Effect of Recent Antirheumatic Drug on Features of Rheumatoid Arthritis-Associated Lymphoproliferative Disorders.

OBJECTIVE: In this study, we examine how advancements in novel antirheumatic drugs affect the clinicopathologic features of lymphoproliferative disorder (LPD) in patients with rheumatoid arthritis (RA). METHODS: In this multicenter study across 53 hospitals in Japan, we characterized patients with RA who developed LPDs and visited the hospitals between January 1999 and March 2021. The statistical tools used included Fisher's exact test, the Mann-Whitney U-test, the log-rank test, logistic regression analysis, and Cox proportional hazards models. RESULTS: Overall, 752 patients with RA-associated LPD (RA-LPD) and 770 with sporadic LPD were included in the study. We observed significant differences in the clinicopathologic features between patients with RA-LPD and those with sporadic LPD. Histopathological analysis revealed a high frequency of LPD-associated immunosuppressive conditions. Furthermore, patients with RA-LPD were evaluated based on the antirheumatic drugs administered. The methotrexate (MTX) plus tacrolimus and MTX plus tumor necrosis factor inhibitor (TNFi) groups had different affected site frequencies and histologic subtypes than the MTX-only group. Moreover, MTX and TNFi may synergistically affect susceptibility to Epstein-Barr virus infection. In case of antirheumatic drugs administered after LPD onset, tocilizumab (TCZ)-only therapy was associated with lower frequency of regrowth after spontaneous regression than other regimens. CONCLUSION: Antirheumatic drugs administered before LPD onset may influence the clinicopathologic features of RA-LPD, with patterns changing over time. Furthermore, TCZ-only regimens are recommended after LPD onset.

Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis.

Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, in PTK2B, LILRA3/LILRB2, DUSP22, and KLHL33, respectively. Two additional significant loci unreported in non-European GWAS were identified, namely HSPA6/FCGR3A and chr21q.22. We found that a single variant associated with the expression of MICB, a ligand for natural killer (NK) cell receptor, could explain the entire association with the HLA-B region. Rs2322599 is strongly associated with the expression of PTK2B Rs103294 risk allele in LILRA3/LILRB2 is known to be a tagging SNP for the deletion of LILRA3, a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 (P = 1.2 × 10-3). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells (P = 8.8 × 10-5, enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between LILRA3 and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.

Beneficial use of serum ferritin and heme oxygenase-1 as biomarkers in adult-onset Still's disease: A multicenter retrospective study.

BACKGROUND: Heme oxygenase (HO)-1 is a heme-degrading enzyme highly expressed in monocyte/macrophage, serum levels of which may be promising biomarker for adult-onset Still's disease (AOSD). We here report data on the use of serum ferritin and HO-1 levels in AOSD. METHODS: Under the Hypercytokinemia Study Group collaboration, we collected sera from a total of 145 AOSD patients. Three independent experts judged whether the patients were definite AOSD depending on the clinical information. These 91 'definite AOSD' patients were further divided into active, remission, and relapse groups. Forty-six cases of systemic vasculitis, sepsis, etc. were included as disease controls. Serum ferritin and HO-1 levels were measured using ELISA. Associations between clinical symptoms, serum ferritin, and HO-1 were explored. Multivariate regression analysis was performed to identify independent variables associated with definite AOSD diagnosis. RESULTS: Serum ferritin and HO-1 levels were significantly higher in active and relapsed AOSD cases compared to disease controls, and were reduced by the treatment. Although a significant correlation was found between serum ferritin and HO-1 levels, a discrepancy was found in some cases such as iron-deficiency anemia. Receiver operating characteristic analysis identified optimal levels of serum ferritin (>819 ng/ml; sensitivity 76.1% and specificity 73.8%), and serum HO-1 (>30.2 ng/ml; sensitivity 84.8% and specificity 83.3%) that differentiated AOSD from controls. Interestingly, 88.9% of patients with AOSD who relapsed exceeded the cut-off value of serum HO-1 > 30.2 ng/ml, but only 50.0% exceeded serum ferritin >819 ng/ml (p = .013), suggesting that serum HO-1 levels may be a convenient indicator of AOSD disease status. Multivariate analysis identified neutrophilia, RF/ANA negativity, sore throat, and elevated serum HO-1 as independent variables associated with AOSD diagnosis. CONCLUSION: We confirmed that serum ferritin and HO-1 serve as highly specific and sensitive biomarkers for AOSD. A future prospective study with large sample size is necessary to determine whether these biomarkers could be included in Yamaguchi's Criteria.

