Naoshi Nishina

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

Interleukin-6 (IL-6) is a monomeric protein that binds to either soluble or membrane-bound IL-6 receptors (IL-6R)1 ,2 Tocilizumab, a humanised anti-IL-6R monoclonal antibody, binds to soluble IL-6R (sIL-6R) and membrane-bound IL-6R, blocking signal transduction pathways through competitive inhibition of IL-6 binding.3 We have previously demonstrated that baseline plasma tumour necrosis factor (TNF) levels are associated with the clinical response to infliximab, anti-TNF monoclonal antibody binding to soluble and membrane-bound TNF.4 Therefore, it is tempting to speculate that baseline serum levels of sIL-6R, rather than those of IL-6, are associated with clinical response to tocilizumab in patients with rheumatoid arthritis (RA). To test this hypothesis, we analysed serum levels of IL-6 and sIL-6R before tocilizumab treatment in our institution and evaluated their association with clinical remission. Consecutive patients with RA in our institution who commenced 8 mg/kg tocilizumab treatment every 4 weeks as the first biologic agent between March 2010 and April 2012 were included. At baseline, serum levels of IL-6 and sIL-6R were measured by electrochemiluminescence assay with the Ultra-Sensitive Kit (Meso Scale …

The effect of tocilizumab on preventing relapses in adult-onset Still's disease: A retrospective, single-center study.

Abstract Objectives. To investigate the clinical effectiveness of tocilizumab (TCZ), a monoclonal antibody against the interleukin-6 receptor, in preventing relapse in patients with adult-onset Stills disease (AOSD). Methods. This retrospective study included clinical data from 40 patients who underwent regular follow-up at our institution in June 2013. Among these patients, 10 received TCZ. The relapse-free rate was analyzed by the Kaplan–Meier method. Results. The age at disease onset (median, interquartile range [IQR]) was 39 (29–52) years. The duration of disease in June 2013 (median, IQR) was 86 (41–193) months. A total of 87 relapses were documented in 27 patients. Ten patients with refractory or relapsing disease received 8 mg/kg of TCZ every 2–4 weeks. After 6 months of TCZ treatment, the median levels of C-reactive protein significantly decreased from 6.3 to 0.01 mg/dl (p < 0.01). Among these 10 patients, 11 relapses were observed before TCZ treatment, and none were observed after the treatment. The relapse-free rate of the 10 patients after starting TCZ was significantly higher than that of all 40 patients after the initial treatments (100% and 67% at 12 months, respectively; p = 0.03). Conclusions. TCZ effectively prevented relapses of AOSD, and it resolved the disease activity.

Anti-citrullinated peptide/protein antibody (ACPA)-negative RA shares a large proportion of susceptibility loci with ACPA-positive RA: a meta-analysis of genome-wide association study in a Japanese population

IntroductionAlthough susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA. We intended to elucidate genetic background of ACPA-negative RA.MethodWe performed a meta-analysis of GWAS comprising 670 ACPA-negative RA and 16,891 controls for 1,948,138 markers, followed by a replication study of the top 35 single nucleotide polymorphisms (SNPs) using 916 cases and 3,764 controls. Inverse-variance method was applied to assess overall effects. To assess overlap of susceptibility loci between ACPA-positive and -negative RA, odds ratios (ORs) of the 21 susceptibility markers to RA in Japanese were compared between the two subsets. In addition, SNPs were stratified by the p-values in GWAS meta-analysis for either ACPA-positive RA or ACPA-negative RA to address the question whether weakly-associated genes were also shared. The correlations between ACPA-positive RA and the subpopulations of ACPA-negative RA (rheumatoid factor (RF)-positive and RF-negative subsets) were also addressed.ResultsRs6904716 in LEMD2 of the human leukocyte antigen (HLA) locus showed a borderline association with ACPA-negative RA (overall p = 5.7 × 10−8), followed by rs6986423 in CSMD1 (p = 2.4 × 10−6) and rs17727339 in FCRL3 (p = 1.4 × 10−5). ACPA-negative RA showed significant correlations of ORs with ACPA-positive RA for the 21 susceptibility SNPs and non-HLA SNPs with p-values far from significance. These significant correlations with ACPA-positive RA were true for ACPA-negative RF-positive and ACPA-negative RF-negative RA. On the contrary, positive correlations were not observed between the ACPA-negative two subpopulations.ConclusionMany of the susceptibility loci were shared between ACPA-positive and -negative RA.

