongoing serological activity even after treatment. Herein, we investigated how physicians decide on the acceptability of pregnancy in patients showing only serological activity. METHODS: A questionnaire was administered from December 2020 to January 2021. It included the characteristics of physicians, facilities, and the allowance for pregnancies of patients using vignette scenarios. RESULTS: The questionnaire was distributed to 4946 physicians, and 9.4% responded. The median age of respondents was 46 years, and 85% were rheumatologists. Pregnancy allowance was significantly affected by the duration of the stable period and status of serological activity [duration: proportion difference 11.8 percentage points (p.p.), P < .001; mild activity: proportion difference -25.8 p.p., P < .001; high activity: proportion difference -65.6 p.p., P < .001]. For patients with high-level serological activity, 20.5% of physicians allowed pregnancy if there were no clinical symptoms for 6 months. CONCLUSIONS: Serological activity had a significant effect on the acceptability of pregnancy. However, some physicians allowed patients with serological activity alone to become pregnant. Further observational studies are required to clarify such prognoses.

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.

Risk factors for hospitalization or mortality for COVID-19 in patients with rheumatic diseases: Results of a nationwide JCR COVID-19 registry in Japan.

OBJECTIVES: The incidence and prognosis of Coronavirus Disease 2019 (COVID-19) and rheumatic disease vary among ethnicities and regions. COVID-19 outcomes in rheumatic disease patients remain unclear, especially in the Asia-Pacific region. This study aimed to clarify the demographic and clinical factors that may influence COVID-19 prognosis in rheumatic disease patients. METHODS: This was a case series of patients registered with the COVID-19 national registry of Japan College of Rheumatology between 3 June 2020 and 30 June 2021. Multivariable logistic regression was used to estimate the risk of hospitalization or death. Age, sex, smoking status, rheumatic disease diagnosis, comorbidities, and rheumatic disease medications are taken immediately before infection was analysed. RESULTS: A total of 220 patients from 55 institutions in Japan were included in the study, among whom 186 (84.5%) were hospitalized and 11 (5.0%) died. COVID-19 treatments were provided to 126 patients (57.3%) and mainly comprised glucocorticoids, favipiravir, remdesivir, and tocilizumab.In the multiple logistic regression model, older age and a history of hypertension were associated with hospitalization, while older age was associated with mortality. No specific treatment was correlated with mortality or hospitalization by the multivariate analysis. CONCLUSIONS: Older age and hypertension were associated with a poor prognosis in Japanese COVID-19 patients with connective tissue disease. Factors not directly related to connective tissue disease were closely associated with the prognosis.

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.

Glycogen synthase kinase 3ß/CCR6-positive bone marrow cells correlate with disease activity in multicentric Castleman disease-TAFRO.

Multicentric Castleman disease-thrombocytopenia, anasarca, reticulin fibrosis of bone marrow, renal dysfunction and organomegaly (MCD-TAFRO)-is an emergent phenotype characterized by lymphoproliferation, fluid collection, hemocytopenia and multiple organopathy. Although studies have demonstrated an aberrant blood cytokine/chemokine profile referred to as "chemokine storm", the pathogenesis remains unclear. We aimed to identify pathogenic key molecules, potential diagnostic targets and therapeutic markers in MCD-TAFRO using serum cytokine/chemokine profiles. We performed the targeted cytokine/chemokine multiplex analysis in six cases of MCD-TAFRO with remission or non-remission status. We observed significant changes in serum concentrations of CCL2, CCL5, and Chitinase-3-like-1 in the MCD-TAFRO patients with active state compared to inactive state. Ingenuity pathway analysis revealed that glycogen synthase kinase 3 (GSK3) and CCR6, which is expressed in megakaryocytes, were detected as upstream positive regulators for activating MCD-TAFRO status. More GSK3ß+ CCR6+ cells like megakaryocytes were detected in the bone marrow of patients with MCD-TAFRO than in those with systemic lupus erythematosus, MCD-not otherwise specified or autoimmune haemophagocytic lymphohistiocytosis. The cellularity of GSK3ß+ CCR6+ cells was correlated with disease activity, including thrombocytopenia and anaemia. In conclusion, GSK3ß and CCR6 of bone marrow cells were potentially involved in the pathogenesis of MCD-TAFRO and may act as diagnostic targets and therapeutic markers.

