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Papers - Kikuchi, Jun

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HIGH LEVELS OF PROTEINS, CELL COUNTS, AND IL-6 IN CEREBROSPINAL FLUID IN PATIENTS WITH NEUROPSYCHIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS ARE ASSOCIATED WITH DAMAGE ACCRUAL OF NON-NEUROPSYCHIATRIC DOMAINS AS WELL AS THAT OF NEUROPSYCHIATRIC DOMAINS

Edamoto M., Kikuchi J., Hanaoka H., Saito S., Hiramoto K., Kaneko Y.

ANNALS OF THE RHEUMATIC DISEASES 81 666 - 666 2022.06

ISSN 0003-4967

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眼窩先端部症候群で再発した好酸球性多発血管炎性肉芽腫症の一例

古橋和謙, 太田裕一朗, 菊池潤, 近藤泰, 齋藤俊太郎, 花岡洋成, 堀内直樹, 大出尚郎, 金子祐子

関東リウマチ (関東リウマチ研究会) 54 46 - 50 2022.03

ISSN 0911-4807

症例は好酸球性多発血管炎性肉芽腫症(EGPA)の56歳男性で、治療抵抗性でパルス療法を含む高用量プレドニゾロンとシクロホスファミド静注(IVCY)、免疫グロブリン大量療法、メポリズマブにより奏効したが、プレドニゾロンを25mg漸減後に両眼視力低下と頭痛が出現した。好酸球、MPO-ANCA陰性であったが、EGPAの血管炎に伴う鞍結節部の肥厚性硬膜炎により病変が眼窩先端部に及び、眼窩先端部症候群でEGPAが再燃したと診断した。リツキシマブ投与と高用量プレドニゾロンの開始により、頭痛は消失し右眼視力・視野、左眼球運動障害は速やかに改善した。肥厚性硬膜炎や左眼の視力低下に対してはパルス療法の追加により、左視力・眼球運動障害の改善が得られた。

Serum cytokines and bone metabolic markers in patients with rheumatoid arthritis treated with biological disease modifying anti-rheumatic drugs

Tamai H., Nishina N., Kikuchi J., Izumi K., Otomo K., Yoshimoto K., Yamaoka K., Takeuchi T., Kaneko Y.

Clinical Rheumatology (Clinical Rheumatology) 2022

ISSN 07703198

Introduction: /objectives Several biological disease-modifying anti-rheumatic drugs (bDMARDs) have been widely used for the management of rheumatoid arthritis (RA). These drugs target different molecules important for the pathophysiology of RA; however, only a few studies have compared the effects of these biological drugs on cytokines and bone metabolic markers. The main aim of this study is to clarify the effects of bDMARDs with different modes of action on the cytokine and bone metabolic marker levels in patients with RA. Methods: Patients with RA who were initiated on infliximab, tocilizumab, or abatacept as the first bDMARD were prospectively enrolled in this study. Serum cytokine and bone metabolic marker levels were measured longitudinally, and changes in their levels were compared. Results: A total of 174 patients were enrolled in this study, with 55, 70, and 49 patients in the infliximab, tocilizumab, and abatacept groups, respectively. At six months, despite the similar clinical effectiveness of the three drugs, changes in the cytokine and bone metabolic marker levels were distinct; interferon-γ and tumor necrosis factor-α levels were significantly increased with infliximab, interleukin-6 levels were increased with tocilizumab, and interleukin-1β and interleukin-8 levels were increased with abatacept treatment. Bone-specific alkaline phosphatase and osteocalcin levels increased more significantly with tocilizumab than with infliximab, while osteopontin and osteonectin levels decreased with infliximab treatment. Conclusions: bDMARDs with different modes of action exert different effects on the cytokine and bone metabolic marker levels in patients with RA.

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Association of Modified Systemic Lupus Erythematosus Responder Index Attainment With Long-Term Clinical Outcomes: A Five-Year Prospective Study

Connelly K., Kandane-Rathnayake R., Hoi A., Louthrenoo W., Hamijoyo L., Luo S.F., Wu Y.J.J., Cho J., Lateef A., Lau C.S., Chen Y.H., Navarra S., Zamora L., Li Z., An Y., Sockalingam S., Hao Y., Zhang Z., Chan M., Katsumata Y., Harigai M., Oon S., Bae S.C., O'Neill S., Gibson K.A., Basnayake B.M.D.B., Kikuchi J., Takeuchi T., Ng K.P.L., Tugnet N., Kumar S., Goldblatt F., Law A., Tee M., Tee C., Tanaka Y., Ohkubo N., Tan J.Y., Karyekar C.S., Nikpour M., Golder V., Morand E.F.

