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Papers - Kikuchi, Jun

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大量ステロイドとトシリズマブ治療経過中に巨細胞性動脈炎による重症脳梗塞を発症した一例

鈴木浩司, 秋山光浩, 花岡洋成, 近藤泰, 齋藤俊太郎, 菊池潤, 金子祐子

関東リウマチ (関東リウマチ研究会) 55 7 - 11 2023.05

ISSN 0911-4807

症例は77歳女性で、発熱、両肩関節の疼痛・挙上困難、顎跛行を主訴とした。血液検査、画像所見(PET-CT、頭部造影MRI)、右側頭動脈生検より、巨細胞性動脈炎と診断した。大量ステロイドとトシリズマブを開始したが、重症脳梗塞を発症し、ステロイドパルスとシクロフォスファミドによる再寛解導入療法を行い、病勢をコントロールできた。脳梗塞に対してはアスピリンとクロピドグレルを開始した。本症例は高齢、高血圧、顎跛行、炎症マーカー低値で、PET-CTで内頸動脈への集積亢進を認めるなど脳梗塞のリスクが高かった。

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

Kikuchi J, Hanaoka H, Saito S, Oshige T, Hiramoto K, Takeuchi T, Kaneko Y

Clinical and experimental rheumatology 2023.01

ISSN 0392-856X

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

Saito S, Suzuki K, Yoshimoto K, Kondo Y, Kikuchi J, Hanaoka H, Kaneko Y, Takeuchi T

Clinical and experimental rheumatology 2022.12

ISSN 0392-856X

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Clinical and immunological effects of hydroxychloroquine in patients with active rheumatoid arthritis despite antirheumatic treatment.

Hiroshi Takei, Satoshi Takanashi, Kotaro Otomo, Hironari Hanaoka, Jun Kikuchi, Kunihiro Yamaoka, Keiko Yoshimoto, Takayuki Abe, Tsutomu Takeuchi, Yuko Kaneko

Modern rheumatology 2022.12

ISSN 1439-7595

OBJECTIVE: To investigate the efficacy and safety of hydroxychloroquine (HCQ) in patients with rheumatoid arthritis (RA). METHODS: Patients with active RA, despite conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), were recruited. HCQ was administered for 24 weeks, in addition to prior treatment. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 achievement at week 24, compared to that of a propensity score matched historical control group. RESULTS: Sixty patients were enrolled and administered HCQ. We also identified 276 patients as candidates for the historical control group. Propensity score matching yielded 46 patients in each group. The proportion of ACR20 achievements at week 24 was significantly higher in the HCQ group than that in the control group (54.4% vs. 28.3%, P = 0.007). The proportion of ACR50 and ACR70 achievement at week 24 were also higher in the HCQ group than those in the control group (ACR50, 30.4% vs. 4.3%, P = 0.006; ACR70, 17.4% vs. 0%, P = 0.005). Neither hydroxychloroquine retinopathy nor any new safety signal was observed during the study. CONCLUSION: The addition of HCQ to csDMARDs was effective, with no new safety signal in patients with RA.

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Associations of improvement in laboratory tests with clinical outcomes in patients with active systemic lupus erythematosus: a multinational longitudinal cohort study

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

The Lancet Rheumatology (The Lancet Rheumatology) 4 ( 12 ) e831 - e841 2022.12

Background: The selection and categorisation of laboratory tests in disease activity measures used within systemic lupus erythematosus (SLE) trial endpoints lack strong evidence. We aimed to determine whether longitudinal improvements in routinely measured laboratory tests are associated with measures of clinical improvement in patients with baseline active SLE. Methods: We included patients from a multicentre longitudinal cohort (recruited between May 1, 2013, and Dec 31, 2019) with active SLE (SLEDAI-2K ≥6) coinciding with an abnormality in at least one of 13 routine laboratory tests, at a visit designated as baseline. At 12 months, we analysed associations between thresholds of improvement in individual laboratory test results, measured as continuous variables, and five clinical outcomes using logistic regression. Primary outcomes were damage accrual and lupus low disease activity state (LLDAS), and secondary outcomes were modified SLE responder index (mSRI), physician global assessment (PGA) improvement of at least 0·3, and flare. Findings: We included 1525 patients (1415 [93%] women and 110 [7%] men, 1328 [87%] Asian ethnicity) in separate subsets for each laboratory test. The strongest associations with LLDAS and damage protection were seen with improvements in proteinuria (complete response: adjusted odds ratio [OR] 62·48, 95% CI 18·79–208·31 for LLDAS, OR 0·22, 95% CI 0·10–0·49 for damage accrual), albumin (complete response: adjusted OR 6·46, 95% CI 2·20–18·98 for LLDAS, OR 0·42, 95% CI 0·20–1·22 for damage accrual), haemoglobin (complete response: adjusted OR 1·97, 95% CI 1·09–3·53 for LLDAS, OR 0·33, 95% CI 0·15–0·71 for damage accrual), erythrocyte sedimentation rate (complete response: adjusted OR 1·71, 95% CI 1·10–2·67 for LLDAS, OR 0·53, 95% CI 0·30–0·94 for damage accrual), and platelets (complete response: adjusted OR 4·82, 95% CI 1·54–15·07 for LLDAS, OR 0·49, 95% CI 0·20–1·19 for damage accrual). Improvement in serological tests were mainly associated with PGA and mSRI. White cell and lymphocyte count improvements were least predictive. Interpretation: Improvements in several routine laboratory tests correspond with clinical outcomes in SLE over 12 months. Tests with the strongest associations were discrepant with laboratory tests included in current trial endpoints, and associations were observed across a range of improvement thresholds including incomplete resolution. These findings suggest the need to revise the use of laboratory test results in SLE trial endpoints. Funding: Abbvie.

