Selection of treatment regimens based on shared decision-making in patients with rheumatoid arthritis on remission in the FREE-J study.

OBJECTIVE: To compare the outcome of various treatment de-escalation regimens in patients with RA who achieved sustained remission. METHODS: At period 1, 436 RA patients who were treated with MTX and bDMARDs and had maintained DAS28(ESR) at <2.6 were divided into five groups based on shared patient/physician decision-making; continuation, dose reduction and discontinuation of MTX or bDMARDs. At end of year 1, patients who achieved DAS28(ESR) <3.2 were allowed to enrol in period 2 for treatment using the de-escalation regimens for another year. The primary and secondary endpoints were the proportion of patients with DAS28(ESR) <2.6 at year 1 and 2, respectively. RESULTS: Based on shared decision-making, 81.4% elected de-escalation of treatment and 48.4% selected de-escalation of MTX. At end of period 1, similar proportions of patients maintained DAS28(ESR) <2.6 (continuation, 85.2%; MTX dose reduction, 79.0%; MTX-discontinuation, 80.0%; bDMARD dose reduction, 73.9%), although the rate was significantly different between the continuation and bDMARD-discontinuation. At end of period 2, similar proportions of patients of the MTX groups maintained DAS28(ESR) <2.6 (continuation or de-escalation), but the rates were significantly lower in the bDMARD-discontinuation group. However, half of the latter group satisfactorily discontinued bDMARDs. Adverse events were numerically lower in MTX and bDMARD-de-escalation groups during period 1 and 2, compared with the continuation group. CONCLUSIONS: After achieving sustained remission by combination treatment of MTX/bDMARDs, disease control was achieved comparably by continuation, dose reduction or discontinuation of MTX and dose reduction of bDMARDs at end of year 1. Subsequent de-escalation of MTX had no impacts on disease control but decreased adverse events in year 2.

A nationwide questionnaire survey on the prevalence of ankylosing spondylitis and non-radiographic axial spondyloarthritis in Japan.

OBJECTIVE: This nationwide study aimed to reveal the prevalence of ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis (nr-ax SpA), and the positivity rate of human leukocyte antigen (HLA) among such patients in Japan. METHODS: The first survey was conducted in 2221 randomly selected facilities (26.3%) in September 2018, where the patients with AS/nr-ax SpA were taken care of from January to December 2017. We estimated the total number of these patients using response and extraction rates. A second survey was conducted in 117 facilities (49.8%) to assess for HLA-B27 positivity rate and clinical features. RESULTS: The estimated total numbers of the patients with AS and nr-ax SpA were 3200 (95% confidence interval [CI]: 2400-3900) and 800 (530-1100), suggesting that the prevalence values of AS and nr-ax SpA in general population were 2.6/100,000 (0.0026%) and 0.6/100,000 (0.0006%), respectively. Although 55.5% (76/137) of patients with AS were HLA-B27-positive, those whose age of onset was estimated to be over 50 years tended to undergo less HLA-B27 testing. CONCLUSION: This study revealed the lower prevalence of AS/nr-ax SpA in Japan, compared to those in other countries. Further studies are required to reveal the association of HLA-B27 with the clinical features.

Long-term efficacy and safety of tocilizumab in refractory Takayasu arteritis: final results of the randomized controlled phase 3 TAKT study.