Arthritis and Rheumatology (Arthritis and Rheumatology) 2022

ISSN 23265191

Objective: In trials of systemic lupus erythematosus (SLE), the SLE Responder Index (SRI) is the most commonly used primary efficacy end point but has limited validation against long-term outcomes. We aimed to investigate associations of attainment of a modified version of the SRI (mSRI) with key clinical outcomes in SLE patients with up to 5 years of follow-up. Methods: We used data from a large multicenter, longitudinal SLE cohort in which patients received standard of care. The first visit with active disease (defined as SLE Disease Activity Index 2000 [SLEDAI-2K] score ≥6) was designated as baseline, and mSRI attainment (defined as a reduction in SLEDAI-2K ≥4 points with no worsening in physician global assessment ≥0.3 points) was determined at annual intervals from baseline up to 5 years. Associations between mSRI attainment and outcomes including disease activity, glucocorticoid dose, flare, damage accrual, Lupus Low Disease Activity State (LLDAS), and remission were studied. Results: We included 2,060 patients, with a median baseline SLEDAI-2K score of 8. An mSRI response was attained by 56% of patients at 1 year, with similar responder rates seen at subsequent annual time points. Compared to nonresponders, mSRI responders had significantly lower disease activity and prednisolone dose and higher proportions of LLDAS and remission attainment at each year, and less damage accrual at years 2 and 3. Furthermore, mSRI responder status at 1 year predicted clinical benefit at subsequent years across most outcomes, including damage accrual (odds ratio [OR] range 0.58–0.69, P < 0.05 for damage accrual ORs at all time points). Conclusion: In SLE patients with active disease receiving standard of care, mSRI attainment predicts favorable outcomes over long-term follow-up, supporting the clinical meaningfulness of SRI attainment as an SLE trial end point.

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Development of Rheumatoid Arthritis in Cavitary Mycobacterium avium Pulmonary Disease: A Case Report of Successful Treatment with CTLA4-Ig (Abatacept).

Hiromu Tanaka, Takanori Asakura, Jun Kikuchi, Makoto Ishii, Ho Namkoong, Yuko Kaneko, Koichi Fukunaga, Naoki Hasegawa

Infection and drug resistance (Infection and Drug Resistance) 15 91 - 97 2022

ISSN 1178-6973

BACKGROUND: Nontuberculous mycobacterial pulmonary disease (NTM-PD) often develops in patients with rheumatoid arthritis (RA), especially during immunosuppressive treatment, including biological disease-modifying antirheumatic drugs. NTM-PD is associated with airway lesions such as bronchiectasis, which is frequently seen in RA patients. Distinguishing which diseases cause the pulmonary lesion is difficult. However, there are limited reports of the development of RA during the follow-up of NTM-PD and how biological agents should be administered in these conditions, especially with cavitary lesions. CASE PRESENTATION: A 62-year-old woman with hemosputum was referred to our hospital, where she was diagnosed with Mycobacterium avium pulmonary disease. She began treatment with several antibiotics, including clarithromycin, ethambutol, rifampicin, and amikacin. In the course of treatment, M. avium became macrolide-resistant. Five years after beginning antibiotic treatment, she felt arthralgia in the fingers and wrists and had a high titer of rheumatoid factor and anticitrullinated peptide antibody, with which we diagnosed RA. Methotrexate, prednisolone, and iguratimod were subsequently administered, but the activity of RA gradually worsened. Meanwhile, M. avium changed to a macrolide-susceptible strain, her sputum smear results remained almost negative, and the NTM-PD disease was well controlled with antimicrobial therapy, despite her having cavitary lesions. Therefore, we started using CTLA4-Ig (abatacept). RA symptoms were substantially ameliorated. The pulmonary lesions and NTM-PD worsened mildly, but her pulmonary symptoms were stable. CONCLUSION: Physicians should be mindful of the etiologies of bronchiectasis, including RA, even in patients with a long-term history of treatment for bronchiectasis and NTM-PD. When NTM-PD is well controlled, even with remaining cavitary lesions, abatacept may be an option for patients with RA based on a comprehensive assessment of disease progression using NTM sputum smear/culture, computed tomography findings, and treatment response.

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Independent associations of lymphopenia and neutropenia in patients with systemic lupus erythematosus: a longitudinal, multinational study.

