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This study investigated the effectiveness of treatment with Janus kinase (JAK) inhibitors in rheumatoid arthritis (RA) assessed by ultrasonography (US) activity, and the influence of patient characteristics and previous treatments.This prospective study assessed 60 treatment initiations among 53 Japanese patients diagnosed with RA who underwent treatment with JAK inhibitors during June 2013 to February 2020. Of the 53 patients, seven patients were enrolled in duplicate because they were treated with two different JAK inhibitors at different periods. For each case, the improvement rate on the power Doppler (PD) score was assessed at 6 month follow-up. Median improvement rate of PD score was used to classify cases as either US responders or non-responders, and patient characteristics were compared between the two groups.All indicators of clinical disease activity and US activity showed a significant improvement at 3 months compared with baseline. Although the JAK inhibitor-cycler group and the interleukin-6 (IL-6) inhibitor inadequate response (IR) group tended to show a later improvement for US activity, all indicators of clinical disease activity and US activity showed a significant improvement at 6 months compared with baseline for both groups. Multivariate analysis showed that concomitant methotrexate use and an IR to the previous biologic or targeted-synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) treatment were independently and significantly associated with US responders.Use of a JAK inhibitor in combination with methotrexate and an absence of IR to any previous b/tsDMARDs demonstrated superior effectiveness for patients with RA.

Introduction Abatacept efficacy in older patients with rheumatoid arthritis (RA) has been primarily demonstrated via retrospective comparisons with younger patients. The objective of this study was to compare efficacy of abatacept in older vs. younger patients with RA, and efficacy of abatacept with that of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) in both age groups. Methods This prospective, multicenter, observational study (UMIN000014913) enrolled csDMARD-refractory patients without previous biological DMARD treatment. Abatacept (A) or csDMARDs (C) were administered at the treating physician’s discretion to older (O, ≥ 65 years) and younger (Y, 20–64 years) patients, producing AO, AY, CO, and CY groups. Clinical efficacy after 24 weeks was evaluated using European League Against Rheumatism (EULAR) erythrocyte sedimentation rate response criteria. Results Overall, 202 patients were evaluated. Compared with the CO group, more patients in the AO group achieved a EULAR good or moderate response (p

Objectives The aim is to evaluate outcomes and risk factors for death in patients with rheumatoid arthritis (RA) who developed Pneumocystis pneumonia (PCP). Methods We included RA patients who were diagnosed with PCP at seven participating community hospitals between July 2005 and October 2020. Clinical features were compared between survivors and non-survivors. Disease-modifying antirheumatic drugs (DMARDs) before PCP onset and after PCP recovery were also examined. Results Seventy RA patients developed PCP, and among them, 60 (85.7%) received methotrexate (MTX) monotherapy (40%) or MTX combination therapy with other DMARDs (45.7%). PCP was more likely to occur after 12 months of MTX monotherapy and within 3 months of MTX combination therapy. Thirteen patients (18.6%) died despite PCP treatment. Multivariable logistic regression analysis revealed that coexisting RA-associated interstitial lung disease (odds ratio, 6.18; 95% confidence interval, 1.17–32.63) and delayed PCP treatment with anti-Pneumocystis drugs (odds ratio, 15.29; 95% confidence interval, 1.50–156.15) are significant risk factors for PCP mortality in RA patients. Most survivors successfully resumed DMARD therapy without PCP prophylaxis; one recurrent PCP case was observed during follow-up (median, 4.1 years). Conclusions To avoid a treatment delay, RA patients should be followed up for signs and symptoms of PCP development, especially those with RA-associated interstitial lung disease.

Objectives: Using multicentre ultrasound (US) cohort data among patients with rheumatoid arthritis (RA), we aimed to identify baseline factors that permit differentiation between two patient cohort...

Objective: To determine whether the positivity of baseline anti-Ro/Sjögren’s syndrome antigen A (SSA) antibodies influences the response to abatacept, we compared therapeutic responses between anti-Ro/SSA antibody-negative and -positive patients with rheumatoid arthritis (RA) using a multicentre RA ultrasonography prospective cohort. Method: We reviewed Japanese patients with RA who started abatacept as the first biological disease-modifying anti-rheumatic drug between June 2013 and April 2018. We assessed 28-joint Disease Activity Score–erythrocyte sedimentation rate (DAS28-ESR) change between baseline and 6 or 12 months after treatment in RA patients treated with abatacept, and European League Against Rheumatism (EULAR) response at 6 and 12 months. The Global OMERACT-EULAR Synovitis Score (GLOESS) was calculated at baseline and at 6 and 12 months. Results: Overall, 51 patients were enrolled and divided into anti-Ro/SSA antibody-negative and -positive groups of 35 and 16, respectively. Median age at baseline was significantly higher in the anti-Ro/SSA antibody-negative group (p = 0.04). The retention rate and percentage of EULAR good responders at 12 months were significantly higher in the anti-Ro/SSA antibody-negative group (both p = 0.02). Anti-Ro/SSA antibody-negative patients exhibited larger decreases in both DAS28-ESR and DAS28-C-reactive protein at 12 months than anti-Ro/SSA antibody-positive patients (p = 0.02 and 0.04, respectively). GLOESS decreased significantly at 6 months in anti-Ro/SSA antibody-negative patients (p = 0.03). Multivariate analyses showed that anti-Ro/SSA antibody positivity was an independent factor associated with change in the DAS28-ESR at 6 months (p Conclusion: Anti-Ro/SSA antibody positivity predicts a poor response to abatacept and low retention rate.