OBJECTIVE: To investigate the long-term efficacy and safety of the IL-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK). METHODS: Patients completing the randomized, double-blind, placebo-controlled period of the TAKT (Takayasu arteritis Treated with Tocilizumab) trial were followed up during open-label extended treatment with weekly s.c. tocilizumab 162 mg for up to 96 weeks or longer, with oral glucocorticoid tapering performed at the investigators' discretion. Endpoints of the extension analysis included steroid-sparing effects of tocilizumab, imaging data, patient-reported outcomes (36-Item Short Form Health Survey) and safety. RESULTS: All 36 patients enrolled in the double-blind period entered the open-label extension; 28 patients received tocilizumab for 96 weeks. The median glucocorticoid dose was 0.223 mg/kg/day at the time of relapse before study entry, 0.131 mg/kg/day (interquartile range 0.099, 0.207) after 48 weeks and 0.105 mg/kg/day (interquartile range 0.039, 0.153) after 96 weeks. Overall, 46.4% of patients reduced their dose to <0.1 mg/kg/day, which was less than half the dose administered at relapse before study entry (mean difference -0.120 mg/kg/day; 95% CI -0.154, -0.087). Imaging evaluations indicated that most patients' disease was improved (17.9%) or stable (67.9%) after 96 weeks compared with baseline. Mean 36-Item Short Form Health Survey physical and mental component summary scores and 7 of 8 domain scores were clinically improved from baseline and maintained over 96 weeks of tocilizumab treatment. No unexpected safety issues were reported. CONCLUSION: These results in patients with Takayasu arteritis provide evidence of a steroid-sparing effect and improvements in well-being during long-term treatment with once-weekly tocilizumab 162 mg, with no new safety concerns. TRIAL REGISTRATION: JAPIC Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch_e.jsp, JapicCTI-142616.

Clinicopathologic characteristics of 342 patients with multicentric Castleman disease in Japan.

Objectives: To assess the clinicopathologic features of Multicentric Castleman disease (MCD) patients in Japan.Methods: We assessed baseline data for 342 Japanese MCD patients with a biopsy-proven diagnosis, enrolled in a prospective, observational study for tocilizumab treatment.Results: Of 342 patients, 86.0% had plasma-cell type. None had a family history of MCD. Median disease duration of MCD was 3.7 years. Mean body weight and body mass index tended to be lower than those in the general Japanese population. The most common clinical presentations besides lymphadenopathy included fatigue (61.7%), pulmonary involvement (42.7%), and splenomegaly (41.8%). Secondary amyloidosis was reported in 34 patients (9.9%). Laboratory abnormalities included decreased hemoglobin and albumin, and increased acute-phase proteins, serum immunoglobulins, and interleukin-6 (IL-6). IL-6 levels among the MCD patients tested in this study were correlated with levels of albumin, hemoglobin, triglyceride, total cholesterol, C-reactive protein, fibrinogen and immunoglobulin G (Spearman's correlation coefficient, |r| = 0.28-0.59).Conclusion: The clinical features and laboratory abnormalities are similar to those previously reported in other countries, besides higher rates of pulmonary involvement, secondary amyloidosis, and ECG abnormalities. Our results imply that IL-6 is involved in MCD pathogenesis. These findings would be informative for diagnosis and appropriate treatment for MCD.

Predictive factors for structural remission using abatacept: Results from the ABROAD study.

OBJECTIVE: To investigate the effect of abatacept (ABA) on preventing joint destruction in biological disease-modifying anti-rheumatic drug (bDMARD)-naïve rheumatoid arthritis (RA) patients in real-world clinical practice. PATIENTS AND METHODS: RA patients were collected from the ABROAD (ABatacept Research Outcomes as a First-line Biological Agent in the Real WorlD) study cohort. They had moderate or high disease activity and were treated with ABA as a first-line bDMARD. Radiographic change between baseline and 1 year after ABA treatment was assessed with the van der Heijde's modified Total Sharp Score (mTSS). Predictive factors for structural remission (St-REM), defined as ΔmTSS ≤0.5/year, were determined. RESULTS: Among 118 patients, 81 (67.5%) achieved St-REM. Disease duration <3 years (odds ratio (OR) = 3.152, p = .007) and slower radiographic progression (shown as 'baseline mTSS/year <3', OR = 3.727, p = .004) were independently significant baseline predictive factors for St-REM irrespective of age and sex. St-REM prevalence increased significantly if clinical remission based on the Simplified Disease Activity Index was achieved at least once until 24 weeks after ABA treatment. CONCLUSION: Shorter disease duration, smaller radiographic progression at baseline, and rapid clinical response were predictive factors for sustained St-REM after ABA therapy in bDMARD-naïve RA patients.

Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis: results from a randomised, double-blind, placebo-controlled, phase 3 trial in Japan (the TAKT study).

OBJECTIVE: To investigate the efficacy and safety of the interleukin-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK). METHODS: Patients with TAK who had relapsed within the previous 12 weeks were induced into remission with oral glucocorticoid therapy. In this double-blind, placebo-controlled trial, patients were randomly assigned 1:1 to receive weekly tocilizumab 162 mg or placebo subcutaneously, and oral glucocorticoids were tapered 10 %/week from week 4 to a minimum of 0.1 mg/kg/day until 19 patients relapsed. The primary endpoint was time to relapse of TAK, defined as ≥2 of the following: objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms or ischaemic symptoms. RESULTS: The intent-to-treat and safety populations included 18 tocilizumab-treated and 18 placebo-treated patients. The per-protocol set (PPS) included 16 tocilizumab-treated and 17 placebo-treated patients. HRs for time to relapse of TAK were 0.41 (95.41% CI 0.15 to 1.10; p=0.0596) in the intent-to-treat population (primary endpoint) based on relapse in eight tocilizumab-treated and 11 placebo-treated patients and 0.34 (95.41% CI 0.11 to 1.00; p=0.0345) in the PPS. The secondary endpoints, time to relapse assessed by Kerr's definition and clinical symptoms only, were consistent with the primary endpoint. Serious adverse events were reported in one tocilizumab-treated and two placebo-treated patients. There were no serious infections and no deaths. CONCLUSION: Although the primary endpoint was not met, the results suggest favour for tocilizumab over placebo for time to relapse of TAK without new safety concerns. Further investigation is warranted to confirm the efficacy of tocilizumab in patients with refractory TAK. TRIAL REGISTRATION NUMBER: JapicCTI-142616.

Tentative diagnostic criteria and disease severity classification for Castleman disease: A report of the research group on Castleman disease in Japan.

OBJECTIVES: To determine the tentative diagnostic criteria and disease severity classification for Castleman disease (CD) and describe the clinical and pathologic features among human herpesvirus 8 (HHV-8) negative idiopathic multicentric CD (iMCD) in the Japanese population. METHODS: We established the working groups for the research of CD in Japan and had meetings to discuss and define the tentative diagnostic criteria and disease severity classification for CD. We subsequently analyzed 142 patients classified into iMCD by using the nationwide Japanese patient registry. RESULTS: We proposed the preliminary diagnostic criteria and disease severity classification for CD based on our discussion. In addition, we made a proposal for the disease activity score. We identified clinical and pathological features of patients with iMCD diagnosed by these diagnostic criteria. In the disease severity classification, 37, 33 and 30% patients were categorized into mild, moderate and severe diseases, respectively. CONCLUSION: This is the first proposal for diagnosis and classification of CD by the Japanese group. Further studies are required to validate whether they can distinguish CD from other inflammatory diseases and to determine their sensitivity and specificity.

Evidence-based clinical practice guideline for adult Still's disease.