Rangi Kandane-Rathnayake, Worawit Louthrenoo, Vera Golder, Shue-Fen Luo, Yeong-Jian J Wu, Aisha Lateef, Jiacai Cho, Zhanguo Li, Yuan An, Laniyati Hamijoyo, Sandra Navarra, Leonid Zamora, Yasuhiro Katsumata, Masayoshi Harigai, Sargunan Sockalingam, Madelynn Chan, Yi-Hsing Chen, Sean O'Neill, Fiona Goldblatt, Yanjie Hao, Zhuoli Zhang, Jun Kikuchi, Tsutomu Takeuchi, Chak Sing Lau, Mandana Nikpour, Eric Morand, Alberta Hoi

Rheumatology (Oxford, England) (Rheumatology (Bulgaria)) 60 ( 11 ) 5185 - 5193 2021.11

ISSN 13100505

OBJECTIVE: The prevalence and associations of leucopenia in SLE remain incompletely understood. We evaluated associations of disease activity and medication use with leucopenia (lymphopenia and neutropenia) in a multinational, prospectively followed SLE cohort. METHODS: Data from the Asia Pacific Lupus Collaboration cohort, in which disease activity and medications were prospectively captured from 2013-18, were used. Predictors of lymphopenia (lymphocyte count < 0.8 x 109/l) and neutropenia (neutrophil count < 1.5 x 109/l) were examined using multiple failure, time-dependent survival analyses. RESULTS: Data from 2,330 patients and 18 287 visits were analysed. One thousand three hundred twelve patients (43.7%) had at least one episode of leucopenia. 867 patients (37.2%) had lymphopenia, observed in 3,065 (16.8%) visits, and 292 (12.5%) patients had neutropenia, in 622 (3.4%) visits. After multivariable analyses, lymphopenia was associated with overall disease activity, ESR, serology, prednisolone, azathioprine, methotrexate, tacrolimus, cyclophosphamide and rituximab use. Methotrexate and ciclosporin were negatively associated with neutropenia. Lupus low disease activity state (LLDAS) was negatively associated with both lymphopenia and neutropenia. CONCLUSION: Both lymphopenia and neutropenia were common in SLE patients but were differentially associated with disease and treatment variables. Lymphopenia and neutropenia should be considered independently in studies in SLE.

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Early combination of pulmonary vasodilators prevents chronic kidney disease progression in connective tissue disease-associated pulmonary hypertension.

Hironari Hanaoka, Sho Ishigaki, Hiroshi Takei, Kazuoto Hiramoto, Shuntaro Saito, Yasushi Kondo, Jun Kikuchi, Yuko Kaneko, Tsutomu Takeuchi

International journal of rheumatic diseases (International Journal of Rheumatic Diseases) 24 ( 11 ) 1419 - 1426 2021.11

ISSN 17561841

AIM: Pulmonary hypertension (PH) and chronic kidney disease (CKD) are interdependent for their development and exacerbation. We evaluated the effect of PH on CKD progression in patients with connective tissue disease (CTD)-associated PH. METHODS: We reviewed consecutive patients with CTD who were diagnosed with PH with right heart catheter (RHC) examinations in our hospital. Patients were divided into 2 groups according to the use of vasodilators: monotherapy or combination therapy. We further divided the patients with combination therapy into early and non-early combination groups. Early combination was defined as the addition of the second vasodilator within 1 month after starting the first drug. The clinical course of hemodynamics and CKD progression were compared. RESULTS: Thirty-eight patients were included in the analysis: 10 were treated with monotherapy and 28 with combination therapy (14 with early and 14 with non-early). At baseline, patients who received combination therapy had a significantly higher mean pulmonary arterial pressure with RHC and a higher right ventricular systolic pressure (RVSP) with echocardiography (P = .04) and showed a greater improvement in RVSP after treatment than those who underwent monotherapy. The incidence of CKD progression was significantly lower in patients who received combination therapy than in those who received monotherapy (P = .05). Among patients who received combination therapy, the early combination group had a lower incidence of CKD progression than the non-early combination group (P = .03). CONCLUSIONS: Early combination therapy is associated with a lower incidence of CKD progression in patients with CTD-associated PH.