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Lupus low disease activity state and remission and risk of mortality in patients with systemic lupus erythematosus: a prospective, multinational, longitudinal cohort study

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

The Lancet Rheumatology (The Lancet Rheumatology) 4 ( 12 ) e822 - e830 2022.12

Background: Treat-to-target goals for patients with systemic lupus erythematosus (SLE) have been validated to protect against organ damage and to improve quality of life. We aimed to investigate the association between lupus low disease activity state (LLDAS) and remission and risk of mortality in patients with SLE. We hypothesised that LLDAS has a protective association with mortality risk. Methods: In this prospective, multinational, longitudinal cohort study, we used data from patients with SLE in the Asia Pacific Lupus Collaboration cohort collected between May 1, 2013, and Dec 31, 2020. Eligible patients were adults (aged ≥18 years) who met either the 1997 American College of Rheumatology modified classification criteria for SLE or the 2012 Systemic Lupus International Collaborating Clinics classification criteria. The primary outcome was all-cause mortality, and LLDAS, remission, and variations of remission with lower glucocorticoid thresholds were the primary exposure variables. Survival analyses were used to examine longitudinal associations between these endpoints and risk of mortality. This study is registered with ClinicalTrials.gov, NCT03138941. Findings: Among a total of 4106 patients in the cohort, 3811 (92·8%) patients were included in the final analysis (median follow-up 2·8 years [IQR 1·0–5·3]; 3509 [92·1%] women and 302 [7·9%] men), of whom 80 died during the observation period (crude mortality rate 6·4 deaths per 1000 person-years). LLDAS was attained at least once in 43 (53·8%) of 80 participants who died and in 3035 (81·3%) of 3731 participants who were alive at the end of the study (p<0·0001); 22 (27·5%) participants who died versus 1966 (52·7%) who were alive at the end of the study attained LLDAS for at least 50% of observed time (p<0·0001). Remission was attained by 32 (40·0%) of 80 who died and in 2403 (64·4%) of 3731 participants who were alive at the end of the study (p<0·0001); 14 (17·5%) participants who died versus 1389 (37·2%) who were alive at the end of the study attained remission for at least 50% of observed time (p<0·0001). LLDAS for at least 50% of observed time (adjusted hazard ratio 0·51 [95% CI 0·31–0·85]; p=0·010) and remission for at least 50% of observed time (0·52 [0·29–0·93]; p=0·027) were associated with reduced risk of mortality. Modifying the remission glucocorticoid threshold (<5·0 mg/day prednisolone) was more protective against mortality than current remission definitions (0·31 [0·12–0·77]; p=0·012), and glucocorticoid-free remission was the most protective (0·13 [0·02–0·96]; p=0·046). Interpretation: LLDAS significantly reduced the risk of mortality in patients with SLE. Remission did not further reduce the risk of mortality compared with LLDAS, unless lower glucocorticoid thresholds were used. Funding: The Asia-Pacific Lupus Collaboration received funding from Janssen, Bristol Myers Squibb, Eli Lilly, and UCB for this study.

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Patterns of Medication Use in Systemic Lupus Erythematosus - A Multi-Centre Cohort Study.

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

Arthritis care & research (Arthritis Care and Research) 74 ( 12 ) 2033 - 2041 2022.12

ISSN 2151464X

OBJECTIVES: Evidence for the utility of medications in settings lacking randomised trial data can come from studies of treatment persistence. We examined patterns of medication use in systemic lupus erythematosus (SLE) using data from a large multicentre longitudinal cohort. METHODS: Prospectively collected data from the Asia Pacific Lupus Collaboration cohort including disease activity (SLEDAI-2K) and medication details, captured at every visit from 2013-18, were used. Medications were categorised as glucocorticoids (GC), anti-malarials (AM), and immunosuppressants (IS). Cox regression analyses were performed to determine the time-to-discontinuation of medications, stratified by SLE disease activity. RESULTS: Data from 19,804 visits of 2,860 patients were analysed. Eight medication categories were observed: no treatment; GC, AM or IS only; GC+AM; GC+IS; AM+IS and GC+AM+IS (triple therapy). Triple therapy was the most frequent pattern (31.4% of visits); single agents were used in 21% of visits and biologicals in only 3%. Time-to-discontinuation analysis indicated that medication persistence varied widely, with the highest treatment persistence for AM and lowest for IS. Patients with time-adjusted mean SLEDAI-2K≥10 had lower discontinuation of GC and higher discontinuation of IS. CONCLUSION: Most patients received combination treatment. GC persistence was high, while IS persistence was low. Patients with high disease activity received more medication combinations but had reduced IS persistence, consistent with limited utility. These data confirm unmet need for improved SLE treatments.