OBJECTIVES: Using an expert- and data-driven methodology, we have constructed the first clinical practice guidelines (CPGs) for adult Still's disease (ASD) after complete systematic review (SR) of the literature based upon the Medical Information Network Distribution Service (Minds) procedure. METHODS: The CPG committee for ASD organized by the Research Team for Autoimmune Diseases, the Research Program for Intractable Disease of the Japanese Ministry of Health, Labour, and Welfare has developed CPG for ASD 2017, according to the procedure proposed by Minds. The CPG development process includes (1) clarification of the purpose of CPG, (2) organization of the steering committee, (3) organization of the CPG committee and secretariat, (4) defining the scope (setting of clinical questions (CQs)), (5) SR, (6) development of recommendations, (7) drafting the CPG, (8) external evaluation and public comments, and (9) release. Because we wanted to construct CPG for ASD to encompass both adult-onset Still's disease (AOSD) and adult patients with systemic juvenile idiopathic arthritis (sJIA), we also included SR data from sJIA in this study. RESULTS: Twenty-six CQs were selected and roughly divided into the following items: (1) clinical findings (CQs 1-4), (2) laboratory findings (CQs 5-8), (3) complications (CQs 9-13), (4) treatment with oral medicine (CQs 14-19), (5) treatment with biological reagents (CQs 20-23), and (6) treatments for sJIA (CQs 25-26). Recommendations and the strength of the recommendations for these CQs were decided by a modified Delphi method. CONCLUSION: We have developed the first published CPG for ASD including AOSD and sJIA, which includes 26 CQs and recommendations. This guideline will help rheumatologists, non-specialized physicians, other healthcare providers, medical and health-related students, and patients and their family members to understand and treat ASD.

Comparison of clinical and pathological features of lung lesions of systemic IgG4-related disease and idiopathic multicentric Castleman's disease.

AIMS: The lung lesion [immunoglobulin (Ig)G4-L] of IgG4-related disease (IgG4-RD) is a condition that occurs together with IgG4-RD and often mimics the lung lesion [idiopathic multicentric Castleman's disease (iMCD-L)] of idiopathic multicentric Castleman's disease (iMCD). Because no clinical and pathological studies had previously compared features of these diseases, we undertook this comparison with clinical and histological data. METHODS AND RESULTS: Nine patients had IgG4-L (high levels of serum IgG4 and of IgG4+ cells in lung specimens; typical extrapulmonary manifestations). Fifteen patients had iMCD-L (polyclonal hyperimmunoglobulinaemia, elevated serum interleukin-6 levels and polylymphadenopathy with typical lymphadenopathic lesions). Mean values for age, serum haemoglobin levels and IgG4/IgG ratios were higher in the IgG4-L group and C-reactive protein levels were higher in the iMCD-L group. All IgG4-RD lung lesions showed myxomatous granulation-like fibrosis (active fibrosis), with infiltration of lymphoplasmacytes and scattered eosinophils within the perilymphatic stromal area, such as interlobular septa and pleura with obstructive vasculitis. All 15 lung lesions of iMCD, however, had marked accumulation of polyclonal lymphoplasmacytes in lesions with lymphoid follicles and dense fibrosis, mainly in the alveolar area adjacent to interlobular septa and pleura without obstructive vasculitis. CONCLUSIONS: Although both lesions had lymphoplasmacytic infiltration, lung lesions of IgG4-RD were characterized by active fibrosis with eosinophilic infiltration within the perilymphatic stromal area with obstructive vasculitis, whereas lung lesions of iMCD had lymphoplasmacyte proliferating lesions mainly in the alveolar area adjacent to the perilymphatic stromal area. These clinicopathological features may help to differentiate the two diseases.

Effectiveness and safety of tocilizumab in achieving clinical and functional remission, and sustaining efficacy in biologics-naive patients with rheumatoid arthritis: The FIRST Bio study.