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Association of SLE Responder Index (SRI) Attainment and Long-term Clinical Outcomes

Connelly Kathryn, Kandane-Rathnayake Rangi, Hoi Alberta, Louthrenoo Worawit, Hamijoyo Laniyati, Cho Jiacai, Lateef Aisha, Luo Shue-Fen, Wu Yeong-Jian, Lau C. S., Chen Yi-Hsing, Navarra Sandra, Zamora Leonid, Li Zhanguo, An Yuan, Sockalingam Sargunan, Hao Yanjie, Zhang Zhuoli, Chan Madelynn, Katsumata Yasuhiro, Harigai Masayoshi, Oon Shereen, Bae Sang-Cheol, O'Neill Sean, Gibson Kathryn, Kikuchi Jun, Basnayake B. M. D. B., Takeuchi Tsutomu, Ng Kristine (Pek Ling), Goldblatt Fiona, Law Annie, Tugnet Nicola, Tanaka Yoshiya, Kumar Sunil, Tee Michael, Tan Jin Yu, Karyekar Chetan, Nikpour Mandana, Golder Vera, Morand Eric

ARTHRITIS & RHEUMATOLOGY 73 2601 - 2603 2021.09

ISSN 2326-5191

High serum IgA and activated Th17 and Treg predict the efficacy of abatacept in patients with early, seropositive rheumatoid arthritis.

Jun Inamo, Yuko Kaneko, Jun Kikuchi, Tsutomu Takeuchi

Clinical rheumatology (Clinical Rheumatology) 40 ( 9 ) 3615 - 3626 2021.09

ISSN 07703198

OBJECTIVE: To identify the predictive biomarkers for achieving remission with abatacept in patients with seropositive rheumatoid arthritis (RA). METHODS: We enrolled patients with RA who were treated with abatacept. We compared the baseline laboratory results and longitudinal immune-phenotyping data between patients who achieved remission and those who did not achieve remission at 6 months according to the clinical disease activity index. RESULTS: One hundred and twenty RA patients were enrolled. In the seropositive patients with early RA (n = 24), high serum IgA levels, anti-citrullinated peptide (CCP) titers, and neutrophil counts before treatment were predictors of remission (area under the curve [AUC], 0.659, 0.741, and 0.704, respectively). Additionally, activated Th17 (aTh17) cells and activated Treg (aTreg) cells before treatment were found to be significantly higher in patients with remission compared to those without remission (2.9% vs 1.1%, P = 0.02; 34.3% vs 17%, P = 0.03, respectively). The measurement of longitudinal cell subpopulation revealed a decrease in the effector CD4 T cell population after abatacept treatment, which correlated with anti-CCP titers and neutrophil counts, and was associated with remission achievement. In seropositive patients with established RA (n = 79), high RF titers and low IFN-γ levels were associated with the good response to abatacept. CONCLUSION: Our study has shown that serum IgA levels, anti-CCP titer, and neutrophil counts are predictive biomarkers for predicting the response to abatacept in patients with seropositive and early RA and may reflect the inhibition of effector CD4 T cell subpopulations by abatacept. Key Points • Serum IgA levels and neutrophil counts are novel biomarkers for predicting the efficacy of abatacept. • Those may reflect the inhibition of effector CD4 T cell subpopulations by abatacept.

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Improvements in Abnormal Laboratory Tests Are Associated with Clinical Outcomes in Patients with Active Systemic Lupus Erythematosus

Connelly Kathryn, Kandane-Rathnayake Rangi, Hoi Alberta, Louthrenoo Worawit, Hamijoyo Laniyati, Cho Jiacai, Lateef Aisha, Luo Shue-Fen, Wu Yeong-Jian, Li Zhanguo, An Yuan, Navarra Sandra, Zamora Leonid, Sockalingam Sargunan, Hao Yanjie, Zhang Zhuoli, Katsumata Yasuhiro, Harigai Masayoshi, Oon Shereen, Chan Madelynn, Chen Yi-Hsing, Bae Sang-Cheol, O'Neill Sean, Gibson Kathryn, Goldblatt Fiona, Kikuchi Jun, Takeuchi Tsutomu, Ng Kristine (Pek Ling), Tugnet Nicola, Basnayake B. M. D. B., Tanaka Yoshiya, Lau C. S., Nikpour Mandana, Golder Vera, Morand Eric

ARTHRITIS & RHEUMATOLOGY 73 2596 - 2598 2021.09

ISSN 2326-5191

Lupus Low Disease Activity State Attainment Provides Significant Protection Against Mortality: A Multi-National, Longitudinal Observational Study