IgG4-Related Disease without Overexpression of IgG4: Pathogenesis Implications

IgG4-related disease is a new disease group that affects multiple organs. It is characterized by high serum IgG4 and abundant infiltration of IgG4-bearing plasma cells in the affected organ. Here, we describe an intriguing case that suggested that IgG4-related disease might present without IgG4 overexpression or infiltration, at least during a relapse. A 47-year-old man had been diagnosed with systemic lupus erythematosus 15 years. He was admitted due to a pituitary mass, systemic lymphadenopathy, and multiple nodules in the lungs and kidneys. The serum IgG4 level was normal and histopathological examination of the pituitary mass showed abundant lymphocyte and plasma cell infiltration with very few IgG4-positive cells. When we examined specimens preserved from 15 years ago, we found high serum IgG4 levels and IgG4-bearing plasma cell infiltration. This resulted in a diagnosis of IgG4-related disease, and we considered the current episode to be a relapse without IgG4 overexpression. This case indicated that, to clarify the pathogenesis of IgG4-related disease, current cases should repeat specimen evaluations over the course of IgG4-related disease to define diagnostic markers.

Pre-treatment interleukin-6 levels strongly affect bone erosion progression and repair detected by magnetic resonance imaging in rheumatoid arthritis patients

Objective To examine the relationship between MRI structural damage and repair and plasma inflammatory cytokines in patients with RA. Methods A total of 88 newly diagnosed, untreated RA patients were enrolled. Contrast MRI of the dominant hand and X-rays of the hands and feet were performed at baseline and 1 year later. MR images were evaluated using RA MRI scoring, and X-ray. Results Progression of bone erosion and repair were observed more frequently in MRI than in X-rays (erosion, 52% vs 26%, P < 0.001; repair, 26% vs 15%, P = 0.003, respectively). Baseline IL-6 levels and seropositivity were independent relevant factors for MRI erosion progression, with IL-6 having stronger effect than seropositivity. A receiver operating characteristic curve identified the baseline IL-6 level of 7.6 pg/ml for predicting erosion progression during 1 year, with an area under the curve of 0.82; higher IL-6 levels resulted in more erosion progression. Baseline low IL-6 was also an independent predictor for MRI erosion repair. Conclusion In newly diagnosed, untreated RA patients, baseline plasma IL-6 levels are responsible for 1-year MRI bone erosion progression and repair.

FRI0001 Baseline soluble interleukin-6 receptor levels predict the clinical effectiveness of tocilizumab in patients with rheumatoid arthritis

