Age and High-dose Oral Glucocorticoid Therapy Increase the Relative Risk of Cytomegalovirus Antigenemia in Patients with Systemic Autoimune Diseases

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1 CMV infection have ben established 4)-7). CMV infection 16 Original ljtok 川山 eduniv1 85 (6) 0~07 (015) Age and High-dose Oral Glucocorticoid Therapy Increase the Relative Risk of Cytomegalovirus Antigenemia in Patients Systemic Autoimune Diseases Yasushi Toshiko KA W AGUCHI KONISHI 1, Eichi, Toshimi T ANAKA KIMURA, Hisae ICHIDA, 1 and Hisashi YAMANAKA 1 Department of Pharmacy, Tokyo Women's Medical University Hospital Institute ofrheumatology, Tokyo Women's Medical University (Acepted September 18, 015) Purpose: Cytomegalovirus (CMV) infection comonly ocurs in patients undergoing imunosupresive therapy; however, the incidence has not ben wel documented. We investigated the incidence and susceptibility factors of CMV antigenemia in imunosupresed patients in daily clinical care setings for the management of systemic autoimune diseases. Methods: Autoimune patients who were hospitalized in Tokyo Women's Medical University Hospital from April 010 to March 01, for CMV infection, defined by positivity the monoclonal antibody CτHRP (CMV antigenemia), were retrospectively investigated acording to types of autoimune disease and imunosupresslve treatment strategles. Resu t 1 : s One-hundred and thirty cases (30 male, 10 female) were included in this study. Patients systemic lupus erythematosus n ( = 37), systemic sclerosis (n = ), polymyositis/ dermatomyositis (n = 1), rheumatoid arthritis vasculitis (n = 3) and vasculitis syndrome (n = 15), and others (Sjogren's syndrome (n = ) 1, adultonset Stils disease (n = ) 1, eosinophilic fascitis (n = ) 1 were enroled. The patients received various imunosuppresive treatments, including glucocorticoid (GC) oral therapy 三 ( 40 mg/ day)(n = 30), GC pulse therapy (n = 30), and/or intravenous cyclophosphamide pulse therapy n ( = 70) % of patients were positive for C7 HRP reactivity, and this varied acording to autoimune disease and treatment strategy. Multivariate analyses revealed that higher age and maximum dose of oral GC were the two factors significantly asociated increased risk of CMV infection, while neither autoimune disease diagnosis nor treatment strategy was a signifi 幽 cant factor. Conclusion: Higher age and high-dose oral GC therapy were asociated increased risk of CMV infection irespective of autoimune disease diagnosis or treatment strategy. Key W ords: cytomegalovirus, systemic autoimune disease, imunosupresive therapy, risk factor, glucocorticoids Introduction Cytomegalovirus (CMV) s i one of the major causes of oportunistic infection after organ transplantation ト 3),and has ben extensively investigated. As a result, guidelines for the management of s i also a major isue in patients systemic autoimune diseases who have ben treated imunosupresive drugs. Along recent advances in imunosupresive therapy, patients Medical 図 : Eichi Tanaka Institute of Rheumatology, Tokyo Women's University, 10- Kawada-cho, Shinjuku-ku, Tokyo, J apan e-tanaka@twmu.ac.jp -0-