Kandane-Rathnayake Rangi, Golder Vera, Louthrenoo Worawit, Chen Yi-Hsing, Cho Jiacai, Lateef Aisha, Hamijoyo Laniyati, Luo Shue-Fen, Wu Yeong-Jian, Navarra Sandra, Zamora Leonid, Li Zhanguo, An Yuan, Sockalingam Sargunan, Katsumata Yasuhiro, Harigai Masayoshi, Hao Yanjie, Zhang Zhuoli, Basnayake B. M. D. B., Chan Madelynn, Kikuchi Jun, Takeuchi Tsutomu, Oon Shereen, Bae Sang-Cheol, O'Neill Sean, Goldblatt Fiona, Gibson Kathryn, Ng Kristine Pek Ling, Law Annie, Tugnet Nicola, Kumar Sunil, Tee Michael, Yu DaeYoung, Karyekar Chetan, Tanaka Yoshiya, Lau C. S., Nikpour Mandana, Hoi Alberta, Morand Eric

ARTHRITIS & RHEUMATOLOGY 73 1793 - 1795 2021.09

ISSN 2326-5191

DEFINING THE PREVALENCE OF UNMET NEED IN SLE: DATA FROM A LARGE MULTINATIONAL LONGITUDINAL SLE COHORT

Kandane-Rathnayake R., Louthrenoo W., Hoi A., Golder V., Chen Y. H., Luo S. F., Wu Y. J. Jan, Lateef A., Cho J., Hamijoyo L., Lau C. S., Navarra S., Zamora L., Li Z., An Y., Sockalingam S., Katsumata Y., Harigai M., Hao Y., Zhang Z., Kikuchi J., Takeuchi T., Basnayake B., Goldblatt F., Chan M., Ng K., Bae S. C., Oon S., O'neill S., Gibson K., Kumar S., Tugnet N., Tanaka Y., Nikpour M., Morandon F.

ANNALS OF THE RHEUMATIC DISEASES 80 218 - 219 2021.06

ISSN 0003-4967

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Proton Pump Inhibitor and Tacrolimus Uses are Associated With Hypomagnesemia in Connective Tissue Disease: a Potential Link With Renal Dysfunction and Recurrent Infection.

Hironari Hanaoka, Jun Kikuchi, Yuko Kaneko, Noriyasu Seki, Hideto Tsujimoto, Kenji Chiba, Tsutomu Takeuchi

Frontiers in pharmacology (Frontiers in Pharmacology) 12 616719 - 616719 2021.05

ISSN 1663-9812

Background: Low levels of serum magnesium perturb renal tubular cell function and lymphocytes, resulting in renal deterioration and an imbalance in mononuclear cells. This study investigated the mechanism and influence of hypomagnesemia in patients with connective tissue disease. Methods: We retrospectively evaluated patients with connective tissue disease and available serum magnesium data who visited Keio University Hospital in 2019. Patients were divided into two groups: those with (serum magnesium < 1.8 mg/dl) and those without hypomagnesemia; their rates of hospitalization for severe infection and cumulative renal deterioration were compared. Patients' fractions of lymphocytes and natural killer and dendritic cell subsets, as measured by fluorescence-activated cell sorting (FACS) analysis, were also compared. Results: Among 284 patients, hypomagnesemia was detected in 63 (22.2%). Multivariate analysis revealed that the use of proton pump inhibitors [odds ratio (OR), 1.48; p = 0.01] and tacrolimus (OR, 6.14; p < 0.01) was independently associated with hypomagnesemia. In addition, the renal deterioration rate was significantly higher in tacrolimus and/or proton pump inhibitor users with hypomagnesemia (p = 0.01). The hospitalization rate for severe infection was also higher in patients with hypomagnesemia (p = 0.04). FACS analysis showed lower CD8+ T cell, CD19+ B cell, natural killer cell, and dendritic cell counts in patients with hypomagnesemia (p = 0.03, p = 0.02, p = 0.02, and p = 0.03, respectively). Conclusion: The use of tacrolimus and proton pump inhibitors may be associated with hypomagnesemia and lead to poor renal outcomes and severe infection in patients with connective tissue disease.

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Risk Prediction Modeling Based on a Combination of Initial Serum Biomarker Levels in Polymyositis/Dermatomyositis–Associated Interstitial Lung Disease

Gono T., Masui K., Nishina N., Kawaguchi Y., Kawakami A., Ikeda K., Kirino Y., Sugiyama Y., Tanino Y., Nunokawa T., Kaneko Y., Sato S., Asakawa K., Ukichi T., Kaieda S., Naniwa T., Okano Y., Kuwana M., Yamaguchi Y., Taniguchi Y., Kikuchi J., Kubo M., Watanabe M., Harada T., Kazuyori T., Kameda H., Kaburaki M., Matsuzawa Y., Yoshida S., Yoshioka Y., Hirai T., Wada Y., Ishii K., Fujiwara S., Saraya T., Morimoto K., Hara T., Suzuki H., Shibuya H., Muro Y., Aki R., Shibayama T., Ohshima S., Yasuda Y., Terada M., Kawahara Y.