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'Not at target': prevalence and consequences of inadequate disease control in systemic lupus erythematosus-a multinational observational cohort study.

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

Arthritis research & therapy (Arthritis Research and Therapy) 24 ( 1 ) 70 - 70 2022.12

ISSN 14786354

BACKGROUND: The unmet need in systemic lupus erythematosus (SLE) with the current standard of care is widely recognised, but few studies have quantified this. The recent definition of treat-to-target endpoints and other thresholds of uncontrolled disease activity provide an opportunity to formally define unmet need in SLE. In this study, we enumerated the prevalence of these states and examined their association with adverse outcomes. METHODS: Data were collected prospectively in a 13-country longitudinal SLE cohort between 2013 and 2019. Unmet need was defined as never attaining lupus low disease activity state (LLDAS), a time-adjusted mean SLEDAI-2K (AMS) > 4, or ever experiencing high disease activity status (HDAS; SLEDAI-2K ≥10). Health-related quality of life (HRQoL) was assessed using SF36 (v2) and damage accrual using the SLICC-ACR SLE Damage Index (SDI). RESULTS: A total of 3384 SLE patients were followed over 30,313 visits (median [IQR] follow-up 2.4 [0.4, 4.3] years). Eight hundred thirteen patients (24%) never achieved LLDAS. Median AMS was 3.0 [1.4, 4.9]; 34% of patients had AMS > 4. Twenty-five per cent of patients had episodes of HDAS. Each of LLDAS-never, AMS>4, and HDAS-ever was strongly associated with damage accrual, higher glucocorticoid use, and worse HRQoL. Mortality was significantly increased in LLDAS-never (adjusted HR [95% CI] = 4.98 [2.07, 12.0], p<0.001) and HDAS-ever (adjusted hazard ratio (HR) [95% CI] = 5.45 [2.75, 10.8], p<0.001) patients. CONCLUSION: Failure to achieve LLDAS, high average disease activity, and episodes of HDAS were prevalent in SLE and were significantly associated with poor outcomes including organ damage, glucocorticoid exposure, poor quality of life, and mortality.

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

Tanemura S., Seki N., Tsujimoto H., Saito S., Kikuchi J., Sugahara K., Yoshimoto K., Suzuki K., Kaneko Y., Chiba K., Takeuchi T.

International immunology (International immunology) 34 ( 10 ) 533 - 544 2022.09

ISSN 0953-8178

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

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Tapering of Corticosteroids or Immunosuppressive Therapy in Stable SLE: A Comparison of Complete Remission, Clinical Remission and Lupus Low Disease Activity State in Protection Against Flares

Cho Jiacai, Shen Liang, Huq Molla, Kandane-Rathnayake Rangi, Golder Vera, Louthrenoo Worawit, Chen Yi-Hsin, Hamijoyo Laniyati, Fen Luo Shue, Wu Yeong-Jian, Zamora Leonid, Zhang Zhouli, Yuan An, Sockalingam Sargunan, Katsumata Yasuhiro, Harigai Masayoshi, Hao Yanjie, Li Zhanguo, Basnayake Duminda, Chan Madelynn, Kikuchi Jun, Takeuchi Tsutomu, Bae Sang-Cheol, Goldblatt Fiona, Oon Shereen, O'Neill Sean, Gibson Kathy, Ng Kristine, Law Hui Nee Annie, Tugnet Nicole, Kumar Sunil, Tee Cherica, Tee Michael, Ohkubo Naoaki, Tanaka Yoshiya, Navarra Sandra, Sing Chak, Hoi Alberta, Morand Eric, Nikpour Mandana, Lateef Aisha

ARTHRITIS & RHEUMATOLOGY 74 1969 - 1972 2022.09

ISSN 2326-5191

Association of Sustained Lupus Low Disease Activity State with Improved Outcomes in SLE: A Multinational Prospective Cohort Study

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

ARTHRITIS & RHEUMATOLOGY 74 3160 - 3161 2022.09

ISSN 2326-5191

Predictors of Organ Damage Accrual by Domains

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

ARTHRITIS & RHEUMATOLOGY 74 4077 - 4080 2022.09

ISSN 2326-5191

SMART-SLE: Serology Monitoring and Repeat Testing in Systemic Lupus Erythematosus

Yeo Ai Li, Kandane-Rathnayake Rangi, Koelmeyer Rachel, Golder Vera, Louthrenoo Worawit, Chen Yi-Hsin, Cho Jiacai, Lateef Aisha, Hamijoyo Laniyati, Fen Luo Shue, Wu Yeong-Jian, Navarra Sandra, Zamora Leonid, Li Zhanguo, Yuan An, Sockalingam Sargunan, Katsumata Yasuhiro, Harigai Masayoshi, Hao Yanjie, Zhang Zhouli, Basnayake Duminda, Chan Madelynn, Kikuchi Jun, Takeuchi Tsutomu, Bae Sang-Cheol, Oon Shereen, O'Neill Sean, Goldblatt Fiona, Gibson Kathy, Ng Kristine, Law Hui Nee Annie, Tugnet Nicole, Kumar Sunil, Tee Cherica, Tee Michael, Tanaka Yoshiya, Ohkubo Naoaki, Sing Chak, Nikpour Mandana, Hoi Alberta, Leech Michelle, Morand Eric

ARTHRITIS & RHEUMATOLOGY 74 642 - 643 2022.09

ISSN 2326-5191

Lupus low disease activity state within 12 months is associated with favourable outcomes in severely active systemic lupus erythematosus.