Background Tocilizumab (TCZ), a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody, specifically inhibits IL-6 activity by competitively binding to soluble (sIL-6R) and membrane-bound IL-6R. As for infliximab, a chimeric anti-TNF-α monoclonal antibody, baseline soluble TNF-α level is associated with the clinical response to infliximab in patients with rheumatoid arthritis (RA) 1. Objectives The aim of this study was to investigate a possible role of baseline serum sIL-6R level on clinical effectiveness to TCZ in RA patients. Methods Consecutive RA patients at our institution who received 8mg/kg of TCZ every 4 weeks between March 2010 and April 2012 after giving a written informed consent were included in this study. The serum level of sIL-6R was measured by electrochemiluminescence assay at baseline. The effects of baseline sIL-6R level on DAS28-ESR value and the rate of clinical remission (DAS28-ESR <2.6) at week 24 were examined. Results Fifty-one patients were enrolled in this study. Median age of the patients was 60 years and median RA duration was 4.5 years. Median DAS28-ESR decreased from 5.11 at baseline to 1.95 at week 24, resulting in the achievement of DAS28-ESR <2.6 in 34 (67%) patients. Median (IQR) sIL-6R at baseline was 1556 (1179-1933) pg/ml. The value of sIL-6R was not correlated with age, disease duration, or DAS28-ESR at baseline. However, baseline sIL-6R level was significantly associated with DAS28-ESR at week 24 (rho=0.37, p<0.01; Figure). Logistic regression analysis revealed that baseline sIL-6R level was a significant predictor for DAS28-ESR remission at week 24 (p<0.01). Cut-off sIL-6R level of 1556 pg/ml discriminated remission from non-remission at a sensitivity of 82% and specificity of 65% (AUC=0.69), and the odds ratio was 6.0 (95%CI: 1.6-22.4). Moreover, 85% of the patients with sIL-6R level < 1556 pg/ml achieved remission, while only 48% in the other patients (p<0.01 by Fisher exact test). Image/graph Conclusions Baseline sIL-6R level is a predictive factor of clinical response to TCZ at week 24 in patients with RA. These results suggest that, as is the case with infliximab, the dosing regimen of TCZ could be adjusted by the amount of the molecular target to be neutralized. References Takeuchi T, et al. Ann Rheum Dis 2011;70:1208 Disclosure of Interest N. Nishina: None Declared, J. Kikuchi Consultant for: Pfizer Japan Inc., M. Hashizume Employee of: Chugai Pharmaceutical Co., Ltd., K. Yoshimoto: None Declared, H. Kameda: None Declared, T. Takeuchi Grant/research support from: Abbott Japan Co., Ltd., Astellas Pharma Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Nippon Shinyaku Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis K.K., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical Co., Ltd.

Adolescent PR3-ANCA-positive hypertrophic pachymeningitis

Rationale: Hypertrophic pachymeningitis (HP) is an uncommon, life-threatening disease that is seen in elderly patients with antineutrophil cytoplasmic antibody (ANCA) positivity. Proteinase-3 (PR3)-ANCA-positive HP has not been reported in adolescents. Here, we report the first case of adolescent PR3-ANCA-positive HP successfully treated with immunosuppressive therapy. Patient concerns: A 14-year-old female presented with fullness and pain in her right ear unresponsive to antibiotics. Laboratory tests showed an elevated C-reactive protein and PR3-ANCA positivity. Computed tomography and magnetic resonance imaging revealed mastoiditis in the right temporal bone. Surgical biopsy revealed severe fibrosis and prominent inflammatory-cell infiltration. She received prednisolone and methotrexate therapy, and then underwent a right mastoidectomy. Five months later, she developed headache, dysarthria, and multiple cranial nerve palsies. Further imaging revealed enhancement and thickening of the right hemispheric dura. Diagnosis: PR3-ANCA-positive HP. Interventions: She was successfully treated with steroid pulse therapy for 3 days, followed by high doses of prednisolone and intravenous cyclophosphamide. Outcome: The treatment resulted in significant improvement of her symptoms, laboratory data, and radiologic findings. Lessons: PR3-ANCA-positive HP can present not only in the elderly, but also in adolescence, and prompt diagnosis and treatment with immunosuppressive therapy is vital.

Development of necrotizing myopathy following interstitial lung disease with anti-signal recognition particle antibody

A 72-year-old man was admitted due to dyspnea on exertion with interstitial shadows and elevated serum creatinine kinase (CK). Despite a close examination, which included magnetic resonance imaging (MRI), we could not diagnose myopathy. Prednisolone was administered and gradually tapered. One year later, anti-signal recognition particle (SRP) antibody was confirmed and he was re-admitted for hypoxemia with elevated CK. MRI revealed muscle edema and a histopathological examination of a muscle biopsy specimen showed necrotizing myopathy. Prednisolone, cyclosporine, and intravenous immunoglobulin were administered. Physicians should carefully monitor muscle symptoms and serum CK levels in cases of interstitial lung disease with anti-SRP antibodies.