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3 Diagnosis vasculitis 18 Table 1 Characteristics of the patients stratified by imunosupresive therapy Mean:!:SD variable GC oral tmhegr/adpay y) (PSL ミ 40 GC pulse therapy IVCY therapy n=30 n=30 n= Gender (male/female) [female %] 8/ [73%] 6/4 [80%] 16/54 [7%] Age (years) 士 : 6! : :!: Number of lymphocytes 1 ( μl) 1,1 04:!: 497, 1 17:!: 796 1,1 95:!: 670 Hemoglobin (g/dl) 11. :! : :! : 11. :! : 9 Platelet (x 10 4 /μl) 6.9:!: :!: 4.8:!:9.3 C-reactive protein (mg/ ) l d. 1 8 士 :!:6.. : 1! : 5 Imunoglobulin G (mg/dl) 1,76:!:683, 1 47:!:54 1,4 37:!: 61 maximum dosage of GC (mg/day) 49.7:!:9.3 土 38.:!: This table shows the patients' characteristics stratified by imunosupresive therapy. GC, glucocorticoid; PSL, prednisolone; IVCY, intravenous cyclophosphamide pulse therapy. Table Cytomegalovirus infection rate Mean:!: SD (median) [minimum-maximum] C7-HRP positive (%) The days from imunosupresive therapy to CMV infection (day) SLE Sc PM/DM RA Vasculitis syndrome :! : (31) 7 [ 一 74] 37.8 土 19.9 (30) [0-7l] 39 1 :.! : 5.3 (8) [14-10] 4.8 士 14.9 (. 1 ) 5 4 [ 一向 4.6:!: 15.9 (40) [15-6] p= (χ test) Imunosupresive therapy C7-HRP positive (%) oral GC therapy (PSL~40 mg/day) GC pulse therapy IVCY therapy p=0.7 (χ test) Time from imunosupresive therapy initiation to CMV infection (day) 3.6:!: 13.3 (8.5) [14 一向 4.8:!: 14.0 (5) [4-57] 35.5:!: 1. 3 (3.5) [7-10] table rates systemic This shows C7-HRP positive rate (%) and days from imunosupresive therapy to CMV infection based on systemic autoimune disease diagnosis or treatment strategy. The of CMV infection were not significant i d 旺 erences among autoimune diseases or treatment strategy. CMV, cytomegalovirus; SLE, systemic lupus erythematosus; Sc, systemic sclerosis; PM/DM, polymyositis/dermatomyositis; R, A rheumatoid arthritis; GC, glucocorticoid; IVCY, intravenous cyclophosphamide pulse therapy.. 1 Patient profile Results One hundred and thirty cases (30 male, 10 female), mean age 5.3 t : 18.0 (range: 18-8) years old, were investigated in this study. Patient diagnoses included SLE, Sc, PM/DM, RA vasculitis, vasculitis syndrome, Sjogren's syndrome, adult-onset Stils disease and eosinophilic fascitis. Patient characterizations based on the treatment strategy were analyzed and listed in Table. 1 Patients who received GC pulse therapy were older and had a higher CRP leve. l The maximum GC dose was highest in the oral GC group.. CMV infection The incidence of CMV infection was investigated based on autoimune disease diagnosis and treatment strategy. C7-HRP positivity was detected in % of patients after 4 to 10 days (median -04 ー

4 14l 9 1 Table 3 Risk factors for cytomegalovirus infection using multivariate analyses Explanatory variable OR (95%C1) p value Diagnosis * (Model ) 1 Age (year) ( ) Maximum dosage f o GC (mg/day) ( ) SLE s v ( Sc) ( ) 0.84 SLE s v ( PM/DM) ( ) SLE s v ( RA vasculitis) 4.89 ( ) 0. 1 SLE s v ( vasculitis) ( ) Sc s v ( PM/DM). 