Tsuneo Kondo

Severe acute thrombotic exacerbation in two cases with anti-phospholipid syndrome after retreatment with rituximab in phase I/II clinical trial for refractory systemic lupus erythematosus

treatment of early oestrogen-receptor-positive breast cancer. 2006. 2 Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003;348:2431–42. 3 Body JJ, Bergmann P, Boonen S et al. Management of cancer treatment-induced bone loss in early breast and prostate cancer – a consensus paper of the Belgian Bone Club. Osteoporos Int 2007;18:1439–50. 4 McCloskey E. Effects of third-generation aromatase inhibitors on bone. Eur J Cancer 2006;42:1044–51. 5 Hillner BE, Ingle JN, Chlebowski RT et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003;21:4042–57. 6 Reid DM et al.; UK Expert Group. The 12th Conference on Osteoporosis. National Osteoporosis Society, 2007.

CD3 ζ defects in systemic lupus erythematosus.

The prototype autoimmune disease, systemic lupus erythematosus (SLE), has been known to be associated with deficiency of ζ chain, a component of the T-cell receptor–CD3 complex. Comprehensive analysis has shown that expression of the CD3 ζ chain is attenuated or absent in over half of SLE patients. Furthermore, aberrant transcripts of the CD3 ζ chain, including spliced variants lacking exon 7 or having a short 3′-untranslated region, have been detected in SLE T cells. Although attenuated expression of the CD3 ζ chain is also observed in cancer patients, infections and other autoimmune diseases, sustained attenuation of the CD3 ζ expression accompanied with aberrant transcripts are only observed in SLE. In this study, the authors review the unique features of CD3 ζ defects observed in SLE and discuss the molecular basis of the defects by recent findings in animal models, single-nucleotide polymorphisms and genome-wide association studies.

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

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.

Era of steroid sparing in the management of immune-mediated inflammatory diseases

Abstract Glucocorticoids (GCs) have played a pivotal role in the treatment of immune-mediated inflammatory diseases (IMIDs) for a long time. However, GCs also incur a significant risk of undesirable adverse events such as Cushingoid changes, osteoporosis, glaucoma and metabolic abnormalities such as diabetes and hypercholesterolemia, which may lead to life-threatening cerebrovascular and cardiovascular events. High-dose GCs may also cause mental disorders and osteonecrosis. Recently, new therapeutic strategies have been developed to reduce the dose or even eliminate the need for GCs; multi-target drug therapies for systemic lupus erythematosus (SLE), biological agents such as tocilizumab and rituximab for systemic vasculitis, and anakinra and tocilizumab for adult-onset still’s disease. Therefore, the era of GC-sparing or GC-free treatment for IMIDs is on the horizon.

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

AB0143 Identification of Aberrant Expression of 14-3-3 Zeta by Multiple-Quantitative Validation Methods in Patients with Rheumatoid Arthritis

Background The 14-3-3 proteins family consists of biologically essential protein kinases with multiple functions, such as in cell proliferation, differentiation, and cell cycle and functional regulation. It is evolutionally conserved and consists of 7 isoforms. Dysregulation of human 14-3-3 has been reported in several diseases such as neurologic disorders and cancers. Although aberrant up-regulation of 14-3-3 eta has been recently discovered in synovial fluid and serum in patients with rheumatoid arthritis (RA), little is known about the role of other family proteins. More interestingly, recent research showed that these proteins, including 14-3-3 zeta (YWHAZ), are activation-induced cytidine deaminase binding factors that work as essential elements in immunoglobulin class-switch DNA recombination [1]. Objectives To validate the presence of 14-3-3 zeta in blood and clarify its immuno-pathological role in RA Methods Peripheral blood samples obtained from untreated or methotrexate-naïve active RA patients who met either the 1987 and/or 2010 classification criteria and healthy individuals (HI) were enrolled. Total RNA was purified and relative mRNA expression was measured by quantitative PCR. Protein expression in peripheral mononuclear cells (PBMC) was evaluated by Western blotting. Further, intracellular expression was analyzed in a subpopulation by flow cytometry, and serum protein levels were measured by ELISA. Statistical correlation of expression with clinical indicators were analyzed. Results In whole blood, expression of 14-3-3 zeta mRNA in RA patients (n=30) was significantly (p=9.0E-07) up-regulated compared to HI (n=27). In PBMC also, Western blotting showed up-regulation of 14-3-3 zeta in RA patients (n=9), to a comparable degree to that of mRNA. On intracellular staining by flow cytometry in 41 RA patients and 13 HI, expression in whole blood from RA patients tended to be increased (average 1.7 times) in the percentage of positive cells (p=0.07). Interestingly, further subpopulation analysis showed a tendency to increased expression in CD20+ B cells only (p=0.07), but no increase in CD14+ or CD8+ cells. With regard to serum concentrations, the proportion of RA patients with a high concentration of 14-3-3 zeta (n=31) was higher than that of HI (n=13), while no correlation was seen with either titers of rheumatoid factors or anti-citrulinated antibodies, unlike the case with 14-3-3 eta. Conclusions We established different quantitation methods for 14-3-3 zeta in peripheral blood. Analysis showed up-regulation of 14-3-3 zeta in RA patients compared with HI. Aberrant expression of 14-3-3 proteins family, including eta and zeta, may link to B cell abnormalities in RA. References Zhenming Xu et.al. Nat Struct Mol Biol. 17(9):1124-35, 2010 Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3949