An elderly woman with rheumatoid arthritis (RA) presented with a chief complaint of abdominal pain and diarrhoea while undergoing treatment with low-dose corticosteroids and abatacept. Endoscopic and histopathological findings revealed manifestations of ulcerative colitis (UC). An intermediate dose of corticosteroids and 5-aminosalicylic acid were administered. Abatacept was discontinued; the anti-TNF biologic, golimumab, was administered for treatment of both RA and UC. However, colitis worsened in response to this therapeutic regimen. Colonoscopy revealed severe mucosal lesions; larvae were detected in samples taken from multiple shallow mucosal ulcers. The patient was diagnosed with Strongyloides stercoralis colitis based on the results of an anti-parasite antibody test and examination of the larval DNA. Furthermore, serology revealed a positive test for antibodies against human T-cell leukaemia virus type 1 (HTLV-1). Immunosuppressive treatment was terminated; ivermectin was administered, which resulted in improvements in colitis symptoms within a few weeks. There are several published reports describing S. stercoralis colitis as a lethal mimic of UC. Corticosteroid and anti-TNF therapies have been reported as among the major risk factors associated with strongyloidiasis in patients with HTLV-1 infection. Therefore, HTLV-1 and Strongyloides infections may be considered in cases of new-onset gastrointestinal symptoms during immunosuppressive therapy, particularly in HTLV-1-endemic regions.

To compare therapeutic efficacy of tumour necrosis factor inhibitor (TNFi) cyclers and non-TNFi switchers in patients with rheumatoid arthritis (RA) having inadequate response to previous TNFis (TNF-IR patients) using composite measures including imaging assessment with power Doppler ultrasonography (PDUS). Patients with RA who had inadequate response to one or more previous TNFi agents with moderate or higher disease activity were enrolled. The outcomes of 56 TNF-IR patients were analysed. Patients were divided into 19 TNFi cyclers and 37 non-TNFi switchers (16 abatacept [ABT] and 21 tocilizumab [TCZ] switchers). Retention ratio at 6 months was significantly higher in non-TNFi switchers than in TNFi cyclers (p

Objective We compared the 52-week effectiveness and safety of tofacitinib (TOF) and abatacept (ABT) in patients with RA in a real-world setting and investigated a role of human leucocyte antigens (HLA)-DRB1 shared epitope (SE) in the effectiveness. Methods RA patients starting TOF (n = 187) and ABT (n = 183) were enrolled. Effectiveness was compared after reducing the selection bias to a minimum using the inverse probability of treatment weighting (IPTW) based on propensity scores. The influence of SE alleles on effectiveness was compared within each treatment group. A treatment group comparison was also performed within SE-positive and SE-negative groups. Results Herpes zoster and some laboratory abnormalities were more frequent in the TOF group than in the ABT group. Patient characteristics did not differ significantly between treatment groups after adjustments with IPTW. The TOF group had a significantly higher proportion of DAS in 28 joints using ESR (DAS28-ESR) remission at week 52 than the ABT group. The DAS28-ESR at week 12 and thereafter was not affected by the copy number of SE alleles in the TOF group, but decreased significantly as the copy number increased in the ABT group. In SE-positive patients, remission and drug retention rates did not differ significantly between the two treatment groups. In SE-negative patients, the TOF group showed significantly higher remission and drug retention rates than the ABT group. Conclusion The present results suggest that TOF is more effective with regard to remission at week 52 based on treatment responses in SE-negative RA patients.

Most of the diseases for which apheresis therapy is indicated are intractable and rare, and each patient has a different background and treatment course prior to apheresis therapy initiation. Therefore, it is difficult to conduct large-scale randomized controlled trials to secure high-quality evidence. Under such circumstances, the American Society for Apheresis (ASFA) issued its guidelines in 2007, which were repeatedly revised until the latest edition in 2019. The ASFA guidelines are comprehensive. However, in the United States, a centrifugal separation method is mainly used for apheresis, whereas the mainstream procedure in Japan is the membrane separation method. The target diseases and their backgrounds are different from those in Japan. Due to these differences, the direct adoption of the ASFA guidelines in Japanese practice creates various problems. One of the features of apheresis in Japan is the development of treatment methods using hollow-fiber devices such as double filtration plasmapheresis (DFPP) and selective plasma exchange and adsorption-type devices such as polymyxin B-immobilized endotoxin adsorption columns. Specialists in emergency medicine, hematology, collagen diseases/rheumatology, respiratory medicine, cardiovascular medicine, gastroenterology, neurology, nephrology, and dermatology who are familiar with apheresis therapy gathered for this guideline, which covers 86 diseases. In addition, since apheresis therapy involves not only physicians but also clinical engineers, nurses, dieticians, and many other medical professionals, this guideline was prepared in the form of a worksheet so that it can be easily understood at the bedside. Moreover, to the clinical purposes, this guideline is designed to summarize apheresis therapy in Japan and to disseminate and further develop Japanese apheresis technology to the world. As diagnostic and therapeutic techniques are constantly advancing, the guidelines need to be revised every few years. In order to ensure the high quality of apheresis therapy in Japan, both the Japanese Society for Apheresis Registry and the guidelines will be inseparable.