1 8 ( ) 0.57 Sc s v ( RA vasculitis) 6.08 ( ) Sc s v ( vasculitis).06 ( ) PM/DM s v ( RA vasculitis) 3.37 ( ) PM/DM s v ( vasculitis) 4 ( ) 0.83 RA vasculitis s v ( vasculitis) ( ) munosupresive therapy* (Mode1) Age (year) ( - 0. ) Maximum dosage f o GC (mg/day) ( ) GC oral therapy s v ( GC pulse therapy) ( ) GC oral therapy s v ( 1VCY therapy) ( ) GC pulse therapy s v ( 1VCY therapy) ( ) both uding dose model Gender This table shows the risk factors r o f CMV infection, which were analyzed by types f o multivariate analyses, n i 1 c uding the disease diagnosis (Model ) 1 r o the treatment strategy (Model ) s a explanatory variables. n 1 models, only two factors, n i 1 c age and maximum f o oral glucocorticoid were significantly asociated an increased risk f o CMV infection. *1n which,, BM1, the number f o lymphocytes, hemoglobin, platelet, albumin, and LDH were not significant factors. GC, glucocorticoid; SLE, systemic lupus erythematosus; Sc, systemic sc 1 erosis; PM/DM, polymyositis/dermatomyositis; RA, rheumatoid arthritis; 1VCY, intravenous cy 1 c ophosphamide pulse therapy. 9.5 days) from the start of imunosupresive therapy, and no significant diference was noted among the diseases (Table. ) Regarding the treatment strategy, glucocorticoid pulse therapy and IVCY resulted in higher rates of CMV infection, but no statisticaly significant diferences were noted (Table. ). 3 Risk factor for CMV infection Risk factors for CMV infection were analyzed by univalent and multivariate methods. First, we conducted a univalent analysis and found that CMV infection was significantly asociated older age (ods ratio [OR]:. 1 04, 95 % confidence intervals [95% CI]: , p< 0.01), lower hemoglobin (OR: 0.84,95% CI: , p = 0.04), lower platelets (OR: 0.96, 95% CI: , p = 0.03), lower serum albu- min level (OR: 0.54, 95% CI: , p = 0.0), higher serum LDH level (OR:. 1 0,95% CI: , p< 0.01), and higher maximum dose of oral GC (OR:. 1 06,95% CI: , p<o.ol). Based on the results of the univalent analysis, we conducted a multivariate analysis concerning two models, including the disease diagnosis (Model1) or the treatment strategy (Model ) as explanatory variables (Table. ) 3 In both models, only two factors, including age (OR:. 1 07, 95% CI: , p < 0.01, and OR:. 1 06, 95 % CI: , p < 0.0, 1 in Model 1 and, respectively) and maximum dose of oral glucocorticoid (OR:. 1 09,95% CI: , p< 0.0, 1 and O R:. 1 09, 95 % CI: , p< 0.0, 1 in Model 1 and, respectively) were significantly asociated an increased risk of CMV infection (Table 3). None of the other factors demonstrated to be significantly asociated CMV infection in our univalent analyses were significantly asociated CMV infection in our multivariate analyses. Discusion In this retrospective analysis, we demonstrated that CMV infection s i comon folowing imunosupresive therapy for systemic autoimune diseases, and determined that higher age and higher doses of oral glucocorticoid were asociated increased risk of CMV infection. These findings are consistent previous reports 引 ) 4) 5 1 Although higher age was a comon risk factor for CMV infection in patients systemic autoimune disease, glucocorticoid treatment s i controversia. l Takizawa et l a reported age greater than 59.3 years and pulsed methylprednisolone (mpsl) therapy were risk factors for porer outcome for CMV infection 9. ) Hanaoka et l a also reported that the risk factors for CMV infection were old age (> 65 years) and high-dose oral glucocorticoids (over 50 mg/ day) or pulsed mpsl therapyi5), whereas Yamashita et l a reported that only advanced age (>70 years) was a risk factor for CMV infection in patients systemic autoimune disease. In this study, the of CMV antigenemia did not vary acros diferent types of systemic autoimune disease. However, some studies have sugested that systemic lupus risk erythematosus (SLE) and polymyositis / dermato- -05-