Jun Kikuchi, Hironari Hanaoka, Shuntaro Saito, Tatsuhiro Oshige, Kazuoto Hiramoto, Yuko Kaneko, Tsutomu Takeuchi

Rheumatology (Oxford, England) (Rheumatology (Oxford, England)) 61 ( 9 ) 3777 - 3791 2022.08

ISSN 1462-0324

OBJECTIVES: To demonstrate the significance of the time to attain lupus low disease activity state (LLDAS) after remission induction therapy in patients with severely active systemic lupus erythematosus (SLE). METHODS: We enrolled 79 patients starting prednisolone ≥0.4 mg/kg/day for active lupus with a British Isles Lupus Assessment Group 2004 index of A ≥ 1 or B ≥ 2, or for severe flare based on the Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI). The time to LLDAS attainment was divided into ≤6, 6-12, and >12 months and non-LLDAS; associations between the timing of LLDAS and flares, damage accrual, and ≥50% LLDAS attainment were examined. RESULTS: The mean SLEDAI was 17; median starting dose of prednisolone, 0.95 mg/kg/day; and mean observational period, 39.7 months. Six (7.6%) and 41 (51.9%) patients achieved LLDAS within 6 and 12 months. Patients with a shorter time to LLDAS achievement were more likely to spend ≥50% of the time in LLDAS and had a lower cumulative prednisolone dose; no differences were observed in damage accrual. Patients requiring longer than 12 months to achieve LLDAS had a higher prevalence of thrombocytopenia and those with non-LLDAS had lower renal function and a higher starting dose of prednisolone and steroid pulse therapy than those who achieved LLDAS within 12 months. CONCLUSION: Achieving LLDAS within 12 months of induction therapy may be favourable in patients with severely active SLE. The low frequency of LLDAS attainment in high-risk populations highlights the need for a new strategy for SLE treatment.

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

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

Clinical Kidney Journal (Clinical Kidney Journal) 15 ( 7 ) 1373 - 1378 2022.07

ISSN 20488505

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

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RISK FACTORS FOR CYTOMEGALOVIRUS INFECTION IN PATIENTS WITH RHEUMATIC DISEASE; SINGLE-CENTER PROSPECTIVE COHORT STUDY.

Ota Y., Kondo Y., Saito S., Kikuchi J., Hanaoka H., Kaneko Y.

ANNALS OF THE RHEUMATIC DISEASES 81 919 - 919 2022.06

ISSN 0003-4967

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COMPARISON OF ATTAINMENT AND PROTECTIVE EFFECTS OF THE LUPUS LOW DISEASE ACTIVITY STATE IN PATIENTS WITH NEWLY DIAGNOSED VERSUS ESTABLISHED SLE - A MULTICENTRE PROSPECTIVE STUDY

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

ANNALS OF THE RHEUMATIC DISEASES 81 91 - 92 2022.06

ISSN 0003-4967

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ASSOCIATION OF LUPUS LOW DISEASE ACTIVITY STATE ATTAINMENT WITH REDUCED ORGAN DAMAGE AND FLARE IN SLE PATIENTS WITH HIGH DISEASE ACTIVITY

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

ANNALS OF THE RHEUMATIC DISEASES 81 286 - 287 2022.06

ISSN 0003-4967

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APTAMER-BASED PROTEOMIC SCREENING IN IDENTIFICATION OF PATHOGENIC SIGNAL PATHWAY AND URINARY BIOMARKERS ASSOCIATED WITH HISTOLOGICAL FINDINGS IN LUPUS NEPHRITIS

Hiramoto K., Saito S., Hanaoka H., Suzuki K., Kikuchi J., Fukui H., Takano R., Miyoshi F., Seki N., Sugahara K., Kaneko Y., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 81 483 - 483 2022.06

ISSN 0003-4967

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COMPARISON OF SARS-COV-2 VACCINE RESPONSE IN PATIENTS WITH INFLAMMATORY RHEUMATIC DISEASE; MRNA-1273 VACCINE INDUCES HIGHER HUMORAL IMMUNOGENICITY THAN BNT162B2

Kondo Y., Takeshita M., Uwamino Y., Namkoong H., Saito S., Kikuchi J., Hanaoka H., Suzuki K., Hasegawa N., Murata M., Kaneko Y.