OBJECTIVE: To evaluate effectiveness and safety of tocilizumab (TCZ) in biologic-naive Japanese patients with rheumatoid arthritis (RA) in real-world settings, and to analyze the relationship between disease duration and clinical outcomes. METHODS: The FIRST Bio study was a postmarketing surveillance study of intravenous TCZ in biologics-naive patients who had a prior inadequate response or were intolerant to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD). Effectiveness, safety, and concomitant csDMARD administration were assessed. RESULTS: Of the 839 patients analyzed, 72.3% completed 52 weeks of treatment. The Clinical Disease Activity Index (CDAI) remission rate at week 52 was 36.8%. Contributing factors for CDAI remission were younger age, early disease stage, and no comorbidities. Health Assessment Questionnaire Disability Index ≤0.5 was achieved in 65.1% of patients, and was significantly associated with disease duration. Discontinuation of concomitant methotrexate (MTX) and glucocorticoids (GCs) was possible in 19.3% and 34.1% of patients, respectively, without decreasing remission rate. The incidence (events/100 patient-years) of serious adverse events was 18.09, the most common being infection. CONCLUSION: These data validate the importance of TCZ treatment in the early stages of RA in biologic-naive patients to achieve increased effectiveness. The safety profile of TCZ was reconfirmed. Furthermore, TCZ therapy may allow discontinuation of concomitant MTX and GCs without affecting remission.

Comparisons of Aluminum and Silica Elution from Various Glass Vials.

To understand the risk of particle formation in glass vials, we investigated the correlation between vial surface condition and alminum (Al) or silicon (Si) elution using various suppliers' vials with or without surface treatment. The elution of Si, which can also be an indicator of Al elution, consists of two phases; the first phase is influenced by roughness of the glass surface at the time of filling, and the second phase is dependent on the fundamental elution rate from the glass tube. When vials were filled with citrate buffer at pH 7, vials with varied surface conditions showed the most obvious differences in Al and Si elution. Sulfur-treated vials showed slightly lower Al and Si elution than the non-treated vials. It is considered that this effect of the sulfur treatment on elution is due to the surface being smoothed during heat treatment after the washing process. Different from the sulfur treatment, silicon dioxide (SiO2)-coated vials hardly showed any Al elution as long as the surface was fully coated with the SiO2 layer. It was found that the protective effect of the SiO2 layer against Al elution is more effective in a vial filled with a solution having a lower pH, due to the lower Si dissolving rate occurring at a lower pH. As shown above, pre-measuring the Si and Al present in a citrate buffer at pH 7 placed within a glass container can be a useful tool for selecting the appropriate container for liquid drugs.

Anti-interleukin-6 receptor antibody (MR16-1) promotes muscle regeneration via modulation of gene expressions in infiltrated macrophages.

BACKGROUND: Although rat anti-mouse IL-6 receptor (IL-6R) antibody (MR16-1) has been reported to effectively ameliorate various tissue damages, its effect on skeletal muscle regeneration has not been determined. Moreover, the localization, persistence and duration of action of this reagent in damaged tissues after systemic administration have not been assessed. METHODS: The MR16-1 was administered i.p. immediately after cardiotoxin (CTX)-induced muscle damage on mice. RESULTS: MR16-1 administered i.p. was observed only to the damaged muscle. This delivered MR16-1 was dramatically decreased from 3 to 7days post-injury concomitantly with a reduction of IL-6R expression. This reduction of the MR16-1 level in the damaged muscle was not rescued by additional administration of MR16-1, suggesting the short half-life of MR16-1 was not the factor for the remaining levels. In addition, a significant inhibitory effect of MR16-1 on phosphorylation of the signal transducer and activator of transcription 3 was observed in the macrophage-enriched area of damaged muscle 3days after injury. Finally, the acceleration of muscle regeneration observed at day 7 post-injury following MR16-1 treatment was associated with reduced expression of fibrosis-related genes, such as interleukin-10 and arginase, in the infiltrated macrophages. CONCLUSIONS: These results suggest that MR16-1 which was found primarily localized in infiltrated macrophages in the damaged muscle might facilitate muscle regeneration via immune modulation. GENERAL SIGNIFICANCE: These findings are deemed to provide further insight into the understanding not only of MR16-1 treatment on muscle regeneration, but also of the other anti-cytokine treatment on the cytokine-related disease.

A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus eyrthematosus in Japanese.

Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Although recent genome-wide association studies (GWAS) have contributed to discovery of SLE susceptibility genes, few studies has been performed in Asian populations. Here, we report a GWAS for SLE examining 891 SLE cases and 3,384 controls and multi-stage replication studies examining 1,387 SLE cases and 28,564 controls in Japanese subjects. Considering that expression quantitative trait loci (eQTLs) have been implicated in genetic risks for autoimmune diseases, we integrated an eQTL study into the results of the GWAS. We observed enrichments of cis-eQTL positive loci among the known SLE susceptibility loci (30.8%) compared to the genome-wide SNPs (6.9%). In addition, we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with SLE susceptibility (rs340630; P = 8.3×10(-9), odds ratio = 1.21). The risk A allele of rs340630 demonstrated a cis-eQTL effect on the AFF1 transcript with enhanced expression levels (P<0.05). As AFF1 transcripts were prominently expressed in CD4(+) and CD19(+) peripheral blood lymphocytes, up-regulation of AFF1 may cause the abnormality in these lymphocytes, leading to disease onset.

IL-6 signal blockade ameliorates the enhanced osteoclastogenesis and the associated joint destruction in a novel FcγRIIB-deficient rheumatoid arthritis mouse model.

OBJECTIVE: We earlier found that TNFα but not interleukin (IL)-17 is indispensable in the pathogenesis of spontaneously occurring rheumatoid arthritis (RA)-like disease in our newly established FcγRIIB-deficient C57BL/6 (B6) mouse model, designated KO1. Here, we examined the role of IL-6 in the pathogenesis of RA features in KO1, with particular reference to cartilage and bone destruction in arthritic joints. METHODS: To evaluate the preventive effect of MR16-1, a rat anti-mouse IL-6 receptor (IL-6R) mAb, 4-month-old preclinical KO1 mice were divided into three groups: the first treated with MR16-1 for 6 months, the second treated with normal rat IgG, as a control, and the third left untreated. The incidence and severity of arthritis, immunological abnormalities, and transcription levels of receptor activator of NF-κB ligand (RANKL), osteoprotegerin (OPG), and inflammatory cytokines/chemokines in ankle joint tissues were compared among the three groups. The therapeutic effect of MR16-1 was examined by treating 7-month-old KO1 mice in the early stages of arthritis for 2 months. RESULTS: Compared with the findings in the KO1 mice left untreated or treated with normal rat IgG, the development of arthritis was markedly suppressed in mice with MR16-1 treatment started from preclinical stages. The suppression was associated with the decrease in production of autoantibodies, rheumatoid factors (RF), and anti-cyclic citrullinated peptide (CCP). Histologically, marked synovitis, pannus formation, and cartilage and bone destruction associated with the increase in tartrate-resistant acid phosphatase (TRAP)-positive osteoclast generation were evident in the two control groups; however, these findings were virtually absent in MR16-1-treated mice. Real-time PCR analysis revealed that the up-regulated expression levels of MCP-1, IL-6, and TNFα, and the aberrantly high RANKL/OPG expression ratio in synovial joint tissues from the two control groups of mice with overt arthritis were significantly suppressed in MR16-1-treated mice. In mice with therapeutic MR16-1 treatment, there was no progression in arthritis score and the RANKL/OPG ratio in joint tissues was significantly suppressed. CONCLUSIONS: Administration of an anti-IL-6R mAb ameliorated spontaneously occurring RA-like disease features, indicating that IL-6, as well as TNFα, plays a pivotal role in the pathogenesis of RA in KO1 mice. Current studies showed that, in addition to the role in enhancing autoantibody production, IL-6 promotes synovial tissue inflammation and osteoclastogenesis, leading to the severe synovitis with pannus formation and the progressive cartilage and bone destruction in multiple joints.

[IL-6 inhibitors prevent bone loss and cartilage degeneration in rheumatoid arthritis].