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.

Prediction of the intolerance or non-responder to Janus kinase inhibitors in patients with rheumatoid arthritis: a preliminary retrospective study with integrative cluster analysis.

OBJECTIVES: To identify the subpopulation of rheumatoid arthritis (RA) non-responders to Janus kinase inhibitors (JAKis) using cluster analysis. METHODS: This retrospective study enrolled RA patients who had been treated with JAKis (tofacitinib or baricitinib) between July 2013 and September 2019 in six centres. The endpoint was set as inadequate response to JAKis (JAKis-IR), defined as either non-response to JAKis or their intolerance. Non-response to JAKis was defined as achieving neither American College of Rheumatology 20% response nor Disease Activity Score (ΔDAS28-CRP) >1.2 at 12 weeks. Withdrawal time point included earlier than after 12 weeks from baseline. A hierarchical cluster analysis was performed with variables related with clinical and serological parameters at baseline. RESULTS: The 132 RA patients enrolled were classified into four groups (Group A-D). Groups consisted of three components defined at baseline, as seropositivity, advanced joint destruction, interstitial lung disease presumably associated with RA (RA-ILD). Group A (n=32): seronegative, presence of advanced joint destruction, absence of RA-ILD. Group B (n=35): seropositive, absence of advanced joint destruction and RA-ILD. Group C (n=20): seropositive, absence of advanced joint destruction, presence of RA-ILD. Group D (n=45): seropositive, presence of advanced joint destruction and RA-ILD. The rate of JAKis-IR in four groups was as follows: A, 34.3%; B, 17.1%; C, 20.0%; and D, 8.9%. The difference in JAKis-IR rate between group A and D was statistically significant. CONCLUSIONS: A subpopulation of RA patients with a combination of the following three components, seronegativity, advanced joint destruction and absence of RA-ILD, was identified as being prone to JAKis-IR.

Determination of diagnostic threshold in harmonization and comparison of clinical utility for five major antiphospholipid antibody assays used in Japan.

BACKGROUND: Anticardiolipin antibodies (aCL) and anti-ß2 -glycoprotein I antibodies (aß2 GPI) are essential in diagnosing antiphospholipid syndrome (APS) according to the international APS guideline. Five commercial assays for aCL and aß2 GPI are available in Japan, but their test results are quite discordant. For harmonization of diagnosing APS, upper reference limit (URL) and diagnostic accuracy of each assay were evaluated and compared by testing common sets of specimens across all assays. METHODS: We evaluated two manual and three automated assays for aCL and aß2 GPI of IgG- and IgM classes. 99%URL (the upper limit of reference interval: as per guideline) together with 97.5%URL were determined by testing sera from 198 to 400 well-defined healthy subjects. Both URLs were compared with the cutoff values, which were determined based on ROC analysis by testing 50 each of plasma specimens from patients with/without APS. Diagnostic accuracy was evaluated as area under curve (AUC) of the ROC curve. RESULTS: A variable degree of discrepancy between URLs and the cutoff values was observed, which was partly attributable to between-year assay variability. 97.5%URLs were set lower and closer to the cutoff values than 99%URLs. For all assays, diagnostic accuracies of both aß2 GPI-IgG and aCL-IgG were generally high (AUC: 0.84-0.93); whereas those for IgM-class assays were low (AUC: 0.57-0.67), implicating its utility is limited to rare IgG negative APS cases. CONCLUSION: To ensure harmonized APS diagnosis, the diagnostic thresholds of the five assays were evaluated by common procedures. Contrary to the guideline, 97.5%URL is rather recommended for diagnosing APS, which showed a closer match to the cutoff value.

Morbidity and mortality in antiphospholipid syndrome based on cluster analysis: a 10-year longitudinal cohort study.