THU0560 Development of symptoms in very early phase in patient with adult onset still disease

Background Adult onset Still Disease (AOSD) is a systemic inflammatory disease presenting various non-specific symptoms like fever, arthralgia and pharyngalgia. Those symptoms are mimicking common cold, which could lead to the delayed diagnosis. However, little is known about the profiles and development of symptoms in very early phase before diagnosis. Objectives To clarify the clinical course of AOSD symptom development in very early phase and its effect on the diagnosis delay. Methods Consecutive patients with AOSD with enough information in our hospital were enrolled. Initial symptoms before and at diagnosis were investigated in detail. The gradual course from the initial symptoms to the fulfilment of Yamaguchi criteria for AOSD was examined. Results A total of 51 patients were enrolled. The mean age at diagnosis was 45.0±18.9 years old and 41 (80%) were female. All patients were met with the Yamaguchi criteria. The mean duration from the first symptom to diagnosis was 50.4 days. The duration from the first symptom to the first visit to the medical facility including a general physician was 19.1 days, and that from the first medical facility visit to the first blood test was 8.0 days. While the first symptom was arthralgia in 29 (34.1%), fever in 20 (23.5%), and eruption in 20 (23.5%), pharyngalgia in 13 (15.3%), at diagnosis, fever was found in all patients, eruption in 47 (92.2%), arthralgia in 45 (88.2%), pharyngalgia in 34 (66.7%), lymphadenopathy and/or splenomegaly in 35 (68.6%), increased white blood cell (WBC) count in 44 (86.3%), ferritin elevation in 42 (82.4%), liver enzyme elevation in 41 (80.4%), negative rheumatoid factor (RF) and anti-nucleolar antibody (ANA) in 30 (58.8%). Arthralgia developed 41.9 days prior to the diagnosis, fever 40.9 days, eruption 29.5 days, pharyngalgia 24.5 days and lymphadenopathy and/or splenomegaly 14.8 days. WBC increase was detected 17.8 days prior to the diagnosis, negative RF and ANA 15.1 days, liver enzyme elevation 14.6 days, and ferritin elevation 10.9 days. At 14 days from the first symptom, 32 (62.7%) met 3 of Yamaguchi criteria, 23 (45.1%) met 4, and 19 (37.3%) met 5. At 28 days, 40 (78.4%) met 3 of Yamaguchi criteria, 32 (62.7%) met 4, and 27 (52.9%) met 5. The duration to diagnosis was significantly shorter in the patients with eruption developing within 7 days since the first symptoms than those without (35.2 vs 74.3 days, p=0.03) Conclusions The mean duration from the first symptom to the diagnosis of AOSD was approximately 50 days, and only a half of the patients met Yamaguchi criteria at 28 days after first symptom. The time of eruption emergence affected the early diagnosis. Disclosure of Interest None declared

SAT0114 Biological Agents DID not Increase the Risk of Nontuberculous Mycobacterium Infection in Rheumatoid Arthritis Patients: A Retrospective Single Center Study