Objectives We aimed to assess the clinical features of human T-cell leukaemia virus type 1 (HTLV-1)-positive rheumatoid arthritis (RA) patients. Furthermore, we investigated the impact of HTLV-1 infection on incidences of serious infections requiring hospitalisation (SIH) and malignancies. Methods A total of 150 sex- and age-matched HTLV-1-negative and 50 HTLV-1-positive RA patients were enrolled from the HTLV-1 RA Miyazaki Cohort Study. Clinical and laboratory data were collected from this cohort database. The incidence rate (IR) for SIH and malignancies from 2015 to 2020 was analysed. Results The median age and female ratio in the study population were 70 years old and 80%, respectively. Although no differences were found in inflammatory marker values between the two groups, the patient global assessment and Health Assessment Questionnaire scores were higher in HTLV-1-positive RA patients. In HTLV-1-negative RA patients, the IR for SIH was 6.37/100 person-years (PY) and 1.32/100 PY for malignancies. In HTLV-1-positive RA patients, SIH occurred in 11.1/100 PY and malignancies in 2.46/100 PY. The crude IR ratio comparing SIH between two groups was 1.74 (95% confidence interval, 1.04–2.84), which was a significant increase. Conclusions HTLV-1-positive RA patients may worsen RA symptoms. HTLV-1 may be a risk factor for SIH.

Objective To explore the variables associated with initial favorable power Doppler (PD) ultrasound (US) response induced by biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients with rheumatoid arthritis (RA). Methods We have been prospectively investigating the course of active RA patients using US after the introduction of b/tsDMARDs in the Kyushu region of Japan since June 2013. One hundred fifty patients have completed the first 6 months of observation at present and have been evaluated. US was assessed in 22 joints of bilateral hands using gray-scale (GS) and PD images on a scale from 0 to 3. The sum of these scores was used as the indicator of US disease activity. We defined PD remission by total PD score=0 at 6 months and investigated the associated variables by multivariate logistic regression analysis. Results The total PD and GS scores and the clinical composite measures significantly improved at 6 months, whereas these reductions were less in bDMARDs switchers as compared with bDMARDs-naive patients. Multivariate logistic regression analysis showed that short disease duration (odds ratio 0.99, 95% confidence interval (CI) 0.99-1.00, p=0.031), the absence of any previous use of bDMARDs (odds ratio 0.27, 95% CI 0.10-0.68, p=0.0047) and low total PD scores (odds ratio 0.85, 95% CI 0.76-0.94, p=0.0003) at baseline were independent predictors of PD remission at 6 months. Conclusion The present prospective US cohort has for the first time shown the variables that are associated with initial PD response to b/tsDMARDs. This article is protected by copyright. All rights reserved.

Objective: Rheumatoid arthritis (RA) treatments have markedly advanced with the introduction of biological agents, e. g., tumor necrosis factor (TNF) inhibitors. TNF inhibitors are demonstrated to be quite effective in combination with methotrexate (MTX), and sufficient doses of both agents are important to control RA's disease activity. However, not all RA patients can be treated with high-dose MTX due to contraindications related to the antimetabolite action of MTX or to tolerability concerns. In daily practice, this has resulted in reduced effectiveness of TNF inhibitors. We sought to determine whether the concomitant use of dose of MTX affected the clinical effectiveness, retention rate, and side effects of certolizumab pegol (CZP) for treating RA in a real-world setting. CZP is a pegylated–conjugated Fab' fragment of a humanized anti-TNF antibody that has high affinity to TNF.Patients and Methods: We divided Japanese RA patients treated with CZP (n = 95, 25–83 years old) into groups based on those with (n = 65) and without (n = 30) concomitant MTX and those treated with a high dose (≥8 mg, n = 41) or low dose (1– n = 24) of MTX. We retrospectively analyzed the concomitant MTX doses' effects and side effects and the patient retention rate.Results: There were no significant differences among the CZP groups with and without MTX or the groups receiving the high vs. low MTX doses in the retention rate, the low disease activity rate, or the inhibitory effect in radiographic joint damage.Conclusion: CZP has the potential to be a useful biological agent to control RA's disease activity and the bone destruction in patients who cannot tolerate a sufficient MTX dose.

BACKGROUND:CD4-positive T cells are the main target of human T-cell leukemia virus type 1 (HTLV-1). Interferon-γ release assays rely on the fact that T-lymphocytes release this cytokine when exposed to tuberculosis-specific antigens and are useful in testing for latent tuberculosis infection before initiating biologic therapy, such as anti-tumor necrosis factor agents. However, the reliability of interferon-γ release assays in detecting tuberculosis infection among HTLV-1-positive patients with rheumatoid arthritis (RA) remains unclear. The present study aimed to evaluate the use of the T-SPOT.TB assay in HTLV-1-positive RA patients. METHODS:Overall, 29 HTLV-1-positive RA patients and 87 age- and sex-matched HTLV-1-negative RA patients (controls) were included from the HTLV-1 RA Miyazaki Cohort Study. Results of the T-SPOT.TB assay for latent tuberculosis infection screening were collected from medical records of patients. RESULTS:Approximately 55% of the HTLV-1-positive RA patients showed invalid T-SPOT.TB assay results (odds ratio: 108, 95% confidence interval: 13.1-890, p < 0.0001) owing to a spot count of >10 in the negative controls. HTLV-1 proviral load values were significantly higher in patients with invalid results compared with those without invalid results (p = 0.003). CONCLUSION:HTLV-1 infection affects T-SPOT.TB assay results in RA patients. Assay results in HTLV-1 endemic regions should be interpreted with caution when screening for latent tuberculosis infection before initiation of biologic therapy.