ANNALS OF THE RHEUMATIC DISEASES 81 370 - 370 2022.06

ISSN 0003-4967

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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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Reversible cerebral vasoconstriction syndrome triggered by tacrolimus mimicked neuropsychiatric involvement in systemic lupus erythematosus

Jun Inamo, Jun Kikuchi, Katsuya Suzuki, Yuko Kaneko, Hidekata Yasuoka, Hirokazu Fujiwara, Kunihiro Yamaoka, Tsutomu Takeuchi

Modern Rheumatology Case Reports (Informa UK Limited) 3 ( 2 ) 119 - 123 2019.07

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Reduced Expression of CX3CR1 in Peripheral CD14++CD16+monocytes Is a Novel Feature of Patients with Systemic Lupus Erythematosus

Yoshimoto Keiko, Suzuki Katsuya, Saito Shuntaro, Kikuchi Jun, Takeuchi Tsutomu

ARTHRITIS & RHEUMATOLOGY 70 2018.09

Accepted, ISSN 2326-5191

Initial predictors of poor survival in myositisassociated interstitial lung disease: A multicentre cohort of 497 patients

Sato S., Masui K., Nishina N., Kawaguchi Y., Kawakami A., Tamura M., Ikeda K., Nunokawa T., Tanino Y., Asakawa K., Kaneko Y., Gono T., Ukichi T., Kaieda S., Naniwa T., Kuwana M., Okano Y., 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.

Rheumatology (United Kingdom) (Rheumatology (United Kingdom)) 57 ( 7 ) 1212 - 1221 2018.07

ISSN 14620324

© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. Objective. To identify initial predictors of poor survival in patients with PM/DM-associated interstitial lung disease (ILD). Methods. We established a multicentre retrospective cohort of incident cases of PM/DM-associated ILD from 44 institutions across Japan (Multicentre Retrospective Cohort of Japanese Patients with Myositisassociated ILD, JAMI). Inclusion criteria were an onset age ≥16 years; PM/DM or clinically amyopathic DM according to the published criteria; imaging evidence of ILD; and availability of serum samples for assays of autoantibodies such as anti-melanoma differentiation-associated gene 5 and anti-aminoacyl tRNA synthetase. We collected demographic data and clinical characteristics recorded at the time of diagnosis, as well as follow-up survival data. Predictors of ILD-related mortality were identified by univariate and multivariate analyses. Results. JAMI enrolled a cohort of 497 patients with PM (15%), classic DM (32%) and clinically amyopathic DM (53%). During the observation period (median 20 months), 76 died of respiratory insufficiency directly related to ILD. Univariate analysis revealed several initial parameters associated with ILD mortality, including demographic, clinical, laboratory, imaging and autoantibody variables. We used multivariate analysis with a stepwise selection of parameters to generate an appropriate predictive model, and identified the following independent risk factors for ILD mortality: age at onset ≥60 years [hazard ratio (HR) = 4.3, 95% CI: 2.4, 7.5], CRP ≥1 mg/dl (HR = 2.6, 95% CI: 1.5, 4.8), peripheral capillary oxygen saturation <95% (HR = 2.0, 95% CI: 1.2, 3.4) and anti-melanoma differentiation-associated gene 5 antibody (HR = 7.5, 95% CI: 2.8, 20.2). Conclusion. We established a large cohort of incident cases of PM/DM-associated ILD, and successfully identified independent predictors of short-term ILD mortality.

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Efficacy and tolerability of six-week extended dosing interval with tocilizumab therapy in a prospective cohort as remission maintenance in patients with rheumatoid arthritis

Jun Kikuchi, Tsuneo Kondo, Akiko Shibata, Ryota Sakai, Yusuke Okada, Kentaro Chino, Ayumi Okuyama, Takahiko Kurasawa, Hirofumi Takei, Koichi Amano

Modern Rheumatology (Taylor and Francis Ltd) 28 ( 3 ) 444 - 451 2018.05

Accepted, ISSN 14397595

Objectives: To prospectively evaluate the efficacy and tolerability of a six-week extended dosing interval with tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in sustained remission. Methods: Patients who received over six doses of intravenous TCZ in clinical remission (disease activity score [DAS] 28–erythrocyte sedimentation rate [ESR] ≤ 2.6) maintained over 3 months between December 2013 and December 2015 were included. Flare was defined as DAS28-ESR &gt
3.2 at two consecutive visits. Results: Twenty-five patients were enrolled
87.5% achieved clinical remission at week 54 after six-week extension and 95.5% achieved a van der Heijde modified total Sharp score (ΔmTSS) ≤0.5. The Health Assessment Questionnaire Disability Index (HAQ-DI) did not increase during 54 weeks. HAQ-DI at baseline and ΔDAS28-ESR at week six positively correlated with increase in DAS28-ESR at week 54. ΔSwollen joint count at week six positively correlated with ΔmTSS at week 54. A total of 12 adverse events occurring in 10 patients did not lead to cessation of TCZ except for one case of recurrent lymphoproliferative disorder at week five. Conclusion: A six-week extended dosing interval of TCZ for patients with RA in sustained remission is proposed as an acceptable treatment option for maintaining efficacy and tolerability.