OBJECTIVE: Using cluster analysis, to identify the subgroup of patients with APS with the poorest prognosis and clarify the characteristics of that subgroup. METHODS: This is a longitudinal retrospective cohort study of APS patients. Using clinical data and the profile of aPL, cluster analysis was performed to classify the patients into subgroups. Events were defined as thrombosis, severe bleeding, and mortality. RESULTS: A total of 168 patients with APS were included. Cluster analysis classified the patients into three subgroups; Cluster A (n = 61): secondary APS, Cluster B (n = 56): accumulation of cardiovascular risks and arterial thrombosis, Cluster C (n = 61): triple positivity of aPL and venous thrombosis. Cluster B showed significantly higher frequency of the events and higher mortality compared with the other clusters (P = 0.0112 for B vs A and P = 0.0471 for B vs C). CONCLUSION: Using cluster analysis, we clarified the characteristics of the APS patients with the poorest prognosis. Risk factors for cardiovascular disease may further increase events in patients with APS.

The assessment of left heart disease in patients with systemic sclerosis and pulmonary hypertension.

OBJECTIVES: Systemic sclerosis associated pulmonary arterial hypertension (SSc-PAH) is of clinical significance owing to its poor outcome. One of the explanations for the outcome is the co-presence of left heart disease (LHD). The aim of this study is to assess LHD phenotype in patients with SSc and pulmonary hypertension (PH). METHODS: This study included consecutive patients with SSc who underwent right heart catheterisation to diagnose PAH. Heart failure with preserved ejection fraction (HFpEF) was evaluated according to the recommendation of 6th WSPH and to the Framingham criteria. RESULTS: In total, 76 patients were enrolled in this study. Of them, 42 had PH (mPAP >20 mmHg) with a normal left ventricle ejection fraction (≥50%). Among the 42 patients, four and three patients were classified "HFpEF not excluded" and "HFpEF confirmed" whereas 10 had a clinical diagnosis of HFpEF according to 6th WSPH and Framingham criteria, respectively. These differences were due mainly to relatively low PAWP (<13 mmHg). By a combination of ROC curve and logistic regression analyses, left atrial dimension and left ventricular end-diastolic volume index assessed with echocardiography and cardiac MRI, respectively, had significantly higher predictive values for detecting the complication of HFpEF rather than PAWP. CONCLUSIONS: Morphological evaluation using echocardiography and cardiac MRI, compared with haemodynamic evaluation by PAWP, may better reflect the copresence of LHD phenotype in patients with SSc and PH. Our data would also indicate a limited elevation of PAWP in patients with SSc, PH and HFpEF.

Efficacy and safety of sodium RISedronate for glucocorticoid-induced OsTeoporosis with rheumaTOid arthritis (RISOTTO study): A multicentre, double-blind, randomized, placebo-controlled trial.

OBJECTIVE: No evidence has shown the efficacy of Sodium Risedronate (Risedronate) for glucocorticoid-induced osteoporosis (GIO) in patients with Rheumatoid arthritis (RA). The aim of this study was to explore the effectiveness and safety of Risedronate for GIO complicated with RA. METHODS: This was a six-month randomized, double-blind, placebo-controlled trial of 95 patients with GIO complicated with RA from 19 centers. The primary endpoint was the change from baseline in lumbar spine bone mineral density (L-BMD). Secondary endpoints included changes in femoral neck and total hip BMD and bone turnover markers, as well as rheumatoid arthritis Disease Activity Score with 28-joint counts. Incident of non-traumatic spine fractures and adverse events were tracked as safety endpoints. RESULTS: Increase in L-BMD was significantly greater in the Risedronate group compared to the Placebo group (Risedronate: 3.49% [95% CI: 1.92-5.05] vs Placebo: 0.12% [95% CI: -2.07 to 2.30], p < .0001). No significant difference was found in the femoral neck and total hip BMD. Although adverse events were observed in 28 patients, none were considered serious. Non-traumatic vertebral fractures were identified in 10 patients. CONCLUSION: Risedronate was effective in increasing L-BMD and was well tolerated in patients with GIO complicated with RA.