Investigation of Small Bowel Abnormalities in HIV-Infected Patients Using Capsule Endoscopy.

HIV infection is reportedly associated with an increased permeability of the intestinal epithelium and can cause HIV enteropathy, which occurs independently of opportunistic infections. However, the characteristics of small bowel abnormalities attributable to HIV infection are rarely investigated. In the present study, we assessed the intestinal mucosal changes found in HIV-infected patients and compared them with the mucosa of healthy control subjects using capsule endoscopy (CE). Three of the 27 HIV-infected patients harbored gastrointestinal opportunistic infections and were thus excluded from subsequent analyses. The endoscopic findings of CE in HIV-infected patients were significantly higher than those in control subjects (55% versus 10%, P = 0.002); however, most lesions, such as red spots or tiny erosions, were unlikely to cause abdominal symptoms. After validating the efficacy of CE for the diagnosis of villous atrophy, we found that the prevalence of villous atrophy was 54% (13/24) among HIV-infected patients. Interestingly, villous atrophy persisted in patients receiving long-term antiretroviral therapy, though most of them exhibited reconstituted peripheral blood CD4+ T cells. Although we could not draw any conclusions regarding the development of small bowel abnormalities in HIV-infected patients, our results may provide some insight regarding the pathogenesis of HIV enteropathy.

Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility.

We analyzed 1,900 Turkish Behçet's disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated SNP was rs1050502, a tag SNP for HLA-B*51. In the Turkish discovery set, we identified three new risk loci, IL1A-IL1B, IRF8, and CEBPB-PTPN1, with genome-wide significance (P < 5 × 10-8) by direct genotyping and ADO-EGR2 by imputation. We replicated the ADO-EGR2, IRF8, and CEBPB-PTPN1 loci by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls further replicated ADO-EGR2 and IRF8, and meta-analysis additionally identified RIPK2 and LACC1. The disease-associated allele of rs4402765, the lead marker at IL1A-IL1B, was associated with both decreased IL-1α and increased IL-1ß production. ABO non-secretor genotypes for two ancestry-specific FUT2 SNPs showed strong disease association (P = 5.89 × 10-15). Our findings extend the list of susceptibility genes shared with Crohn's disease and leprosy and implicate mucosal factors and the innate immune response to microbial exposure in Behçet's disease susceptibility.

On-demand ultrasonography assessment in the most symptomatic joint supports the 8-joint score system for management of rheumatoid arthritis patients.

OBJECTIVES: To investigate whether on-demand ultrasonography (US) assessment alongside a routine examination is useful in the management of rheumatoid arthritis (RA). METHODS: US was performed in eight (bilateral MCP 2, 3, wrist and knee) joints as the routine in a cumulative total of 406 RA patients. The most symptomatic joint other than the routine joints was additionally scanned. Power Doppler (PD) and gray-scale images were scored semiquantitatively. Eight-joint scores were calculated as the sum of individual scores for the routine joints. RESULTS: The most symptomatic joint was found among the routine joints in 209 patients (Group A) and in other joints in 148 (Group B). The PD scores of the most symptomatic joint correlated well with the 8-joint scores in Group A (rs = 0.66), but not in Group B (rs = 0.33). The sensitivity and specificity of assessment of the most symptomatic joint for routine assessment positivity were high (84.0% and 100%, respectively) in Group A, but low (50.0% and 61.8%, respectively) in Group B. Additional examination detected synovitis in 38% of Group B with negative results in the routine. CONCLUSIONS: On-demand US assessment in the most symptomatic joint, combined with the routine assessment, is useful for detecting RA synovitis.

Musculoskeletal ultrasonography delineates ankle symptoms in rheumatoid arthritis.