Our previous study showed that the effectiveness of tumor necrosis factor (TNF) inhibitors was attenuated in anti-human T-cell leukemia virus type 1 (HTLV-1) antibody-positive patients with rheumatoid arthritis (RA). We aimed to evaluate the effectiveness and safety of non-TNF inhibitors in anti-HTLV-1 antibody-positive patients with RA. We reviewed patients with RA who received abatacept or tocilizumab as the first biologic agent. We used the data of patients treated with TNF inhibitors from our previous study to compare the effectiveness between the anti-HTLV-1 antibody-positive patients treated with TNF inhibitors and non-TNF inhibitors using the inverse probability of treatment weights (IPTW) method. A total of 359 patients were divided into anti-HTLV-1 antibody-negative and -positive patients of 332 and 27, respectively. No statistically significant difference was observed in the change in the clinical disease activity index between the anti-HTLV-1 antibody-positive and -negative patients. The results using the IPTW method showed a significant association between the non-TNF inhibitors treatment and a better response. None of the patients developed adult T-cell leukemia/lymphoma or HTLV-1-associated myelopathy/tropical spastic paraparesis during the 24 weeks. Our results indicate that non-TNF inhibitors treatment is safety, and the effectiveness is not attenuated also in anti-HTLV-1 antibody-positive patients.

In this article, we discussed leukocytapheresis (LCAP) for rheumatoid arthritis (RA). Recently, a simple and practical on-line continuous LACP system has been developed. It is equipped with a direct hemoperfusion column (Cellsorba®, Asahikasei Medical Co., Ltd.) packed with fine-diameter polyester fibers, which are commonly used to adsorb white blood cells to prevent a graft-versus-host reaction during blood transfusion. Clinical trials revealed that LCAP is a effective and safe therapy for patients with drug-resistant RA or RA complicated with vasculitis. Because the procedure is simple and requires no plasma substitutes and the volume needed for extracorporeal circulation is less than that for other plasmapheresis, LCAP might be accepted as an optional therapeutic modality for active RA that was refractory to conventional drug therapy including biological agents. The mechanism of the efficiency of LCAP on RA is unclear. LCAP may cause a reduction of activated T cells from affected joints, down-regulation of Pgp on helper T cells and restoration of Treg function, and that may modify the abnormal cytokine balance. These findings may explain some of the mechanisms by which the articular symptoms are improved by LCAP.

A 70-year-old Japanese female was diagnosed with seropositive rheumatoid arthritis (RA) in January 2008. She had high disease activity and was treated with prednisolone, methotrexate (MTX) and infl...

Objective: Successful rheumatoid arthritis (RA) outcome depends on treatment efficacy in the early stages of the disease and its sustainability. It is thus critical to identify factors predicting treatment persistence with biological agents, such as abatacept. We compared clinical profiles, including early changes in autoantibody titres at 3 months, between patients with RA demonstrating sustained persistence and those discontinuing abatacept treatment. Method: We prospectively enrolled 71 and 78 active RA patients treated with abatacept and tumour necrosis factor inhibitors (TNF-Is), respectively, who had previous disease-modifying anti-rheumatic drug) failure. Clinical characteristics were compared between non-continuation and continuation groups stratified according to abatacept or TNF-I persistence for at least 12 months from treatment initiation. Results: Significantly larger decreases in rheumatoid factor titre and anti-citrullinated protein autoantibody (ACPA) titre were observed in the continuation group of abatacept therapy at 3 months, and early reduction in ACPA titre remained a significant and independent predictor of sustained persistence with abatacept in multivariate analysis. In addition, we obtained the area under the receiver operator characteristics curve of 0.904 from a model including baseline ACPA titre and reduction of ACPA titre at 3 months. Sustained reduction of RA disease activity score at 12 months was significantly and independently associated with reduced ACPA titre at 3 months. Conclusions: Persistence with abatacept and sustained therapeutic response are associated with an early reduction in ACPA titre. Prediction of abatacept continuation and efficacy will facilitate the optimal design of therapy in the early stages of RA.

We aimed to evaluate the utility of a simplified ultrasonography (US) scoring system, which is desired in daily clinical practice, among patients with rheumatoid arthritis (RA) receiving biological/targeted synthetic disease-modifying antirheumatic drugs (DMARDs).A total of 289 Japanese patients with RA who were started on tumor necrosis factor inhibitors, abatacept, tocilizumab, or Janus kinase inhibitors between June 2013 and April 2019 at one of the 15 participating rheumatology centers were reviewed. We performed US assessment of articular synovia over 22 joints among bilateral wrist and finger joints, and the 22-joint (22j)-GS and 22-joint (22j)-PD scores were evaluated as an indicator of US activity using the sum of the GS and PD scores, respectively.The top 6 most affected joints included the bilateral wrist and second/third metacarpophalangeal joints. Therefore, 6-joint (6j)-GS and -PD scores were defined as the sum of the GS and PD scores from the 6 synovial sites over the aforementioned 6 joints, respectively. Although the 22j- or 6j-US scores were significantly correlated with DAS28-ESR or -CRP scores, the correlations were weak. Conversely, 6j-US scores were significantly and strongly correlated with 22j-US scores not only at baseline but also after therapy initiation.Using a multicenter cohort data, our results indicated that a simplified US scoring system could be adequately tolerated during any disease course among patients with RA receiving biological/targeted synthetic DMARDs., Medicine, 100(1), e23254; 2021