MicroRNA-9 ameliorates destructive arthritis through down-regulation of NF-κB1-RANKL pathway in fibroblast-like synoviocytes.

We investigated the effect of miR-9 on fibroblast-like synoviocytes (FLS) from RA patients and animal arthritis model. The binding of miR-9 to NF-κB1 3'UTR was analyzed by luciferase reporter assay and immunoprecipitation. ChIP assay and luciferase promoter assay were performed to identify the binding of NF-κB1 to RANKL promoter and its activity. FLS were treated with miR-9/anti-miR-9 to evaluate cell proliferation and the expression of RANKL. Therapeutic effect of intra-articular miR-9 was evaluated in type-II collagen-induced arthritis in rats. miR-9 bound to the 3'-UTR of NF-κB1 and downregulated NF-κB1. NF-κB1 bound to RANKL promoter and increased the promoter activity of RANKL. RANKL was downregulated by miR-9. Proliferation of FLS was increased by miR-9 inhibitor. miR-9 dampened experimental arthritis by lowering inflammatory state, reducing RANKL and osteoclasts formation. Our findings revealed miR-9-NF-κB1-RANKL pathway in RA-FLS, further, miR-9 ameliorated inflammatory arthritis in vivo which propose therapeutic implications of miR- 9 in RA.

Myofascia-dominant involvement on whole-body MRI as a risk factor for rapidly progressive interstitial lung disease in dermatomyositis.

OBJECTIVE: Rapidly progressive interstitial lung disease (RPILD) is a major cause of death in patients with DM. Although clinically amyopathic DM (CADM) represents risk for RPILD, the incidence rate of RPILD in patients with CADM varies widely. Whole-body (WB) MRI can reveal involvement of systemic muscle and myofascia. The objective of this study was to explore the risk factors for RPILD in patients with DM using WB-MRI. METHODS: This retrospective study comprised 41 patients with DM who underwent WB-MRI before the initiation of treatment in our hospital. Muscular and myofascial signals were scored on 42 muscular groups. The myofascia/muscle ratio was calculated and used to define the relevance of myofascia-dominant involvement. RPILD was defined as worsening of dyspnoea, hypoxaemia and radiographic ILD/fibrosis within 3 months from the onset of respiratory symptoms. RESULTS: Among the 41 patients, 17 had CADM and 30 had ILD, including 10 patients with RPILD. All patients including those with CADM showed abnormal signal intensity in both muscle and myofascia (median score: 15 and 23, respectively). Muscle signal scores positively correlated with the serum creatine kinase level (r = 0.714; P< 0.001). Patients with RPILD showed a significantly higher myofascia/muscle ratio than those without RPILD (1.929 vs 1.200; P= 0.027). Logistic regression analysis identified higher myofascia/muscle ratio as independent risk factors for developing RPILD. CONCLUSION: Myofascia-dominant involvement was defined and appreciated in patients with DM using WB-MRI. This may be one of the risk factors for RPILD.

Right ventricular dimension index by cardiac magnetic resonance for prognostication in connective tissue diseases and pulmonary hypertension.