OBJECTIVES: To clarify the use of musculoskeletal ultrasonography (US) of ankle joints in rheumatoid arthritis (RA). METHODS: Consecutive RA patients with or without ankle symptoms participated in the study. The US, clinical examination (CE), and patients' visual analog scale for pain (pVAS) for ankles were assessed. Prevalence of tibiotalar joint synovitis and tenosynovitis were assessed by grayscale (GS) and power Doppler (PD) US using a semi-quantitative grading (0-3). The positive US and CE findings were defined as GS score ≥2 and/or PD score ≥1, and joint swelling and/or tenderness, respectively. Multivariate analysis with the generalized linear mixed model was performed by assigning ankle pVAS as a dependent variable. RESULTS: Among a total of 120 ankles from 60 RA patients, positive ankle US findings were found in 21 (35.0%) patients. The concordance rate of CE and US was moderate (kappa 0.57). Of the 88 CE negative ankles, US detected positive findings in 9 (10.2%) joints. Multivariate analysis revealed that ankle US, clinical disease activity index, and foot Health Assessment Questionnaire, but not CE, was independently associated with ankle pVAS. CONCLUSION: US examination is useful to illustrate RA ankle involvement, especially for patients who complain ankle pain but lack CE findings.

Continuous evolution of clinical phenotype in 578 Japanese patients with Behçet's disease: a retrospective observational study.

BACKGROUND: It has been suggested that the phenotypes of Behçet's disease (BD) in Japan are changing. To ask whether the evolution of BD holds true in recent-onset cases in Japan, we performed a retrospective study. METHODS: We reviewed the records of 578 patients with BD who met the 1987 revised diagnostic criteria of the Behçet's disease research committee of Japan. The patients were divided into three groups based on the date of disease onset. We compared the demography, clinical features, and treatments among them with or without adjustment for the observation period. Patients having oral ulcers, genital ulcers, regional skin involvement, and uveitis are categorized as having complete-type BD, and the associated factors were determined by univariate and multivariate logistic regression analyses. RESULTS: Male patients had a higher propensity for uveitis and central nervous system (CNS) involvement, whereas female patients had higher rates of genital ulcers and arthritis. We found a significant trend in reduction of complete-type, genital ulcer, HLA-B51 carriers, and increment of gastrointestinal BD over time. Multiple regression analysis identified HLA-B51 positivity, earlier date of disease onset, and younger age of onset as independently associated with complete-type BD. Although treatments had been also chronologically changed, the causative relationship between therapeutic agents and phenotypical changes was not determined from the study. CONCLUSION: The present study revealed that phenotypical evolution was characterized by decreased incidence of the complete type and increment of gastrointestinal involvement in Japanese patients with BD during the last 30 years.

Non-IgG4-related Multifocal Fibrosclerosis.

Multifocal fibrosclerosis (MFS), which causes systemic and chronic connective tissue inflammation, has been associated with IgG4 and regarded as an identical entity with "IgG4-related disease (IgG4-RD)". Although a few cases of MFS mimicking IgG4-RD histopathologically, despite the absence of a serum IgG4 elevation and IgG4-positive plasma cell infiltration, have been reported, there is, so far, little information regarding such exceptional cases. We herein demonstrate a case of non-IgG4-related MFS presenting with periaortitis and parotiditis, whose histological findings were consistent with IgG4-RD despite the absence of elevated serum and tissue IgG4 levels.

Digital PCR assay detection of circulating Mycobacterium tuberculosis DNA in pulmonary tuberculosis patient plasma.

Nucleic acid amplification tests are a major diagnostic tool for pulmonary tuberculosis (PTB). Recently, digital PCR (dPCR) assay has improved sensitivity for the detection of small copy numbers of target molecules. The aim of this study is to explore the utility of dPCR for detecting Mycobacterium tuberculosis (MTB) DNA in PTB patient plasma. Total DNA was purified from plasma samples of newly diagnosed sputum smear-positive PTB patients. Copy numbers of MTB-specific genes in the samples were quantified with dPCR assays targeted for IS6110 or gyrB. A total of 33 PTB patients were enrolled. Significant differences between PTB patients and controls were observed in copy numbers of both targets: IS6110 mean ± SD, 144.8 ± 538.3 vs 0.44 ± 0.49 (copies/20 µL, p = 0.004; Mann-Whitney U test) and gyrB mean ± SD, 359.0 ± 2116 vs 0.07 ± 0.28 (copies/20 µL, p = 0.011; Mann-Whitney U test), respectively. This test had sensitivities of 65% or 29% and a specificity of 93% or 100% with the IS6110-targeted or gyrB-targeted assays, respectively. A dPCR assay successfully detected MTB DNA in PTB patient plasma. This minimally invasive and accurate method has potential to become an alternative diagnostic option.