Arthritis and Rheumatology (Arthritis and Rheumatology) 73 ( 4 ) 677 - 686 2021.04

ISSN 23265191

Objective: To establish predictive models for mortality in patients with polymyositis/dermatomyositis–associated interstitial lung disease (PM/DM-ILD) using a combination of initial serum biomarker levels. Methods: The Multicenter Retrospective Cohort of Japanese Patients with Myositis-Associated ILD (JAMI) database of 497 incident cases of PM/DM-ILD was used as a derivation cohort, and 111 cases were additionally collected as a validation cohort. Risk factors predictive of all-cause mortality were identified by univariate and multivariable Cox regression analyses using candidate serum biomarkers as explanatory variables. The predictive models for mortality were generated in patients with and those without anti–melanoma differentiation–associated gene 5 (MDA-5) antibody, using a combination of risk factors. Cumulative survival rates were assessed using Kaplan-Meier analysis, and were compared between subgroups using the Breslow test. Results: In the derivation cohort, C-reactive protein (CRP) and Krebs von den Lungen 6 (KL-6) levels were identified as independent risk factors for mortality in both anti–MDA-5–positive and anti–MDA-5–negative patients. We then developed a prediction model based on anti–MDA-5 antibody status, CRP level, and KL-6 level, termed the “MCK model,” to identify patients at low (<15%), moderate (15–50%), or high (≥50%) risk of mortality, based on the number of risk factors. The MCK model successfully differentiated cumulative survival rates in anti–MDA-5–positive patients (P < 0.01 for low versus moderate risk and P = 0.03 for moderate versus high risk) and in anti–MDA-5–negative patients (P < 0.001 for low versus moderate risk). The utility of the MCK model was replicated in the validation cohort. Conclusion: Our findings indicate that an evidence-based risk prediction model using CRP and KL-6 levels combined with anti–MDA-5 antibody status might be useful for predicting prognosis in patients with PM/DM-ILD.

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Lymphadenopathy in IgG4-related disease: a phenotype of severe activity and poor prognosis, with eotaxin-3 as a new biomarker.

Satoshi Takanashi, Jun Kikuchi, Takanori Sasaki, Mitsuhiro Akiyama, Hidekata Yasuoka, Keiko Yoshimoto, Noriyasu Seki, Kunio Sugahara, Kenji Chiba, Yuko Kaneko, Tsutomu Takeuchi

Rheumatology (Oxford, England) (Rheumatology (United Kingdom)) 60 ( 2 ) 967 - 975 2021.02

ISSN 14620324

OBJECTIVE: To clarify relevant proteins and clinical characteristics of a phenotype of IgG4-related disease (IgG4-RD) with lymphadenopathy. METHODS: We enrolled patients newly diagnosed with IgG4-RD in our department between January 2000 and June 2018 and performed proteomic analysis to measure serum concentrations of 1305 proteins. We extracted proteins overexpressed in patients with IgG4-RD with lymphadenopathy by comparing between those with lymphadenopathy, those without lymphadenopathy and healthy controls. We further reviewed all the patients with IgG4-RD in our institution and investigated the characteristics and prognosis of the patients with IgG4-RD with lymphadenopathy. RESULTS: Eighty-five patients with IgG4-RD were enrolled, of which, 55% had lymphadenopathy. Proteomic analysis in 31 patients with IgG4-RD and 6 healthy controls revealed that eotaxin-3 was a potential serum biomarker in the patients with lymphadenopathy versus those without lymphadenopathy and healthy controls. A cohort of 85 patients with IgG4-RD demonstrated that patients with lymphadenopathy showed a significantly higher serum IgG4, IgG4:IgG ratio, IgG4-RD responder index and eosinophilia (P < 0.001 for all), irrelevant of the extent to which organ involvement developed. Patients with lymphadenopathy treated with glucocorticoid alone relapsed with significantly higher rates than those without lymphadenopathy (P = 0.03). CONCLUSION: Lymphadenopathy in IgG4-RD represents a phenotype associated with high disease activities, eosinophilia and relapsing disease. Eotaxin-3 is a novel biomarker related to IgG4-RD with lymphadenopathy.