OBJECTIVES: Pulmonary hypertension (PH) in patients with CTD is a heterogeneous condition affected by left heart disease, chronic lung disease and thromboembolism as well as pulmonary vascular disease. Recent studies using cardiac magnetic resonance (CMR) have shown that right ventricular dysfunction is predictive for mortality in patients with PH, but limited to pulmonary arterial hypertension. This study aimed to analyse prognostic factors in PH-CTD. METHODS: This retrospective analysis comprised 84 CTD patients, including SSc, who underwent both CMR and right heart catheterization from 2008 to 2018. Demographics, laboratory findings, and haemodynamic and morphological parameters were extracted. The prognostic value of each parameter was evaluated by multivariate analysis using covariables derived from propensity score to control confounding factors. RESULTS: Of 84 patients, 65 had right heart catheterization-confirmed PH (54 pulmonary arterial hypertension, 11 non-pulmonary arterial hypertension). Nine out of these PH patients died during a median follow-up period of 25 months. In 65 patients with PH, right ventricular end-diastolic dimension index (RVEDDI) evaluated by CMR was independently associated with mortality (hazard ratio 1.24; 95% CI: 1.08-1.46; P = 0.003). In a receiver operating characteristic analysis, RVEDDI highly predicted mortality, with area under the curve of 0.87. The 0.5-2-year follow-up data revealed that RVEDDI in both survivors and non-survivors did not significantly change over the clinical course, leading to the possibility that an early determination of RVEDDI could predict the prognosis. CONCLUSION: RVEDDI simply evaluated by CMR could serve as a significant predictor of mortality in PH-CTD. A further validation cohort study is needed to confirm its usability.

Low C4 as a risk factor for severe neuropsychiatric flare in patients with systemic lupus erythematosus.

OBJECTIVE: This study aimed to explore the risk factors for 'severe' neuropsychiatric (NP) flare in patients with systemic lupus erythematosus (SLE). METHODS: This retrospective study comprised newly diagnosed 184 adult SLE patients who visited Hokkaido University Hospital between 2006 and 2017. In this study, severe NP flare was defined as the occurrence of at least one newly developed British Isles Lupus Assessment Group A score in the neurological domain. Overall severe NP flare-free survival was estimated by Kaplan-Meier analysis. Clinical and demographic profiles at SLE diagnosis were assessed as potential risk items in the adjusted multivariate Cox regression model. RESULTS: The median follow-up period was 7.9 years (interquartile range (IQR) 4.6-12.3) years. A total of 28 (15.2%) patients had one or more severe NP flares during the observation period. The median time from patient enrolment date to severe NP flare occurrence was 3.1 years (IQR 0.9-6.3 year). The 2- and 10-year severe NP flare-free survival rates were 92.7% and 86.0%, respectively. Among the manifestations of severe NP flare, psychosis was the most frequent (19.1%). In the multivariate model, low serum levels of C4 (hazard ratio (HR) = 3.67, p = 0.013) and severe NP manifestations at SLE diagnosis (HR = 7.11, p < 0.001) emerged as independent risk factors for developing severe NP flare. CONCLUSION: The first severe NP flare presented early in the course of SLE. Low C4 level and severe NP manifestations at SLE diagnosis could predict the development of severe NP flare.

Anti-cyclic citrullinated peptide antibody titers decrease in rheumatoid arthritis patients treated with tocilizumab: A pilot study.

Objectives: To analyze the effects of tocilizumab on peripheral B-cell subpopulation and its ability to produce anti-cyclic citrullinated peptide (CCP) antibody in patients with rheumatoid arthritis (RA).Methods: Thirteen consecutive RA patients initiated with tocilizumab were enrolled in our prospective study. Anti-CCP antibody titers and clinical parameters were evaluated during treatment. Peripheral blood B-cell subsets were analyzed using flow cytometry according to the Human Immunology Project.Results: Disease activity was significantly improved and anti-CCP antibody titers significantly decreased at week 24 compared to baseline. The percentages of post-switch memory B cells in CD19+ cells transiently increased at week 12, but there was no significant difference in any of the investigated B-cell subpopulations at week 24 compared to baseline. The ratios of post-switch memory to naïve B cells (post-switch/naïve) correlated negatively with anti-CCP antibody titers regardless of the time-points.Conclusion: Our study indicated that tocilizumab has a potential to reduce anti-CCP antibody production presumably by affecting post-switch/naïve ratio, and that anti-CCP antibody titers reflect B-cell distribution/subpopulation. As anti-CCP antibodies are produced in lymph nodes or ectopic lymphoid structures in synovial tissues, not in circulation, transient increment of post-switch memory B cells after tocilizumab treatment may reflect the altered balance of B-cell distribution between circulation and arthritic joints, resulting in suppressed production of anti-CCP antibody in situ.