Effect of adiponectin-encoding gene ADIPOQ single nucleotide polymorphisms +45 and +276 on serum lipid levels after antiretroviral therapy in Japanese patients with HIV-1-infection.

OBJECTIVES: To investigate the association between single nucleotide polymorphisms (SNPs) in the adiponectin-encoding gene ADIPOQ and changes in serum lipid levels in HIV-1-infected patients after antiretroviral therapy (ART). METHODS: ART-naïve HIV-1-infected patients were recruited to this prospective analysis. SNP +45 and SNP +276 genotype was determined by direct sequencing. Multivariate linear regression analysis was performed to analyse the effects of genotype, and predisposing conditions on serum total cholesterol and triglyceride in the 4 months before and after ART initiation. RESULTS: The study enrolled 78 patients with HIV-1-infection (73 male, five female; age range 22-67 years). HIV-1 viral load ≥5 log10 copies/ml, baseline total cholesterol ≥160 mg/dl, and CD4(+) lymphocyte count <200/µl were associated with increased serum total cholesterol levels after ART initiation. Protease inhibitor treatment and body mass index ≥25 kg/m(2) were associated with increased triglyceride levels after ART initiation. There were no significant associations between SNP +45 or SNP +276 genotype and serum total cholesterol or triglyceride levels. CONCLUSIONS: SNP +45 and SNP +276 genotype is not associated with changes in serum total cholesterol or triglyceride levels after ART initiation.

(18)F-FDG and (18)F-NaF PET/CT demonstrate coupling of inflammation and accelerated bone turnover in rheumatoid arthritis.

OBJECTIVE: To compare the findings in rheumatoid arthritis (RA)-affected joints between (18)F-fluorodeoxyglucose (FDG) and (18)F-fluoride (NaF) positron emission tomography (PET)/computed tomography (CT). METHODS: We enrolled twelve RA patients who started a new biologic agent (naïve 9 and switch 3). At entry, both hands were examined by (18)F-FDG PET/CT, (18)F-NaF PET/CT, and X-ray. Intensity of PET signals was determined by standardized uptake value max (SUVmax) in metacarpophalangeal (MCP), proximal interphalangeal (PIP), and ulnar, medial, and radial regions of the wrists. Hand X-rays were evaluated according to the Genant-modified Sharp score at baseline and 6 months. RESULTS: Both (18)F-FDG and (18)F-NaF accumulated in RA-affected joints. The SUVmax of (18)F-FDG correlated with that of (18)F-NaF in individual joints (r = 0.65), though detail distribution was different between two tracers. (18)F-NaF and (18)F-FDG signals were mainly located in the bone and the surrounding soft tissues, respectively. The sum of SUVmax of (18)F-NaF correlated with disease activity score in 28 joint (DAS28), modified health assessment questionnaire (MHAQ), and radiographic progression. (18)F-FDG and (18)F-NaF signals were associated with the presence of erosions, particularly progressive ones. CONCLUSION: Our data show that both (18)F-FDG and (18)F-NaF PET signals were associated with RA-affected joints, especially those with ongoing erosive changes.

Deep-inspiration breath-hold 18F-FDG-PET/CT is useful for assessment of connective tissue disease associated interstitial pneumonia.

OBJECTIVE: To examine clinical utility of (18)F-flurodeoxyglucose (FDG)-positron emission tomography (PET)/CT for assessment of interstitial lung disease (ILD) in patients with connective tissue diseases (CTDs). METHODS: A total of 69 (18)F-FDG PET/CT scans were conducted under deep inspiratory breath hold (DIBH) conditions in 45 CTD patients with ILD, including 16 dermatomyositis/polymyositis, nine systemic scleroderma and seven rheumatoid arthritis. Intensity and distribution of (18)F-FDG signals in PET/CT were determined by standardized uptake value (SUVmax) and visual score in 18 regions, respectively. ILD was defined as active when immunosuppressive therapy was initiated or intensified. RESULTS: Both SUVmax and visual score were higher in active phase (n = 32) than inactive phase (n = 37) (both p < 0.05), regardless of the underlying CTD and plain CT findings. The both parameters reduced after initiating or intensifying treatment in the follow-up study of 17 active patients except two died patients who showed increased visual score. Another two died patients showed high visual score (15 and 6/18, respectively). Changing ratio of visual score, but not SUVmax was correlated with KL-6 (r(2) = 0.38, p < 0.05) and CRP (r(2) = 0.52, p < 0.05). CONCLUSION: The DIBH (18)F-FDG PET/CT procedure sensitively illustrates active ILD lesions in CTD and the extended signal distribution is associated with unfavorable clinical outcome.