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Milk fat globule epidermal growth factor 8 (MFG-E8) on monocytes is a novel biomarker of disease activity in systemic lupus erythematosus.

Mari Ushikubo, Shuntaro Saito, Jun Kikuchi, Masaru Takeshita, Keiko Yoshimoto, Hidekata Yasuoka, Kunihiro Yamaoka, Noriyasu Seki, Katsuya Suzuki, Hisaji Oshima, Tsutomu Takeuchi

Lupus (Lupus) 30 ( 1 ) 61 - 69 2021.01

ISSN 09612033

BACKGROUND: Milk fat globule epidermal growth factor (MFG-E8) is related secreted protein which links phosphatidylserine on apoptotic cells and integrin αvβ3/5 on phagocytes. To clarify the clinical significance of MFG-E8 in SLE, we analyzed the correlation between expression level of MFG-E8 in circulating phagocytic leukocytes and clinical parameters of patients. METHODS: The study was conducted under a multi-center, prospective cohort design. Patients with one or both BILAG A or B, or SLEDAI- 2 K ≥ 4 with clinical symptoms were defined as the active SLE group. Expression of MFG-E8 on monocytes and concentration in serum were measured by FACS and ELISA, respectively. RESULTS: 96 subjects were enrolled. The absolute number and proportion of MFG-E8-positive monocytes to total monocytes were significantly higher in the active SLE group (p < 0.01). Importantly, the proportion was also significantly correlated with SLEDAI-2K, clinical SLEDAI, as well as serum levels of anti-ds-DNA antibody and complement and C1q. In addition, the proportion of MFG-E8-positive monocytes to total monocytes was significantly decreased from baseline in active SLE patients after 6 months' treatment and increased concordantly with disease activity in 6 refractory cases. Further, in receiver operating characteristic curve analysis for discrimination between active and inactive SLE, the AUC of the proportion of MFG-E8 was 0.854, which was equivalent to classical activity markers such as anti-ds DNA antibody (0.776), complement (0.897) and C1q (0.815). CONCLUSIONS: The proportion of MFG-E8-positive monocytes to total monocytes in peripheral blood was positively associated with disease activity in SLE and may be a novel biomarker of disease activity.

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Refractory IgG4-related Pleural Disease with Chylothorax: A Case Report and Literature Review.

Komei Sakata, Jun Kikuchi, Katsura Emoto, Tomomi Kotaki, Yuichiro Ota, Naoshi Nishina, Hironari Hanaoka, Kotaro Otomo, Katsuya Suzuki, Yuko Kaneko, Tsutomu Takeuchi

Internal medicine (Tokyo, Japan) (Internal Medicine) 60 ( 13 ) 2135 - 2143 2021

ISSN 09182918

We herein report a rare case of a 66-year-old man with refractory chylothorax. Although he had been treated with moderate doses of prednisolone (PSL) on suspicion of pleuritis with Sjögren syndrome, the pleural effusion expanded after the reduction of PSL. Further workup including histopathological examinations of pleura led to the diagnosis of IgG4-RD with bilateral chylothorax without any leakage from the thoracic duct. Combination therapy with high-dose PSL plus rituximab successfully decreased the pleural effusion. This is a very rare case of IgG4-related pleuritis with chylothorax and the first report of its successful treatment with rituximab.

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Successful Treatment of Anti-MDA5 Antibody-Positive Dermatomyositis-Associated Rapidly Progressive-Interstitial Lung Disease by Plasma Exchange: Two Case Reports.

Rina Takahashi, Tadashi Yoshida, Kohkichi Morimoto, Yasushi Kondo, Jun Kikuchi, Shuntaro Saito, Sho Ishigaki, Yuko Kaneko, Tsutomu Takeuchi, Hiroshi Itoh, Mototsugu Oya

Clinical medicine insights. Case reports (Clinical Medicine Insights: Case Reports) 14 11795476211036322 - 11795476211036322 2021

