Kentaro Chino

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

Abstract 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 Two patients were withdrawn: one because of inefficacy at 6 weeks and the other because of flare at 6 months.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.

Corticosteroid- and cyclophosphamide-free treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis using tocilizumab

the 4 exhibited fi brinoid necrosis in the glomerular capillaries (Figure 1B). Immunofl uorescence and electron microscopy revealed no immune or electron-dense deposits. No fi ndings supporting systemic rheumatoid vasculitis such as hypocomplementemia or extremely high RF were observed. Therefore, we diagnosed the condition as ANCA-associated vasculitis (AAV) complicated by RA. Tocilizumab was initially started at 8 mg/kg/month for RA; after that, systemic symptoms such as fever abated markedly, and polyarthralgia diminished gradually. After 1 year of tocilizumab treatment, serum creatinine levels decreased from 101 to 80 μ mol/L (1.14 to 0.90 mg/dL; GFR MDRD , 62 mL/min/1.73 m 2 ) with no proteinuria. Serum MPO – ANCA and RF levels returned to normal, and repeated renal biopsies demonstrated histological remission according to the absence of active vasculitis. Mononeuritis multiplex improved according to a test of nerve conduction velocity. Interstitial pneumonia did not change after this treatment. Thus, we successfully treated a patient with AAV complicated by RA using tocilizumab without the use of corticosteroids or cyclophosphamide. Several reports have suggested that tocilizumab alleviates small-vessel vasculitis regardless of renal involvement [2 – 4]. On the other hand, tocilizumab-induced immune complex glomerulonephritis or leukocytoclastic vasculitis has been reported in cases of RA [5,6]. However, these factscould not be denied using tocilizumab against AAV. As there are several reports on D-penicillamine-induced AAV, there is a possibility of bucillamineinduced AAV in this case. However, there are no case reports of bucillamine-induced AAV in the literature, and only a few cases of hypersensitivity vasculitis by bucillamine are described in the investigator ’ s brochure. There is a report that ANCA seroconversion could not be induced by penicillamine [7]. In addition, in this case, AAV developed after the cessation of bucillamine. Therefore, it is unlikely that bucillamine might cause AAV in this case. Rituximab may also be a suitable option for systemic vasculitis with RA [8]. However, concomitant corticosteroids are necessary with rituximab for remission induction therapy. Tocilizumab has strong anti-infl ammatory eff ects and may be an alternative to corticosteroids for the treatment of systemic vasculitis. Moreover, tocilizumab normalized serum MPO – ANCA and RF levels in our Mod Rheumatol, 2015; 25(5): 810–811

Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head

Idiopathic osteonecrosis of the femoral head (IONFH) is an ischemic disorder that causes bone necrosis of the femoral head, resulting in hip joint dysfunction. IONFH is a polygenic disease and steroid and alcohol have already known to increase its risk; however, the mechanism of IONFH remains to be elucidated. We performed a genome-wide association study using ~60,000 subjects and found two novel loci on chromosome 20q12 and 12q24. Big data analyses identified LINC01370 as a candidate susceptibility gene in the 20q12 locus. Stratified analysis by IONFH risk factors suggested that the 12q24 locus was associated with IONFH through drinking capacity. Our findings would shed new light on pathophysiology of IONFH.

Successful treatment with tocilizumab monotherapy for Takayasu arteritis developing during infliximab therapy in a patient with ulcerative colitis

Abstract A 23-year-old female patient with ulcerative colitis (UC) who had been successfully treated with infliximab (IFX) plus 5-aminosalicylated acid (5-ASA) developed Takayasu arteritis (TAK). She refused to take glucocorticoids to treat TAK. IFX was discontinued, and 8 mg/kg of tocilizumab (TCZ) was added to 5-ASA. Her symptoms such as fever and chest pain disappeared within a week along with serum CRP. TCZ was administered every 2 weeks for 2 months and monthly thereafter. After 1-year treatment of TCZ monotherapy, arterial wall thickening also improved. In addition, UC has been in remission without any gastrointestinal symptoms. TCZ monotherapy is effective for TAK and might not compromise UC.

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

Abstract 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 >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.

THU0576 Tocilizumab Mono-Therapy for Polymyalgia Rheumatica ∼ A Single-Center, Open, Single-Arm Trial