Background:In clinical rheumatology, interferon-γ release assays (IGRAs) have been reported as a useful diagnostic test for latent tuberculosis infection (LTBI) before beginning the administration of biologics such as anti-TNF therapies (1). CD4-positive T cells are the main target in Human T-cell leukaemia virus type 1 (HTLV-1) infection. Several reports suggest that the reaction of tuberculin skin test (TST) is attenuated in HTLV-1-positive individuals compared with that in HTLV-1-negative individuals (2). However, it remains unclear whether IGRAs are reliable for detecting TB infection among HTLV-1-positive RA patients.Objectives:The present study aimed to investigate the usefulness of the T-SPOT.TBassay in HTLV-1-positive RA patients. In addition, the association between the existence of IFN-γ producing T cells and HTLV-1 proviral loads (PVLs) in HTLV-1-positive RA patients was analysed on the basis of the T-SPOT.TBassay results.Methods:We reviewed the medical records of 75 HTLV-1-negative and 29 HTLV-1-positive RA patients were suspected cases of LTBI and evaluated using the T-SPOT.TBassay as a clinical practice from April 2012 to July 2019. The results of T-SPOT.TBwere collected from medical records, retrospectively. Peripheral blood samples were obtained from HTLV-1-positive RA patients for the analysis of HTLV-1 PVLs values. The study protocol was approved by the research ethics committees of our hospitals.Results:Approximately 55% of the HTLV-1-positive RA patients showed invalid results for the T-SPOT.TBassay (p < 0.0001); the cause of invalid results was a spot-forming count of >10 spots in the negative controls of the T-SPOT.TBassay among HTLV-1-positive RA patients. Among HTLV-1-positive RA patients, HTLV-1 PVL values were significantly higher in 16 patients who showed invalid results than in 13 patients who did not (p = 0.003). There were no between-group differences in female patient ratio, age, RA disease activity and therapeutic regimens. IFN-γ producing cells were detected in the peripheral blood of HTLV-1-positive RA patients without stimulation with TB-specific antigens.Conclusion:The incidence of invalid results for the T-SPOT.TBassay has been reported to be as low as 0.6% (3). The results of this assay for screening of LTBI in HTLV-1-positive RA patients should be interpreted with caution. Furthermore, our results show that an increase in IFN-γ producing T cell numbers due to HTLV-1 infection in RA patients may affect the pathogenesis of RA.References:[1]Iannone, F., et al.J. Rheumatol. Suppl.91, 41-46 (2014).[2]Tachibana, N., et al.Int. J. Cancer42, 829-831 (1988).[3]Rego, K., et al.Tuberculosis (Edinb.)108, 178-185 (2018).Acknowledgments:We would like to thank Dr Yuki Hashikura and Ms Yuki Kaseda of the University of Miyazaki for their technical support in this work. We would also like to acknowledge Ms Yumiko Kai at the Institute of Rheumatology, Zenjinkai Shimin-no-Mori Hospital, for her help in data management.A part this work was supported by a grant from the Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development (Grant No. JP19ek0109356), a Health and Labor Sciences Research Grant on Rare and Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan (Grant No. 19FC1007), and a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.Disclosure of Interests:Kunihiko Umekita Paid instructor for: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Speakers bureau: Bristol-Myers Squibb, Yayoi Hashiba: None declared, Risa Kudou: None declared, Shunichi Miyauchi: None declared, Masatoshi Kimura: None declared, Motohiro Matsuda: None declared, Chihiro Iwao: None declared, Yumi Kariya: None declared, Takeshi Kawaguchi: None declared, Katoko Takajo: None declared, Koushou Iwao: None declared, Yuuki Rikitake: None declared, Ichiro Takajo: None declared, Toshihiko Hidaka Paid instructor for: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Speakers bureau: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Akihiko Okayama: None declared

Objectives To compare retention of tocilizumab (TCZ) as monotherapy vs combination therapy with MTX in RA patients achieving clinical improvements during the first year. Methods We performed a multicentre cohort study using a real-life registry containing RA patients who had begun TCZ with or without MTX between April 2008 and November 2016. Among patients with ≥50% improvement of clinical disease activity index (CDAI) during the first year (CDAI50 responders), we evaluated whether MTX use may have affected TCZ discontinuation during the second and subsequent years (maintenance therapy). Results Among 510 patients with high or moderate CDAI, 328 (64.3%) were CDAI50 responders. The rate of MTX use was 53.0% among responders and 54.4% among non-responders. During maintenance therapy (mean follow-up 30.7 months), 43.9% of CDAI50 responders discontinued TCZ. The most common cause was efficacy loss followed by adverse events. Kaplan-Meier estimates for TCZ retention were 48.3 months (95% CI 42.0, 54.5) for monotherapy and 50.0 months (95% CI 45.9, 54.0) for combination therapy. According to Gray’s test, there was no significant impact of MTX use on cumulative incidence of efficacy loss or adverse events. In the Fine-Gray competing risk regression model, CDAI >10 at the start of maintenance therapy and age were predictive factors for TCZ discontinuation due to efficacy loss (hazard ratio 2.58, 95% CI 1.41, 4.72) and adverse events (hazard ratio 1.04, 95% CI 1.01, 1.08), respectively. Conclusion There was no significant difference in TCZ retention between monotherapy and combination therapy with MTX.

Objective: This study aimed to investigate the time-sequential changes of risk factors for adult T-cell leukemia (ATL) development in human T-cell leukemia virus type 1 (HTLV-1)-positive rheumatoid arthritis (RA) patients. Methods: HTLV-1 infection was screened using particle agglutination assay and confirmed via western blotting in 365 RA patients. Twenty-three HTLV-1-positive RA patients were included in the study cohort. Blood samples were obtained from these patients at each observation time point. The values of HTLV-1 proviral load (PVL) and serum soluble IL-2 receptor (sIL2-R), which are risk factors for ATL development, were measured using real-time PCR and enzyme immunoassay, respectively. Results: The study cohort comprised 79 person-years. The median HTLV-1 PVL and sIL2-R values of the HTLV-1-positive RA patients were 0.44 copies per 100 white blood cells (WBCs) and 406 U/mL, respectively. Three HTLV-1-positive RA patients showed a high PVL value. No remarkable changes were observed in the PVL and sIL2-R values during the observation period. However, one elderly HTLV-1-positive RA patient who had a high PVL value developed ATL during treatment with methotrexate and infliximab. Conclusion: A thorough clinical assessment of the risk factors for ATL development may be necessary in daily clinical practice for RA patients in HTLV-1-endemic areas in Japan.