Potential therapeutics for antiphospholipid antibody associated thrombocytopenia: A systematic review and meta-analysis.

Objectives: Thrombocytopenia is frequently observed in antiphospholipid antibody (aPL) carriers. Due to the paradoxical risks of thrombosis and hemorrhage, the management of aPL-associated thrombocytopenia (APAT) is often deductive. We aimed to investigate the efficacy and safety of therapeutic approaches for APAT through a systematic review.Methods: Four therapeutic approaches for APAT, including antiplatelet agents, glucocorticoids, splenectomy and thrombopoietin receptor agonists, were selected. Clinical trials evaluating therapeutic outcomes including the remission, complications, mortality and relapse, were searched in MEDLINE, EMBASE and CENTRAL from the inception dates to 28 November 2016. A meta-analysis was performed to calculate risk ratios (RRs) and 95% confidence intervals (CIs) using random-effects models.Results: Out of 1407 papers, eight controlled clinical trials were included. In patients with APAT, the remission rates were higher in patients on glucocorticoids (RR 8.33 [95% CI 3.07-22.6]) or splenectomy (RR 8.37 [95% CI 1.61-43.7]) than in patients without those treatments. There was no significant association between glucocorticoids and thrombosis (RR 1.57 [95% CI, 0.17-14.9]) or between splenectomy and hemorrhage (RR 0.17 [95% CI 0.02-1.28]). The extracted data of mortality and relapse rate were not available for synthesis.Conclusion: Glucocorticoids or splenectomy seemed suitable therapeutic approaches for APAT.

Pre-conception status, obstetric outcome and use of medications during pregnancy of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) in Japan: Multi-center retrospective descriptive study.

Objective: To describe the pre-conception status, pregnancy outcomes, and medication prevalence in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Crohn's disease (CD), and ulcerative colitis (UC).Methods: E-mail-based questionnaire survey for the Japan Maternal Fetal Intensive Care Unit Network hospitals inquiring prevalence and clinical features of SLE, RA, CD and UC complicated pregnancies for 2 years.Results: The number of SLE, RA, CD and UC among 69,810 deliveries was 184, 139, 27 and 178, respectively. Less than half of pregnancies were planned. Assisted reproductive technology (ART) pregnancy rates were higher in SLE, RA and UC than in the general population (11.4, 23.0 and 7.4 vs 5.1%, p < .001 each). Preterm delivery, preeclampsia, and fetal growth restriction (FGR) were more frequent in SLE than in the general population (39.4 vs. 5.6% p < .001, 15.0 vs. 6.0% p < .001, 12.9 vs 4.2% p < .001). Prevalence of preterm delivery in RA and UC (27.5 vs. 5.6% p < .001, 11.3 vs. 5.6% p < .05) and FGR in CD (28.6 vs. 4.2% p < .001) was also higher than that in the general population.Conclusion: SLE, RA, CD, and UC complicated pregnancies were at high risks of obstetric adverse outcome. High ART rates necessitate pre-conception counseling in SLE, RA, and UC pregnancies.

Pathogenic roles of anti-C1q antibodies in recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) is often considered idiopathic, however excessive complement activation has been observed in pregnancy related manifestations. Anti-C1q antibodies (anti-C1q) are associated with the activation of complement pathway in lupus patients, while it remains unclear in RPL. Firstly, we showed that both the prevalence and titre of anti-C1q were significantly higher in unexplained RPL than in healthy parous individuals. Secondly, we established the murine model of anti-C1q induced pregnancy loss using a monoclonal anti-mouse C1q antibody, JL-1. In mice treated with JL-1, high ratio of pregnancy loss and fetal growth restriction were frequently observed and complement activation occurred. C5a receptor (C5aR) blockade cancelled these pathogenic changes in mice treated with JL-1. In conclusion, our study reveals an association between the prevalence of anti-C1q and RPL. Additionally, our murine model has indicated that anti-C1q can induce reproductive failure, which might be ameliorated by therapy targeting the C5-C5aR axis.