Dysregulation of cytokines, including interleukin-6 (IL-6), is involved in joint destruction in rheumatoid arthritis (RA). The concentration of IL-6 is increased not only in the affected joints but also in the serum. Locally, IL-6 provides the formation of pannus through the synthesis of vascular endothelial growth factor (VEGF). In addition, IL-6 contributes to the production of matrix metalloproteinases which digest collagen and proteoglycan of cartilage. Furthermore, IL-6 induces the differentiation and activation of osteoclasts. IL-6 can be delivered systemically to a similar extent as hormones, may induce systemic osteoporosis. Tocilizumab (TCZ), a humanized anti-IL-6 receptor antibody, inhibiting IL-6 signaling, has provided beneficial outcomes, such as achievement of clinical remission, protective effects against bone and cartilage destruction. Because of the beneficial outcomes, new drugs inhibiting IL-6 signaling are developed, and the clinical trials are ongoing.

Validation of the classification criteria for cryoglobulinaemic vasculitis.

OBJECTIVE: The aim of this study was to validate the classification criteria for cryoglobulinaemic vasculitis (CV). METHODS: Twenty-three centres were involved. New patients with CV (group A) and controls, i.e. subjects with serum cryoglobulins but lacking CV based on the gold standard of clinical judgment (group B) and subjects without cryoglobulins but with clinical features that can be observed in the course of CV (group C), were studied. Positivity of serum cryoglobulins was necessary for CV classification. Sensitivity and specificity of the criteria were calculated by comparing group A vs group B. The group A vs group C comparison was done to demonstrate the possible diagnostic utility of the criteria. RESULTS: The study included 268 patients in group A, 182 controls in group B and 193 controls in group C (small vessel vasculitis, 51.8%). The questionnaire (at least 2/3 positive answers) showed 89.0% sensitivity and 93.4% specificity; the clinical item (at least 3/4 clinical involvement) showed 75.7% sensitivity and 89.0% specificity and the laboratory item (at least 2/3 laboratory data) showed 80.2% sensitivity and 62.4% specificity. The sensitivity and specificity of the classification criteria (at least 2/3 positive items) were 89.9% and 93.5%, respectively. The comparison of group A with group C demonstrated the clinical utility of the criteria in differentiating CV from CV mimickers. CONCLUSION: Classification criteria for CV were validated in a second, large, international study confirming good sensitivity and specificity in a complex systemic disease.

Immune response to influenza vaccine and pneumococcal polysaccharide vaccine under IL-6 signal inhibition therapy with tocilizumab.

OBJECTIVES: To evaluate humoral immune response to influenza vaccine and polysaccharide pneumococcal vaccine in patients with rheumatoid arthritis (RA) or Castleman's disease (CD) during tocilizumab therapy. METHODS: Thirty-eight patients (28 RA and 10 CD) receiving tocilizumab and 39 RA patients receiving TNF inhibitors and/or synthetic DMARDs subcutaneously received a single dose of a split-virion inactivated influenza vaccine containing A(New Caledonia (NC):H1N1), A(Hiroshima (HIR):H3N2) and B(Malaysia (MAL)) strains. Twenty-one RA patients using tocilizumab also received 23-valent polysaccharide pneumococcal vaccine. Antibody titers were measured every 4 weeks for a total of 12 weeks after vaccination. RESULTS: In the tocilizumab group, seroprotective titers (40-fold or more) were obtained in 36/38(95%) for A(NC), 35/38(92%) for A(HIR) and 32/38(84%) for B(MAL). In the patients with baseline antibody titer < 40-fold, 11/11(100%), 7/8(88%) and 18/20(90%) patients showed four-fold or more increase in the titer from baseline to A(NC), A(HIR) and B(MAL), respectively. Patients using TNF inhibitors and/or DMARDs showed similar responses. Pneumococcal antibody titers increased at least two-fold in more than 9 of 12 serotypes, which continued for longer than 12 weeks in all the patients. CONCLUSION: Interleukin-6 (IL-6) blocking therapy with tocilizumab did not affect the humoral immune response to both influenza and pneumococcal vaccines.

Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy (DREAM) study.

OBJECTIVES: To investigate the duration of remission and low disease activity (LDA) after cessation of tocilizumab (TCZ) treatment in rheumatoid arthritis patients who showed remission or LDA as assessed by DAS28 in response to preceding TCZ monotherapy, and to explore the factors contributing to prolonged efficacy duration. METHODS: Disease activity was monitored for 56 weeks. The rate of continued efficacy was estimated by Kaplan-Meier curves. RESULTS: A total of 187 patients were eligible. At baseline of this study, median disease duration was 7.8 years, preceding TCZ treatment period was 4.0 years and DAS28 was 1.5. The rate of continued LDA at 52 weeks was 13.4 % according to the Kaplan-Meier estimate. 19 patients (10 %) were completely drug-free and 17 patients (9.1 %) fulfilled DAS28 remission at 52 weeks. Multivariate Cox regression analysis identified low serum IL-6 and normalisation of MMP-3 levels at cessation of TCZ as independent predictive markers for longer duration of LDA. In patients with low serum IL-6 (<12.9 pg/mL) and normal MMP-3 levels, the rate of continued LDA reached 38.0 % at 52 weeks. CONCLUSIONS: TCZ monotherapy may induce biologics-free remission or LDA without concomitant use of synthetic DMARDs. Serum levels of IL-6 and MMP-3 are useful markers for identifying patients who could discontinue TCZ without acute disease flare.

Retreatment efficacy and safety of tocilizumab in patients with rheumatoid arthritis in recurrence (RESTORE) study.

OBJECTIVES: To evaluate the safety and efficacy of retreatment with tocilizumab (TCZ) in patients who had participated in the DREAM study (Drug free remission/low disease activity after cessation of tocilizumab [Actemar] monotherapy study) and had experienced loss of efficacy. METHODS: Patients were retreated with TCZ or other disease modifying antirheumatic drugs (DMARDs). Disease activity was measured using the 28-joint disease activity score (DAS28) for 12 weeks. RESULTS: A total of 164 eligible patients, including 161 who experienced loss of efficacy within 52 weeks of the DREAM study, resumed treatment: 157 with TCZ and 7 with DMARDs and/or infliximab. Of TCZ-treated patients, 88.5 % (139 patients) achieved DAS28 <2.6 within 12 weeks, whereas among patients treated with DMARDs and/or infliximab only 14.3 % (1 patient) achieved DAS28 <2.6. Adverse events were observed in 70 TCZ-treated patients (44.0 %), but no serious infusion reactions were observed. CONCLUSIONS: Retreatment with TCZ was well-tolerated and effective in patients who had responded to the preceding TCZ monotherapy but had experienced loss of efficacy after cessation of TCZ.

Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement.

BACKGROUND: Suppression of the immunoinflammatory cascade by targeting interleukin 6 (IL-6) mediated effects constitutes a therapeutic option for chronic inflammatory diseases. Tocilizumab is the only IL-6 inhibitor (IL-6i) licensed for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), but also other agents targeting either IL-6 or its receptor are investigated in various indications. OBJECTIVE: To review published evidence on safety and efficacy of IL-6i in inflammatory diseases. METHODS: We performed systematic literature searches in Medline and Cochrane, screened EULAR and American College of Rheumatology meeting-abstracts, and accessed http://www.clinicaltrials.gov. RESULTS: Comprehensive evidence supports the efficacy of tocilizumab in RA in DMARD-naïve patients, and after DMARD- and TNFi-failure. Randomised comparisons demonstrate superiority of tocilizumab in JIA, but not ankylosing spondylitis (AS). Other indications are currently investigated. Additional IL-6i show similar efficacy; safety generally appears acceptable. CONCLUSIONS: IL-6i is effective and safe in RA and JIA, but not in AS. Preliminary results in other indications need substantiation.