Background Incidence and prognosis of nontuberculous mycobacterium (NTM) infection in patients with rheumatoid arthritis (RA) is reported to be worse than general population, especially when treated with biological agents such as tumor necrosis factor (TNF) inhibitors. The influence of biological agents, however, remains unclear in Japanese RA patients. Objectives To investigate the risk of NTM infection and exacerbation in Japanese RA patients treated with biological agents. Methods We retrospectively reviewed the medical records of all RA patients under regular follow up at our institution in December 2012. They were observed through October 2014. NTM was diagnosed according to the criteria proposed by the American Thoracic Society and Infectious Diseases Society of America although some cases were diagnosed by chest physicians. Exacerbations of NTM in this study were defined as clinical or radiographic exacerbations so that chest physicians decided to change therapy for NTM to control the activity of NTM. Results This study included 1649 patients. At baseline, 27 patients had already been diagnosed as NTM and 7 were newly diagnosed during observation period. The prevalence rate and incidence rate (95% confidence interval [CI]) of NTM in RA patients was 1637 (1025-2250) per 100,000 patients and 250 (7-435) per 100,000 patient-years, respectively. Baseline characteristics are shown in Table. Of 1622 patients without NTM and of 27 patients with NTM, 762 and 7 patients had been treated with at least 1 biological agent before December 2012 or NTM diagnosis, respectively (Table). Prior use of biological agents was not associated with increased risk of NTM, rather associated with significantly decreased risk (odds ratio [OR], 0.40; 95% CI, 0.16-0.96; p=0.049). Among biological agents, TNF inhibitors were not associated with increased risk of NTM, either (OR, 0.43; 95% CI, 0.16-1.13; p=0.10). Of all 34 patients diagnosed as NTM, 29 (85%) were female. The age at NTM diagnosis (median, interquartile range [IQR]) was 63 (54.8-70.3) years old. The median (IQR) disease duration of RA at the time of NTM diagnosis was 9.7 (6.3-20.4) years, with 3 patients who were diagnosed as RA during the course of NTM. NTM species included M. avium complex in 32 patients, M. kansasii in 1 patient, and M. abcsessus in 1 patient. Radiographic features included 27 nodular/bronchiectatic (NB) disease, 2 fibrocavitary (FC) disease, 7 NB+FC disease and 3 other disease. After diagnosed as NTM, 12 patients were treated with biological agents; 5 patients by etanercept (ETN); 2 by tocilizumab (TCZ); and 5 by abatacept (ABT). Four of them experienced exacerbation (1 with ETN, 2 with TCZ, and 1 with ABT, respectively). Three of the other 22 receiving non-biological therapy also experienced exacerbation (methotrexate, salazosulfapyridine, and tacrolimus, respectively). Treatment with biological agents was not associated with exacerbation, either (OR, 3.2; 95% CI, 0.57-17.5; p=0.21). Respiratory failure and death was not detected during observation period among patients with NTM. Conclusions Japanese patients with RA showed high prevalence and incidence rate of NTM infection and biological agents did not increase the risk of NTM infection or the exacerbation of NTM. We should be careful when treating RA patients with NTM regardless of therapy. Disclosure of Interest H. Takei: None declared, N. Nishina: None declared, K. Suzuki Grant/research support from: Eisai.Co.Ltd. and Bristol-Myers Squibb Company, K. Yamaoka Consultant for: Pfizer, Chugai Pharma, Mitsubishi-Tanabe Pharma, Takeda Industrial Pharma, GlaxoSmithKline, Nippon Shinyaku, Eli Lilly, Janssen Pharma, Eisai Pharma, Astellas Pharma and Actelion Pharmaceuticals., Speakers bureau: Pfizer, Chugai Pharma, Mitsubishi-Tanabe Pharma, Takeda Industrial Pharma, GlaxoSmithKline, Nippon Shinyaku, Eli Lilly, Janssen Pharma, Eisai Pharma, Astellas Pharma and Actelion Pharmaceuticals., T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., and Taisho Toyama Pharmaceutical Co., Ltd.,SymBio Pharmaceuticals Ltd., Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical K.K.,abbivie GK, Daiichi Sankyo Co.,Ltd., Bristol–Myers K.K., Nipponkayaku Co.Ltd., Paid instructor for: Mitsubishi Tanabe Pharma Co., Eisai Co., Ltd., Abbivie GK, Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Astellas Pharma, and Diaichi Sankyo Co.,Ltd., Celtrion, Nipponkayaku Co.Ltd