ISSN 1179-5476

Background: Patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) are frequently accompanied by rapidly progressive-interstitial lung disease (RP-ILD). They are often refractory to intensive immunosuppressive therapy and have poor prognosis. Case presentation: A 73-year-old woman presented with fever, cold symptoms, and skin eruption for a month. She also exhibited muscle weakness on upper extremities slightly. The titer of anti-MDA5 antibody was extremely high, and computed tomography showed ground glass opacity and reticular shadows in the lungs. She was diagnosed as anti-MDA5 antibody-positive classical DM-associated RP-ILD and treated with intensive immunosuppressive therapy. However, the titer of anti-MDA5 antibody did not decrease satisfactorily, and plasma exchange was alternatively initiated. The titer decreased remarkably, and she obtained disease remission. Similarly, a 63-year-old woman presented with stiffness of the neck and hands, fever and cough. She was also diagnosed as anti-MDA5 antibody-positive classical DM-associated RP-ILD, because she had skin eruptions, slight muscle weakness, an elevation in anti-MDA5 antibody, and RP-ILD. She was unresponsive to intensive immunosuppressive therapy, but plasma exchange successfully improved the titer of anti-MDA5 antibody, the symptoms, and the findings of computed tomography. Conclusions: Although anti-MDA5 antibody-positive DM-associated RP-ILD has a high mortality rate, this report suggests the usefulness of plasma exchange to improve the prognosis.

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COVID-19 infection in patients with systemic lupus erythematosus: Data from the Asia Pacific Lupus Collaboration.

Jiacai Cho, Rangi Kandane-Rathnayake, Worawit Louthrenoo, Alberta Hoi, Vera Golder, Yi-Hsing Chen, Shue Fen Luo, Yeong-Jian Jan Wu, Laniyati Hamijoyo, Chak Sing Lau, Sandra Navarra, Leonid Zamora, Michael Tee, Angelito Flora Jr, Zhan-Guo Li, Yuan An, Sargunan Sockalingam, Yasuhiro Katsumata, Masayoshi Harigai, Yanjie Hao, Zhuoli Zhang, Jun Kikuchi, Tsutomu Takeuchi, Duminda Basnayake, Fiona Goldblatt, Madelynn Chan, Kristine Pek Ling Ng, Sang-Cheol Bae, Shereen Oon, Sean O'Neill, Kathy Gibson, Sunil Kumar, Annie Hui Nee Law, Nicola Tugnet, Yoshiya Tanaka, Mandy Nikpour, Eric Morand, Aisha Lateef

International journal of rheumatic diseases 23 ( 9 ) 1255 - 1257 2020.08

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Identification of molecules associated with response to abatacept in patients with rheumatoid arthritis.

Waka Yokoyama-Kokuryo, Hayato Yamazaki, Tsutomu Takeuchi, Koichi Amano, Jun Kikuchi, Tsuneo Kondo, Seiji Nakamura, Ryoko Sakai, Fumio Hirano, Toshihiro Nanki, Ryuji Koike, Masayoshi Harigai

Arthritis research & therapy 22 ( 1 ) 46 - 46 2020.03

BACKGROUND: Abatacept (ABA) is a biological disease-modifying antirheumatic drug (bDMARD) for rheumatoid arthritis (RA). The aim of this study was to identify molecules that are associated with therapeutic responses to ABA in patients with RA. METHODS: Peripheral blood was collected using a PAX gene Blood RNA kit from 45 bDMARD-naïve patients with RA at baseline and at 6 months after the initiation of ABA treatment. Gene expression levels of responders (n = 27) and non-responders (n = 8) to ABA treatment among patients with RA at baseline were compared using a microarray. The gene expression levels were confirmed using real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Gene expression analysis revealed that the expression levels of 218 genes were significantly higher and those of 392 genes were significantly lower in the responders compared to the non-responders. Gene ontology analysis of the 218 genes identified "response to type I interferon (IFN)" with 24 type I IFN-related genes. RT-qPCR confirmed that there was a strong correlation between the score calculated using the 24 genes and that using OAS3, MX1, and IFIT3 (type I IFN score) (rho with the type I IFN score 0.981); the type I IFN score was significantly decreased after treatment with ABA in the responders (p < 0.05), but not in the non-responders. The receiver operating characteristic curve analysis of the type I IFN score showed that sensitivity, specificity, and AUC (95% confidence interval) for the responders were 0.82, 1.00, and 0.92 (0.82-1.00), respectively. Further, RT-qPCR demonstrated higher expression levels of BATF2, LAMP3, CD83, CLEC4A, IDO1, IRF7, STAT1, STAT2, and TNFSF10 in the responders, all of which are dendritic cell-related genes or type I IFN-related genes with significant biological implications. CONCLUSION: Type I IFN score and expression levels of the nine genes may serve as novel biomarkers associated with a clinical response to ABA in patients with RA.

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