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Persistent fever and destructive arthritis caused by dialysis-related amyloidosis

Kotaro Matsumoto, Jun Kikuchi, Yuko Kaneko, Hidekata Yasuoka, Kazuko Suzuki, Hirobumi Tokuyama, Kaori Kameyama, Kunihiro Yamaoka, Tsutomu Takeuchi

Medicine (United States) (Lippincott Williams and Wilkins) 97 ( 1 ) e9359 2018.01

Accepted, ISSN 00257974

Rationale: Dialysis-related amyloidosis (DRA) can present rheumatic manifestations in patients on long-term hemodialysis. Typical articular symptoms with DRA involve carpal-tunnel syndrome, effusion in large joints, spondyloarthropathy, or cystic bone lesions, which are usually with non-inflammatory processes. Patient concerns: A 64-year-old man on hemodialysis for &gt
30 years was admitted because of intermittent fever, polyarthritis, and elevated serum C-reactive protein (CRP) level, which was continuous for 2 years. Several antibiotics were ineffective for 3 months before his admission. On physical examination, joint swelling was observed at bilateral wrists, knees, ankles, and hip joints. Laboratory tests revealed elevation of serum inflammatory markers and β2-microglobulin (β2-MG). Synovial fluid showed predominant infiltration of polymorphonuclear leukocytes and the increase of β2-MG level. Diagnosis: Significant deposition of β2-MG with inflammatory cell infiltration was found in biopsied samples from synovium, skin, and ileum. Interventions: We decided to switch to the hemodialysis column with membrane that can effectively absorb β2-MG in circulation. Outcomes: The relief of symptoms and a decrease of CRP level by changing the membrane lead to the final diagnosis of DRA. Lessons: Our case demonstrates that DRA arthropathy can be inflammatory and destructive, and also develop systemic inflammatory signs and symptoms. In such cases, aggressive absorption of β2-MG in circulation might help the amelioration of symptoms.

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[Mixed connective tissue disease with pulmonary hypertension developing in a chronic myeloid leukemia patient on dasatinib treatment].

Watanuki S, Kikuchi T, Toyama T, Abe R, Nakayama H, Karigane D, Shimizu T, Kikuchi J, Matsumoto K, Yasuoka H, Kataoka M, Okamoto S, Mori T

[Rinsho ketsueki] The Japanese journal of clinical hematology 59 ( 2 ) 174 - 177 2018

Accepted, ISSN 0485-1439

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Polymyositis with elevated serum IgG4 levels and abundant IgG4 + plasma cell infiltration

Ryusuke Anan, Mitsuhiro Akiyama, Yuko Kaneko, Jun Kikuchi, Kazuko Suzuki, Shiro Matsubara, Tsutomu Takeuchi

Medicine (United States) (Lippincott Williams and Wilkins) 96 ( 48 ) e8710 2017.12

Accepted, ISSN 1536-5964

Introduction: Polymyositis (PM) is a type of autoimmune, inflammatory myopathy. IgG4-related disease (IgG4-RD) is a recently recognized disease entity characterized by elevated serum IgG4 levels and IgG4 + plasma-cell infiltration of various organs. However, several reports have described cases of other diseases that present with those features, suggesting the importance of careful differential diagnosis. Herein, we report the first case of PM with elevated serum IgG4 levels and IgG4 + plasma cells in the muscles, mimicking IgG4-RD. A 73-year-old woman visited our hospital because of proximal muscle weakness of both thighs. Her blood test showed high levels of serum creatinine kinase, aldolase, and IgG4. Magnetic resonance imaging of the thighs showed muscle edema. Needle electromyography showed findings typical of myositis. Histological analysis of her left quadriceps revealed infiltration of IgG4 + plasma cells as well as CD8 + T cells. Scattered necrotic and regenerating muscle fibers with no specific findings for IgG4-RD (storiform fibrosis and obliterative phlebitis) were typical for PM. We diagnosed her condition as PM and treated her with 40 mg/day of prednisolone that decreased levels of muscle enzymes and improved muscle weakness. Conclusion: Our case indicated that PM could present with high serum IgG4 levels and IgG4 + plasma-cell infiltration, mimicking IgG4-RD. Although the mechanism of IgG4 elevation in such PM is unclear, our case highlights the necessity to recognize that high serum IgG4 levels and IgG4 + plasma-cell infiltration in organs are not specific for IgG4-RD.

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Simplified Disease Activity Index remission at month 6 is an independent predictor of functional and structural remissions at month 12 during abatacept treatment in patients with rheumatoid arthritis: A multi-center, prospective cohort study in Japan

Hayato Yamazaki, Fumio Hirano, Tsutomu Takeuchi, Koichi Amano, Jun Kikuchi, Mari Kihara, Waka Yokoyama, Takahiko Sugihara, Kenji Nagasaka, Hiroyuki Hagiyama, Yoshinori Nonomura, Ryoko Sakai, Michi Tanaka, Ryuji Koike, Toshihiro Nanki, Hitoshi Kohsaka, Nobuyuki Miyasaka, Masayoshi Harigai

MODERN RHEUMATOLOGY (TAYLOR & FRANCIS LTD) 27 ( 5 ) 787 - 794 2017

Accepted, ISSN 1439-7595

Objective: To evaluate association of clinical remission at month 6 with functional and structural remissions at month 12 during abatacept treatment in patients with rheumatoid arthritis (RA).
Methods: This 12-month prospective, multicenter cohort study enrolled 168 patients with RA who started abatacept. Outcomes were assessed using composite measures, quality of life indices, and the van der Heijde-modified total Sharp score (mTSS). The logistic regression analysis was applied to identify factors associated with outcomes and their odds ratios (OR) with 95% confidence interval (95% CI).
Results: At month 6 and 12, 21.4% and 26.2% of the patients achieved Simplified Disease Activity Index (SDAI) remission (SDAI < 3.3), and 40.6% and 41.7% achieved Health Assessment Questionnaire-Disability Index (HAQ-DI < 0.5) remission. Among 129 patients whose mTSS progression was evaluated at month 12, 83 (64.3%) achieved structural remission (DmTSS <= 0.5 for 12 months). SDAI remission at month 6 was identified as a significant predictor of both functional (OR, 3.732; 95% CI, 1.328-10.489) and structural remissions (OR, 4.301; 95% CI, 1.298-14.243) at month 12 after adjusting for covariates.
Conclusions: Aiming for SDAI remission at month 6 is an appropriate strategy to obtain good functional and structural outcomes at month 12.

