Eiko Nishi

The efficacy of mizoribine for the treatment of rheumatoid arthritis and its correlation with renal function.

Abstract Objectives. To evaluate the correlation between the efficacy of mizoribine (MZR) and the factors that might effect MZR concentration: renal function and dosage and administration of MZR in patients with rheumatoid arthritis (RA). Methods. The efficacy of MZR treatment was prospectively evaluated in 97 RA regardless of dosage, at the 14 participated institutions. The Disease Activity Score 28-CRP3 was used to assess RA activity. The renal function was evaluated based on the serum creatinine and serum cystatin-C (Cys-C). The patients were followed up for 24 weeks. Results. The patients with a mean age 66.2 years included 18 male. The renal function assessment showed increased creatinine in 16.4% of patients and increased Cys-C in 54.5%, suggesting the higher sensitivity of Cys-C to detect impaired renal function than creatinine. In patients with good or moderate response according to the European League against Rheumatism classification criteria, the Cys-C was significantly higher compared with those with no response. MZR treatment was significantly more effective in patients with an arithmetic product of the single MZR dose used and Cys-C of 179 or more. Conclusions. The efficacy of MZR may increase in proportion to its single dose, or increased Cys-C level in patients with impaired renal function.

AB0497 The Euro-Lupus Protocol plus Tacrolimus for Lupus Nephritis: Potentiality of Multi-Target Therapy

Background Multi-target therapy using two immunosuppressive drugs with different mechanism of action such as mycophenolate mofetil and tacrolimus (Tac) for lupus nephritis (LN) 1 seems to be a promising treatment strategy. On the other hand, we reported a case of LN with class IV plus V unresponsive to cyclophosphamide (CY), which was successfully treated with the addition of Tac 2. Objectives To assess the effectiveness of combination therapy with CY and Tac for class III and IV (or III/IV plus V) LN as a remission induction therapy and to discuss the potentiality of this multi-target therapy by reference to renal pathological findings. Methods We evaluated 13 patients with active LN who received renal biopsy at Saitama Medical Center between January 2007 and December 2012. The complete renal remission was defined as the spot urine protein/creatinine ratio <0.5g/gCr or urine protein (±)/(−) values in urinalysis and normal eGFR or improvement of eGFR according to the EULAR/ERA-EDTA recommendation. Renal pathological findings were assessed according to the 2003 ISN/RPS classification for LN. Activity and chronicity were evaluated by NIH semiquantitative histologic scoring system. Results All cases were class IV. Six cases had membranous nephropathy (Class IV + V). CY was initiated as a remission induction therapy with 500mg/biweekly for three months (the Euro-Lupus protocol). Starting dose of prednisolone (PSL) was 1mg/kg/day. Methylprednisolone pulse therapy was not used to avoid the increase of cumulative steroids dose. Seven out of 13 cases received multi-target therapy with Tac (CY + Tac group). In the other 6 cases, Tac (n=1) or azathioprine (n=4) was prescribed as a maintenance therapy after CY (CY-IS group). The average of cumulative steroids at 6 months was 4093.3mg in CY + Tac group and 3644.8mg in CY-IS group (p=0.84). The average of daily oral PSL at 6 months was 13.0mg in CY + Tac group and 12.5mg in CY-IS group (p=0.63). The complete remission rate at 12 months was 85.7% in CY + Tac group and 66.7% in CY-IS group (p=0.41). Although chronicity was observed more commonly in CY + Tac group (p=0.032), the remission rate in patients with chronicity was 85.7% in CY + Tac group and 33.3% in CY-IS group (p=0.097). In CY + Tac group, side effects including infections were not increased as compared to CY-IS group. Although transient increase of serum creatinine was observed in two cases in CY + Tac group, renal function recovered after the dose reduction of Tac. Conclusions This retrospective study shows that multi-target therapy such as the Euro-Lupus protocol plus Tac may be effective for refractory LN with chronicity in renal pathological findings. Prospective cohort studies should be conducted to detect the efficacy and safety of multi-target therapy for active and chronic LN in the future. References Bao H, Liu Z-H, Xie H-L, Hu W-X, Zhang H-T, Li L-S. Successful treatment of class V+IV lupus nephritis with multitarget therapy. J Am Soc Nephrol 2008;19(10):2001-10. Kurasawa T, Nagasawa H, Nishi E, Takei H, Okuyama A, Kondo T, et al. Successful treatment of class IV+V lupus nephritis with combination therapy of high-dose corticosteroids, tacrolimus and intravenous cyclophosphamide. Intern Med 2013;52(10):1125-30. Disclosure of Interest R. Sakai: None declared, A. Shibata: None declared, K. Chino: None declared, A. Okuyama: None declared, T. Kondo: None declared, E. Nishi: None declared, H. Takei: None declared, H. Nagasawa: None declared, K. Amano Grant/research support: Astellas Pharma Inc. and Chugai Pharmaceutical Co., Ltd. DOI 10.1136/annrheumdis-2014-eular.4247

AB0209 Retrospective analysis of rheumatoid arthritis patients complicated with mtx-related lymphoproliferative diseases

Background Methotrexate (MTX) is the anchor drug in the management of rheumatoid arthritis (RA) in the world. In Japan, maximal dose of weekly MTX was increased up to 16 mg/week from 8 mg/week in 2011. Although RA disease activity has been controlled much better with higher dose and longer duration of MTX therapy, there are increasing reports of MTX-related lymphoproliferative diseases (MTX-LPD) especially in Japan. Objectives To evaluate the clinical characteristics of the RA patients who developed MTX-LPD. Methods A retrospective study was done to review the medical records of 39 patients (14 men and 25 women) with MTX-LPD in our institute. Results Baseline characteristics of 39 patients at the diagnosis of MTX-LPD were following (average); age 64.3, RA disease duration 11.4 years, serum CRP 7.5 mg/dL, serum MMP-3 value 314.5 ng/dL, MTX dose 7.8 mg/w, MTX treatment period 4.8 years. The pathological diagnosis; 17 diffuse large B cell,5 Hodgkin, and 3 follicular lymphoma. EBV was detected in 10 of 31 cases. MTX was stopped soon after the diagnosis of MTX-LPD in all but one patient who was very active RA and showed no aggravation of LPD. After MTX cessation, 16 patients needed chemotherapy for LPD. LPD resolved spontaneously in the other 22 patients, but DMARDs including biologics were prescribed later for RA flare and 11 developed LPD again. There were no significant difference of the prescription with or without LPD relapse. Among 8 patients who died, most of them received chemotherapy. Conclusions MTX-LPD in RA developed more frequently in male patients who had long MTX treatment period and high CRP and MMP-3. Some of them had grave prognosis despite chemotherapy after MTX was withdrawn. In patients taking MTX for a long time with longstanding active disease may have risk of MTX-LPD. References Hoshida Y, et al.: Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication. J Rheumatol. 2007 Feb;34(2):322-31 Tokuhira M, et al.: Clinicopathological analyses in patients with other iatrogenic immunodeficiency-associated lymphoproliferative diseases and rheumatoid arthritis. Leuk Lymphoma. 2012 Apr;53(4):616-23 Acknowledgements We are very thankful to Michihide Tokuhira, Associate Professor of hematology in our institute, for his terrific advice for histological and hematological investigation of LPD. Disclosure of Interest None Declared