Renal involvement is frequently present in patients with rheumatoid arthritis (RA). Approximately 15–25% of patients with RA have renal insufficiency, defined as a glomerular filtration rate (GFR)

Objective To evaluate the effectiveness of tumor necrosis factor (TNF) inhibitors for the treatment of human T lymphotropic virus type I (HTLV-I)-positive patients with rheumatoid arthritis (RA) in an area endemic for HTLV-I infection. Methods We conducted an observational study of 585 RA patients in whom TNF inhibitors were newly introduced as a first biologic disease-modifying antirheumatic drug in an area in southwestern Japan that is endemic for HTLV-I infection. Results Fifty patients (8.5%) were anti-HTLV-I antibody-positive. The ages of the patients in this group were significantly higher at entry compared with the ages of patients who were anti-HTLV-I antibody-negative (n = 535). The median Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) was 5.21. Among the total group of patients, 82% were anti-citrullinated protein antibody (ACPA)-positive. The persistence rate of TNF inhibitors at 24 weeks was 89%. The median DAS28-ESR was significantly decreased at 24 weeks in each group. The European League Against Rheumatism (EULAR) response rate was significantly better in the anti-HTLV-I antibody-negative patients (P = 0.0277). Multiple regression analysis demonstrated that anti-HTLV-I antibody status was significantly associated with the EULAR response rate and change in the DAS28-ESR and was prominent especially in the ACPA-negative subjects. No patients developed adult T cell leukemia/lymphoma (ATL) or HTLV-I-associated myelopathy (HAM) during the 24-week treatment period. Conclusion The efficacy of TNF inhibitors may be attenuated in anti-HTLV-I antibody-positive patients with RA. ATL and HAM did not develop when TNF inhibitors were used for 24 weeks, but the long-term risk is not known.

Objective To investigate the response to and safety of anti–tumor necrosis factor (anti-TNF) therapy in human T lymphotropic virus type I (HTLV-I)–positive patients with rheumatoid arthritis (RA). Methods Therapeutic response was evaluated in 10 HTLV-I–positive and 20 HTLV-I–negative patients with RA (sex and age matched) at 3 months after the beginning of anti-TNF therapy using the European League Against Rheumatism improvement criteria. As secondary end points, the discontinuation rate of anti-TNF therapy and its safety, especially the development of adult T cell leukemia (ATL), were evaluated over a 2-year period. Results Significantly higher baseline levels of C-reactive protein (CRP) were observed in HTLV-I–positive patients than in HTLV-I–negative patients (P = 0.0003). The response rate to anti-TNF therapy was lower in HTLV-I–positive patients than in HTLV-I–negative patients. The median CRP level, erythrocyte sedimentation rate, and Disease Activity Score in 28 joints at 3 months after anti-TNF treatment in HTLV-I–positive patients were significantly higher than in HTLV-I–negative patients (P = 0.003, P = 0.03, and P = 0.003, respectively). The discontinuation rate due to insufficient response was significantly higher in HTLV-I–positive patients than in HTLV-I–negative patients (P = 0.013). During the 2-year observation period, no patients developed ATL. Conclusion These data suggest that HTLV-I–positive patients with RA had higher inflammation and greater resistance to anti-TNF treatment than HTLV-I–negative patients. Further study is necessary to determine whether HTLV-I infection should be measured when anti-TNF agents are administered to patients with RA, especially in areas were HTLV-I is endemic.

Objectives We assessed the impact of tocilizumab (TCZ), a humanised monoclonal anti-interleukin-6 receptor antibody, on antibody response following administration of the 23-valent pneumococcal polysaccharide vaccine (PPV23). Methods A total of 190 patients with rheumatoid arthritis (RA) received PPV23. Patients were classified into TCZ (n=50), TCZ + methotrexate (MTX) (n=54), MTX (n=62) and RA control (n=24) groups. We measured serotype-specific IgG concentrations of pneumococcal serotypes 6B and 23F using ELISA and functional antibody activity using a multiplexed opsonophagocytic killing assay, reported as the opsonisation indices (OIs), before and 4–6 weeks after vaccination. Positive antibody response was defined as a 2-fold or more increase in the IgG concentration or as a ≥10-fold or more increase in the OI. Results IgG concentrations and OIs were significantly increased in all treatment groups in response to vaccination. The TCZ group antibody response rates were comparable with those of the RA control group for each serotype. MTX had a negative impact on vaccine efficacy. Multivariate logistic analysis confirmed that TCZ is not associated with an inadequate antibody response to either serotype. No severe adverse effect was observed in any treatment group. Conclusions TCZ does not impair PPV23 immunogenicity in RA patients, whereas antibody responses may be reduced when TCZ is used as a combination therapy with MTX.