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Corticosteroid-free treatment of tocilizumab monotherapy for microscopic polyangiitis: a single-arm, single-center, clinical trial

Ryota Sakai, Tsuneo Kondo, Jun Kikuchi, Akiko Shibata, Kentaro Chino, Ayumi Okuyama, Hirofumi Takei, Koichi Amano

Modern Rheumatology 26 ( 6 ) 900 - 907 2016.11

ISSN 1439-7595

Objectives: To assess the efficacy of tocilizumab (TCZ) monotherapy for the remission induction of microscopic polyangiitis (MPA) in a prospective single-arm, single-center, cohort, pilot study. Methods: Eligible patients were aged between 20 and 80 years and were newly diagnosed with MPA according to Watts’ classification algorithm. Seven patients received 8 mg/kg of intravenous TCZ fortnightly for the first 2 months (5 courses), and monthly for the next 10 months (10 courses). One year after TCZ monotherapy, the patients were followed-up without any treatment. The protocol did not permit the use corticosteroids or any other immunosuppressants. Complete remission (CR) was defined as the Birmingham Vasculitis Activity Score of 0 at two consecutive visits made at least a month apart. Results: CR was achieved in two of six patients (33.3%) at 6 months and three patients (50.0%) at 12 months. Two patients were withdrawn: one because of inefficacy at 6 weeks and the other because of flare at 6 months. One patient voluntarily withdrew after CR at 3 months. Four patients (66.7%) could be kept drug-free after 1 year of TCZ without relapse for 6–15 months at the last visit. Conclusion: TCZ monotherapy may be an alternative treatment strategy in some patients with MPA.

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Proportions of Circulating Follicular Helper T Cells and Complement Levels, White Blood Cell Counts, and Skin Manifestations in Patients with Active Systemic Lupus Erythematosus

Jun Kikuchi, Masaru Takeshita, Katsuya Suzuki, Yoshiaki Kassai, Takahiro Miyazaki, Tsutomu Takeuchi

ARTHRITIS & RHEUMATOLOGY (WILEY) 68 2016.10

Accepted, ISSN 2326-5191

Methotrexate-associated Intravascular Large B-cell Lymphoma in a Patient with Rheumatoid Arthritis

Kikuchi, J., Kaneko, Y., Kasahara, H., Emoto, K., Kubo, A., Okamoto, S. and Takeuchi, T.

Intern Med (JAPAN SOC INTERNAL MEDICINE) 55 ( 12 ) 1661 - 5 2016

Accepted, ISSN 1349-7235

Intravascular large B-cell lymphoma (IVLBCL) is a rare and clinically aggressive lymphoma with an unfavorable prognosis. We report the case of a 50-year-old woman who was diagnosed with IVLBCL during treatment with methotrexate (MTX) and biologic agents for rheumatoid arthritis. The symptoms showed partial improvement only after the cessation of both treatments. She subsequently received chemotherapy and achieved a complete remission and has remained free of recurrence for 2 years without any further treatment. We herein describe a rare case of IVLBCL which presented with the features of an MTX-associated lymphoproliferative disorder.

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Infliximab and etanercept have distinct actions but similar effects on cytokine profiles in rheumatoid arthritis

Masaru Takeshita, Katsuya Suzuki, Jun Kikuchi, Keisuke Izumi, Takahiko Kurasawa, Keiko Yoshimoto, Koichi Amano, Tsutomu Takeuchi

CYTOKINE (ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD) 75 ( 2 ) 222 - 227 2015.10

Accepted, ISSN 1043-4666

Objective: Pro-inflammatory cytokines, especially TNF alpha, play a central role in the pathogenesis of rheumatoid arthritis (RA). The available TNF inhibitors are only slightly different from one another in terms of clinical efficacy, at least at the group level, but their structures and modes of action are not identical. Infliximab (IFX) and etanercept (ETN) differ in their ability to induce antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, and in their ability to bind TNFO. The purpose of our study was to elucidate the different cytokine pathways through which these two drugs enact their clinical efficacy.
Methods: Serum from 44 RA patients treated with IFX and 24 patients treated with ETN was studied. All patients had been given these biologics at identical dosages and intervals for one year. The concentrations of 11 inflammatory cytokines and their receptors (IL-1 beta, IL-2, IL-6, IL-6R, IL-8, IL-10, IL-12, TNF alpha, TNF beta, IFN gamma, and GM-CSF) were measured at weeks 0, 22, and 54 using a high-sensitivity electro-chemiluminescence assay. Cytokine profiles were analyzed along with clinical efficacy.
Results: IL-6 was significantly decreased in the ETN + MTX and IFX + MTX groups, although not in the ETN-only group; this change was consistent with changes in disease activity. IFN gamma was gradually increased only in the non-remission subgroup of the IFX group, and not at all in the ETN group. TNF(3 increased after starting IFX regardless of clinical efficacy.
Conclusion: IL-6 inhibition is a pathway affected by both IFX and ETN. In addition, IFN gamma increase is a distinctive feature of the inefficacy of IFX. (C) 2015 Elsevier Ltd. All rights reserved.