Background Polymyalgia rheumatica (PMR) is a chronic inflammatory rheumatic disease that mainly affects the elderly. Corticosteroids (CSs) are a definite mainstay for the treatment of PMR; however, their use is associated with severe, serious clinical complications, such as osteoporotic fractures, diabetes, hyperlipidemia, cardio-cerebral vascular events, and glaucoma. Therefore, CS-free treatment strategies may be necessary for some patients with PMR. Interleukin-6 (IL-6) may be involved in the pathogenesis of PMR; furthermore, some case reports have already shown the efficacy of tocilizumab (TCZ), an anti-IL-6 receptor antibody, in the treatment of patients with PMR who had been intolerant or refractory to glucocorticoids [1, 2, 3]. Objectives To assess the efficacy and safety of TCZ monotherapy for PMR Methods Thirteen PMR patients (3 males, 10 females) diagnosed by the 2012 ACR/EULAR classification criteria between Jan 2013 and Feb 2015 were enrolled after obtaining a written informed consent. TCZ (8 mg/kg) was administered biweekly for the first 2 months (5 infusions) and every 4 weeks for subsequent 24 weeks. ESR, CRP, visual analog scale (VAS) assessment of the patients global health, and PMR activity score were prospectively measured every 4 weeks and were evaluated at week 24 and 52. Remission was defined as a PMR activity score less than 1.5 as proposed by Leeb [4]. Results Baseline patient characteristics revealed various comorbidities in 11 of the patients; hypertension in seven, hyperlipidemia in five, diabetes mellitus in three, osteoporotic vertebral fractures in two, history of angina pectoris in one, history of brain infarction in one, history of hematemesis due to NSAID ulcer in one, and glaucoma in one patient. At week 24, nine patients achieved low disease activity as per the PMR activity score criteria, including three in remission. Two patients discontinued TCZ because of no response: one at week 6 and the other at week 16. Two patients discontinued TCZ due to adverse events [Editor 1]; pulmonary infiltrate at week 8, pemphigoid at week 50. The nine remaining patients achieved remission at week 52. There were no serious adverse events [Editor 2] except for pemphigoid during the 52-week treatment period. Conclusions TCZ monotherapy was effective in most (nine out of 13 [Editor 1]) PMR patients, although the response was not as rapid as that to CSs. TCZ monotherapy may be a good alternative therapy to CSs for the elderly with various comorbidities. References Unizony S, et al.: Arthritis Care Res 2012; 64(11):1720–1729 Macchioni P, et al.: Aemin Arthritis Rheum 2013; 43(1): 113–118 Toussirot E, et al.: J Rheumatol 2016 43(1): 249–251 Leeb BF, et al.: Arthritis Rheum 2007; 57(5): 810–815 Disclosure of Interest K. Chino: None declared, A. Shibata: None declared, A. Okuyama: None declared, T. Kondo: None declared, J. Kikuchi: None declared, R. Sakai: None declared, H. Takei: None declared, K. Amano Grant/research support from: Chugai Pharmaceutical Co. Ltd.

AB0530 Efficacy and Safety of Multi-Target Therapy Using a Combination of Cyclophosphamide and Tacrolimus in Patients with Refractory Lupus Nephritis: A Prospective, Single-Arm, Open-Label Study of 13 Patients

Background Pulsed cyclophosphamide (pCYC) for lupus nephritis (LN) has limited effects in some cases; mycophenolate mofetil is an off-label pharmaceutical agent in Japan. Objectives To assess the effectiveness of multi-target therapy with pCYC and tacrolimus (Tac) for treating LN, including refractory cases. Methods We have done a prospective, single-arm, open-label study at our center (UMIN4893). Thirteen patients with active LN were enrolled. Prednisolone was started at 1 mg/ kg/day, aiming to reduce the dose to 10 mg/day after 6 months. Intravenous cyclophosphamide was administered as per the Euro-Lupus protocol (500 mg biweekly for 3 months). The trough concentration of Tac was adjusted to 5–10 ng/ml as per National Health Insurance. Complete remission (CR) was defined as a spot urine protein/creatinine (UPCR) ratio of <0.5 g/gCr and normal eGFR or eGFR improvement as per EULAR/ERA-EDTA recommendations and KDIGO guidelines. Results The mean age was 41.5 years (male:female =2:11); UPCR, 3.4 g/gCr; serum creatinine, 1.00 mg/dl; C3, 44.8 mg/dl (90.0–140.0 mg/dl); and C4, 5.7 mg/dl (18.0–30.0 mg/dl). One, eight and three patients belonged to Classes III, IV, and IV + V, respectively, and one had no data. Eleven out of the 13 patients completed the treatment protocol; 2 patients withdrew. The CR at 6 months was 69.2% (n=9/13). Side effects, including infections, did not increase as compared to conventional therapy with pCYC, except a transient increase in serum creatinine with Tac. Conclusions Multi-target therapy such as pCYC and Tac can be a therapeutic option for refractory LN. Disclosure of Interest R. Sakai: None declared, A. Shibata: None declared, K. Chino: None declared, T. Kondo: None declared, A. Okuyama: None declared, H. Takei: None declared, K. Amano Grant/research support from: Astellas, Chugai, Pfizer, Tanabe-Mitsubishi, Consultant for: Zenyaku Kogyo, Paid instructor for: Chugai, Pfizer, Santen, Tanabe-Mitsubishi, Speakers bureau: AbbVie, Actellion, Astellas, Bristol-Myers-Squibb, Chugai, Diichi-Sankyo, Eisai, Pfizer, Tanabe-Mitsubishi

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