Supplemental Digital Content is available in the text, To determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) in clinical practice. We performed a multicenter prospective study in Japan of biological disease-modifying antirheumatic drug (bDMARD)-naive RA patients with moderate to high disease activity treated with conventional synthetic DMARDs (csDMARDs) at study entry. We longitudinally observed 408 patients for 1 year and assessed disease activity every 3 months. CRRP was defined as yearly progression of modified total Sharp score (mTSS) > 3.0 U. We also divided the cohort into 2 groups based on disease duration (

Objective Severe myelosuppression is a serious concern in the management of rheumatic disease patients receiving methotrexate (MTX) therapy. This study was intended to explore factors associated with the development of MTX-related myelosuppression and its disease severity. Methods We retrospectively examined a total of 40 cases of MTX-related myelosuppression that had been filed in the registries of participating rheumatology and hematology divisions. Data before onset were compared with those of 120 controls matched for age and sex. Cytopenia was graded according to the National Cancer Institute criteria for adverse events. Data before and at onset were compared between the severe and non-severe groups. Results Non-use of folic acid supplements, concurrent medications, and low renal function were significantly associated with the development of myelosuppression (p < 0.001, p < 0.001, and p = 0.002, respectively). In addition, significantly lower MTX dosages, higher blood cell counts, and lower hemoglobin levels were seen in the myelosuppression group (p < 0.001). No patients exhibited leukocytopenia, neutropenia, or thrombocytopenia in routine blood monitoring taken within the past month. One-fourth developed myelosuppression within the first two months (an early-onset period). Myelosuppression was severe in approximately 40% of patients. Hypoalbuminemia and non-use of folic acid supplements were significantly associated with the severity of pancytopenia (p = 0.001 and 0.008, respectively). Besides these two factors, early onset and the use of lower doses of MTX were significantly associated with the severity of neutropenia (p = 0.003, 0.007, 0.003, and 0.002, respectively). Conclusions Myelosuppression can occur abruptly at any time during low-dose MTX therapy, but severe neutropenia is more likely to occur in the early-onset period of this therapy. Contrary to our expectations, disease severity was not dependent on MTX doses. Serum albumin levels and folic acid supplementation are the important factors affecting the severity of MTX-related pancytopenia and neutropenia.

Objective.The aim of the Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan (JESMR) study is to compare the efficacy of continuation versus discontinuation of methotrexate (MTX) when starting etanercept (ETN) in patients with active rheumatoid arthritis (RA).Methods.In total, 151 patients with active RA who had been taking MTX were randomized to either ETN 25 mg twice a week with 6–8 mg/week MTX (the E+M group), or ETN alone (the E group). The primary endpoint at Week 52 was the radiographic progression assessed by van der Heijde-modified Sharp score.Results.The mean progression in total score at Week 52 was not significantly different, statistically, between the E+M group and the E group (0.8 vs 3.6, respectively; p = 0.06). However, a significant difference was observed in radiographic progression between Weeks 24 and 52 (0.3 vs 2.5; p = 0.03), and the mean progression of the erosion score was negative in the E+M group, which was significantly better than the E group at Week 52 (–0.2 vs 1.8; p = 0.02). Clinically, the cumulative probability plot of the American College of Rheumatology (ACR)-N values at Week 52 clearly demonstrated a superior response in the E+M group than in the E group. ACR20, 50, and 70 response rates at Week 52 in the E+M group (86.3%, 76.7%, and 50.7%) were significantly greater than those in the E group (63.8%; p = 0.003, 43.5%; p < 0.0001 and 29.0%; p = 0.01, respectively).Conclusion.MTX should be continued when starting ETN in patients with active RA. (ClinicalTrials.gov: NCT00688103)

Leukocytapheresis (LCAP) is an apheresis technique for depleting pathogenic leukocytes from the circulating blood to improve the condition of the patient. LCAP sensu lato has been applied for the treatment of various rheumatic diseases: other treatments include thoracic duct drainage, photopheresis, centrifugal LCAP, granulocytapheresis (GCAP) and filtration LCAP. Among these modalities, GCAP and filtration LCAP are most commonly used in Japan for two reasons; the equipment and procedure are simple and practical and adverse events are rare and minor. In this article, LCAP, in particular filtration LCAP, for the treatment of rheumatic diseases is reviewed.

In terms of the relationship between synovial inflammation and radiographic changes, including both joint damage repair and progression,1 in rheumatoid arthritis (RA), pre-existing joint damage and persistent synovitis may promote joint destruction, while in the absence of synovitis, damaged joints may heal.2 ,3 Although presentation of radiographic results using cumulative probability plots has substantially improved understanding of clinical trial data,4 the effects of treatments on radiographic progression and improvement (regression) in individual RA patients has not yet been fully explained. In the JESMR study,5 ,6 151 active RA patients unresponsive to treatment with methotrexate (MTX) were randomised into 1 of 2 treatment groups: etanercept (ETN) 50 mg/week with 6–8 mg/week of MTX (the E+M group), or ETN alone (the E group). Radiographs of the hands and feet before ETN (baseline) and during the first year of treatment were available from 53 (72%) and 68 (88%) patients in the E and E+M groups, respectively. Baseline characteristics of patients were comparable between those with and without available radiographic data in each treatment group (data not shown). However, most patients without data did not complete the study up to Week 52 as per protocol, chiefly due to lack of efficacy in the E group.6 The mean baseline total Sharp-van der Heijde score (TSS)7 was 114.5 in the E group and 113.1 in the E+M …