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Peripheral blood CD4(+)CD25(+)CD127(low) regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: increase in regulatory T cells correlates with clinical response

Kikuchi, J., Hashizume, M., Kaneko, Y., Yoshimoto, K., Nishina, N. and Takeuchi, T.

Arthritis Res Ther (BIOMED CENTRAL LTD) 17 10 - 10 2015

Accepted, ISSN 1478-6362

INTRODUCTION: Tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, is clinically effective against rheumatoid arthritis (RA), and several reports have indicated how TCZ influences a number of mechanisms underlying RA pathogenesis. However, it is still unclear whether TCZ affects inflammatory cells in peripheral blood and whether any such changes are associated with clinical response. We evaluated associations between proportions of subsets of peripheral immune cells and clinical response in patients with RA treated with TCZ. METHODS: Thirty-nine consecutive patients with RA who started to receive TCZ as their first biologic between March 2010 and April 2012 were enrolled. The proportions of several subsets of peripheral cells with their levels of expression of differentiation markers, activation markers and costimulatory molecules were measured sequentially from baseline to week 52 by flow cytometry analysis. RESULTS: Clinical Disease Activity Index (CDAI) remission was achieved in 53.8% of patients at week 52 of TCZ therapy. The proportions of CD4(+)CD25(+)CD127(low) regulatory T cells (Treg) and HLA-DR(+) activated Treg cells significantly increased with TCZ therapy (P < 0.001 and P < 0.001, respectively), whereas proportions of CD3(+)CD4(+)CXCR3(-)CCR6(+)CD161(+) T helper 17 cells did not change over the 52 weeks. The proportions of CD20(+)CD27(+) memory B cells, HLA-DR(+)CD14(+) and CD69(+)CD14(+) activated monocytes, and CD16(+)CD14(+) monocytes significantly decreased (P < 0.001, P < 0.001, P < 0.001 and P < 0.001, respectively). Among them, only the change in Treg cells was inversely correlated with the change in CDAI score (rho = -0.40, P = 0.011). The most dynamic increase in Treg cells was observed in the CDAI remission group (P < 0.001). CONCLUSION: This study demonstrates that TCZ affected proportions of circulating immune cells in patients with RA. The proportion of Treg cells among CD4(+) cells correlated well with clinical response.

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Baseline levels of soluble interleukin-6 receptor predict clinical remission in patients with rheumatoid arthritis treated with tocilizumab: implications for molecular targeted therapy

Naoshi Nishina, Jun Kikuchi, Misato Hashizume, Keiko Yoshimoto, Hideto Kameda, Tsutomu Takeuchi

ANNALS OF THE RHEUMATIC DISEASES (BMJ PUBLISHING GROUP) 73 ( 5 ) 945 - U167 2014.05

Accepted, ISSN 0003-4967

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[Discussion meeting on rheumatoid arthritis: progress in diagnosis and treatment].

Takeuchi T, Atsumi T, Nagaoka S, Oribe M, Kikuchi J

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 101 ( 10 ) 2926 - 2942 2012.10

Accepted, ISSN 0021-5384

A Case of IgA-related Enteropathy Complicated with Gastrointestinal Bleeding and Progressive IgA Nephropathy: A Possible Variant Henoch-Schonlein Purpura?

Shoko Nakamura, Tadakazu Hisamatsu, Jun Kikuchi, Masayuki Adachi, Yoshiyuki Yamagishi, Hiroyuki Imaeda, Naoki Hosoe, Makoto Naganuma, Hirotoshi Ebinuma, Susumu Okamoto, Takanori Kanai, Haruhiko Ogata, Hironari Hanaoka, Yoshiaki Furuya, Yoshinaga Kawano, Kanako Bokuda, Hiroyuki Sasamura, Hiroshi Uchida, Takashi Endo, Akinori Hashiguchi, Kaori Kameyama, Makio Mukai, Toshifumi Hibi

INTERNAL MEDICINE (JAPAN SOC INTERNAL MEDICINE) 49 ( 16 ) 1755 - 1761 2010

Accepted, ISSN 0918-2918

Here, we report an adult patient with IgA-related enteropathy complicated with massive intestinal bleeding and acute renal failure, but without skin lesions. Surgical resection of the small intestine and steroid pulse therapy was performed. Histopathology revealed significant deposition of IgA and C3 in the small vessels of the intestine and the kidney mesangium. Although skin purpura was absent, the histopathology and clinical manifestations suggested that the pathophysiology was similar to Henoch-Schnlein purpura (HSP), implying IgA-related enteropathy as a subclass of HSP. Retrospective analysis indicates that terminal ileum lesions may be a poor prognostic indicator.

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