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6 Japanese) 1 after Society after Society Hematopoietic apanese) evaluation complicated patient review. lupus 5) The Clinical practice guidelines for the cytomegalovirus infection renal transplantation by J apanese for Clinical Renal Transplantation in 01 n i ( 6) Guidelines for cytomegalovirus infection Hematopoietic cell Transplantation (Second edition) by The J apan for Cel Transplantation n i ( J 7) Koton CN, Kumar D, Caliendo AM et al : International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation 89: , 010 8) Y oda Y, Hanaoka R, Ide H et : l a Clinical of patients inflamatory autoimune diseases by cytomegalovirus antigenemia. Mod Rheumatol16: , 06 9) Takizawa Y, Inokuma S, Tanaka Y et : l a Clinical characteristics of cytomegalovirus infection in rheumatic diseases: multicentre survey in a large population. Rheumatology (Oxford) ,08 10) Eisenstein EM, Wolf DG: Cytomegalovirus infection in pediatric rheumatic diseases: a Pediatr Rheumatol Online J : ) Ramos-Casals M, Cuadrado MJ, Alba P et : al Acute viral infections in patients systemic erythematosus: description of 3 cases and re- lupus: Ishi Incidence vascular prognosis elevated view of the literature. Medicine (Baltimore) 87: ,08 1) Sekigawa 1, Nawata M, Seta N et : 1 a Cytomegalovirus infection in patients systemic lupus erythematosus. Clin Exp Rheumatol 0: , 0 13) Tsai WP, Chen MH, Le MH et : l a Cytomegalovirus infection causes morbidity and mortality in patients autoimune diseases, particularly systemic in a Chinese population in Taiwan. Rheumatol Int 3: , 01 14) Yamashita M, T, Iwama N et : l a and clinical features of cytomegalovirus infection diagnosed by cytomegalovirus p 65 antigenemia asay during high dose corticosteroid therapy for colagen diseases. Clin Exp Rheumatol 4: ,06 15) Hanaoka R, Kurasawa K, Maezawa R et : l a Reactivation of cytomegalovirus predicts por in patients on mtenslve imunosupresive treatment for colagen-vascular diseases. Mod Rheumato1:438-45,01 16) Fujimoto D, Matsushima A, Nagao M et : l a Risk factors asociated blod cytomegalovirus p65 antigen levels in patients autoimmune diseases. Mod Rheumato13: , 013 謬原病患者に対する免疫抑制療法とサイトメガロウイルス C7 HRP 抗原検査陽性例に対する検討 1 東京女子医科大学病院薬剤部 東京女子医科大学附属膝原病リウマチ痛風センター ニシトシコタナカエイイチイチダヒサエ小西寿子 1 田中栄一 市田久恵 ヤスシキムラトシミヤマナカヒサシ川口鎮司 木村利美 1 山中寿 目的 自己免疫疾患患者に対して免疫抑制療法を行った場合にサイトメガロウイルス (CMV) 感染を生じるこ とは稀ではない. 本研究は日常診療において免疫抑制療法を受けた自己免疫疾患患者における CMV 感染 ( 症状を 呈し組織から CMV が検出される CMV 感染症とは異なる ) の現状を明らかにする. [ 方法 J 010 年 4 月 1 日 ~ 01 年 3 月 31 日に東京女子医科大学病院リウマチ科に入院し 1 グルココルチコイド (GC) 経口療法 (PSL 孟 40 mg/ 日 ), GC パルス療法,3 シクロホスフアミド静注療法 (IVCY) の治療を行い, 治療開始後に抗原血症検査 (C7-HRP) が施行された患者に対し後ろ向きに自己免疫疾患別, 免疫抑制療法別の CMV 感染率を算出し, 多変量一 解析にて CMV 感染のリスク因子を検討した. [ 結果 対象患者 130 例 ( 男性 30, 女性 10) の平均年齢は 5.3 t : 18.0 歳で, 疾患別には全身性エリテマトーデス (n = 37), 全身性強皮症 (n = ), 多発性筋炎 皮膚筋炎 (n = ), 1 悪性関節リウマチ (n=3), 血管炎 (n = 15), その他 (n=3) の症例であり, 免疫抑制療法別には GC 経口療法 (PSL 註 40 mg) (n = 30), GC パルス療法 (n = 30), IVCY 療法 (n = 70) であった. C7 HRP 陽性率は, 疾患別また は免疫抑制療法別に.7~46.7% であり, 治療開始から CMV 陽性までの期間は 4~10 日 ( 中央値 9.5 日 ) であっ た多変量解析において, 加齢および GC 最大投与量が有意な CMV 感染のリスク因子であったが, 各疾患や免疫 抑制療法の違いは有意なリスク因子ではなかった. [ 結語 免疫抑制療法の内容や自己免疫疾患の種類に関わら ず, 加齢および GC 最大投与量が CMV 感染の有意なリスク因子であった -07-