Objective The aim of this study was to clarify the mechanism of leucocytapheresis (LCAP) in patients with RA. Methods Protein profiles of blood samples from two patients with RA obtained via LCAP column inlet and outlet lines were analysed by two-dimensional fluorescence difference gel electrophoresis and mass spectrometry. The lactoferrin (LTF) levels of peripheral and circulating blood samples from seven patients obtained via the LCAP column blood circuit were then determined by ELISA. Peripheral blood samples from 14 patients with RA were exposed to unwoven polyester fibre filters and the LTF level was determined. In addition, morphological changes in neutrophils after exposure to the filter were examined by optical microscopy, electronic microscopy and LTF immunostaining. Results LTF levels were increased in both samples from the LCAP column outlet and peripheral blood at the end of LCAP treatment. Furthermore, peripheral blood samples exposed to the filter revealed a decreased number of neutrophils and an increased level of LTF. Morphological analysis of the exposed neutrophils showed vacuolization of the cytoplasm and degranulation of LTF-positive granules. These data suggest that LTF stored in the granules of neutrophils is released from the neutrophils caught in the LCAP column. Conclusion Because LTF has been reported to have multiple anti-inflammatory properties, increased levels of LTF may contribute to the clinical effect of LCAP in patients with RA.

The presence of antiphospholipid antibodies and/or lupus anticoagulant (LA) increase the risk of thrombosis, while the onset of thrombosis is usually sudden. The objective of this study was to determine whether or not some episodes triggered thrombotic events in patients possessing antiphospholipid antibodies. Fifteen patients who presented with thrombosis (primary antiphospholipid syndrome (APS), six cases; secondary APS, nine cases) were retrospectively examined to discover whether or not any specific episodes occurred prior to a total of 21 thrombotic events. In five events occurring in five female patients, specific episodes were identified, including the wearing of tight underwear, dehydration due to fever and standing in hot and humid weather, fever following the extraction of a carious tooth, steroid pulse therapy, toxemia during pregnancy, and intrauterine fetal death. To prevent the occurrence of thrombosis in patients possessing antiphospholipid antibodies, it appears to be important to avoid such triggering episodes and also to reduce the risk factors for thrombosis.

The purpose of this study is to determine the changes in CD4+ T lymphocyte subsets in the circulating blood and synovial fluid following filtration leukocytapheresis (LCP) therapy for patients with rheumatoid arthritis (RA). A Cellsorba column packed with polyester fibers was used for the removal of circulating leukocytes. For patients with RA, filtration LCP or sham procedures were performed 3 times with 1 week intervals between procedures. T lymphocyte surface markers in the peripheral blood and synovial fluid were measured by flow cytometry. The proportions of activated CD4+ T cells (CD4+DR+, CD4+CD25+, and CD4+CD71+) and CD4+CD29+ T cells increased significantly in the peripheral blood, but the counts of these cells were significantly reduced in the synovial fluid after 2 treatment sessions in the LCP group. No significant changes were observed in the proportion of these cells in the control group. Our findings suggest that filtration LCP may cause a redistribution of activated T cells from affected joints into the circulating blood.

Objective To determine the efficacy and safety of filtration leukocytapheresis (LCP) for the treatment of rheumatoid arthritis (RA). Methods Twenty-five patients with drug-resistant RA were randomly assigned to undergo filtration LCP and 7 to undergo sham apheresis (control group) in a randomized, double-blind, placebo-controlled study. Three apheresis procedures were performed, with 1-week intervals between procedures. The efficacy of filtration LCP was evaluated according to the American College of Rheumatology definition of improvement in RA. Medications for each patient were unchanged for at least 6 months prior to enrollment and throughout the study. Results Tender joint counts, swollen joint counts, patient assessment of pain and global severity, physician assessment of global severity, and Health Assessment Questionnaire Disability Index were significantly improved in the LCP group compared with the control group (P < 0.05 for patient assessment of pain; P < 0.01 for all others). Seventy-nine percent of the patients in the LCP group exhibited significant overall improvement, while none of the patients in the control group were improved (P < 0.001). Conclusion The results indicate that filtration LCP is an effective and well-tolerated treatment for patients with drug-resistant RA.

In systemic lupus erythematosus (SLE), peripheral neuropathies are relatively uncommon and rarely present as the initial symptom. We herein describe a 61-year-old woman who developed a sudden onset of drop foot, which was indistinguishable from Guillain-Barre syndrome based on the clinical symptoms alone. Antibodies against ganglioside GM1 were detected in the serum, while no antibodies to Campylobacter jejuni were observed. An electrophysiological study showed axonal impairment rather than demyelination. A pathological examination of a sural nerve biopsy specimen and further laboratory examinations suggested the observed peripheral neuropathies to have arisen due to lupus vasculitis. The serological activities of SLE responded well to treatment with corticosteroids, mizoribine and immunoadsorption therapies, however, the drop foot symptoms did not change remarkably.(Internal Medicine 38: 729-732, 1999)

RAMAK-1, a new spontaneously immortalized synovial cell line consisting of type B lining cells, was recently derived from a patient with rheumatoid arthritis (RA). The present study was designed to characterize RAMAK-1 cells in terms of expression of adhesion molecules and cytokine production. RAMAK-1 cells constitutively express intercellular adhesion molecule-1. In contrast, vascular cell adhesion molecule-1 (VCAM-1) expression by the cells was not observed in the absence of stimulation. However, when stimulated by tumor necrosis factor-α, VCAM-1 expression was readily apparent and sustained over 48 h. RAMAK-1 cells spontaneously produced interleukin (IL)-6, IL-8 and granulocyte macrophage colony stimulating factor, but not IL-1α nor IL-1β. However, when stimulated with IL-1β, the cells expressed IL-1α and IL-1β mRNA. This cell line presents functional responses when stimulated with pro-inflammatory cytokines and may be useful in elucidating the initial lesions of the synovial lining layer of RA.