Impact of Corticosteroids on Mortality in Patients with Acute Respiratory Distress Syndrome: A Systematic Review and Meta-analysis.

OBJECTIVE: The impact of corticosteroids on acute respiratory distress syndrome (ARDS) mortality remains controversial following the publication of numerous trials, observational studies and meta-analyses. An updated meta-analysis is warranted, as a few original studies on this topic have been published since the last meta-analysis. METHODS: We searched for eligible articles using four databases. In particular, we included full-length original articles providing sufficient data for evaluating the impact of corticosteroid treatment on adult ARDS mortality in the form of odds ratios. A fixed model with the confidence interval method was used. An assessment of publication bias and sensitivity analyses were also conducted. RESULTS: We included 11 of 185 articles. The pooled odds ratio for corticosteroids with respect to all-cause mortality involving 949 patients was 0.77 [95% confidence interval (CI): 0.58-1.03, p=0.079] with strong heterogeneity(I2=70%, p<0.001). The results of the sensitivity analysis, Begg-Kendall test (τ=0.53, p=0.024)and funnel plot consistently suggested the existence of strong publication bias. After six potentially unpublished cohorts were filled using Duval's trim and fill method, the pooled odds ratio shifted to 1.11 (95% CI0.86-1.44, p=0.427). In addition, the sensitivity analyses suggested that corticosteroid treatment has a different impact on mortality depending on the comorbidities and trigger events. CONCLUSION: We were unable to confirm, based on the data of published studies, the favorable impact of corticosteroid therapy on mortality in overall ARDS cases. Published articles exhibit strong publication bias,and previous meta-analyses may be affected by this publication bias. Further research focusing on pathophysiology- or trigger event-specific ARDS is anticipated.

Intrapulmonary Delivery of CpG Microparticles Eliminates Lung Tumors.

CpG oligonucleotides (ODN) stimulate the innate immune system by triggering cells that express TLR9. The resulting response promotes tumor regression, an effect optimized by delivery of CpG ODN to the tumor site. This work examines the effect of instilling CpG ODN adsorbed onto polyketal microparticles (CpG-MP) into the lungs of mice with non-small cell lung cancer. Intrapulmonary delivery of CpG-MP improved ODN uptake and retention at the tumor site, thereby inducing a stronger Th1 response than systemically administered or unadsorbed CpG ODN. CpG-MP reversed the immunosuppression that characterized the tumor microenvironment by (i) decreasing the number of immunosuppressive Tregs and M2 macrophages while (ii) increasing the number of tumoricidal CD8(+) T cells and M1 macrophages. These effects promoted tumor regression and culminated in 82% permanent survival of mice with otherwise fatal Lewis lung cancer.

Adalimumab in the management of Behçet's disease.

Behçet's disease (BD) is a relapsing, systemic, inflammatory disorder that affects various organ systems. Most of the manifestations of BD are self-limiting, but ocular attacks are an exception. Gastrointestinal tract, central nervous system, and cardiovascular system manifestations are relatively infrequent but may be resistant to conventional immunosuppressive treatment and therefore life-threatening. Tumor necrosis factor alpha antagonists are increasingly being used in patients whose BD is inadequately controlled by standard immunosuppressive regimens. Most of the current experience regarding the treatment of refractory BD involves the use of infliximab; however, adalimumab has also been successfully used in cases of BD refractory to both conventional therapy and infliximab. Compared with infliximab, adalimumab offers several other advantages, such as the ability to self-administer at home, better patient compliance, and an improved side effect profile. Here, we review clinical experience of the use of adalimumab to treat the serious manifestations of BD. Adalimumab is a promising drug for the treatment of BD, and its randomized, prospective study in a large number of patients is warranted to fully determine its efficacy in the refractory BD setting.

Takayasu arteritis and ulcerative colitis: high rate of co-occurrence and genetic overlap.

OBJECTIVE: Takayasu arteritis (TAK) is a systemic vasculitis affecting large arteries and large branches of the aorta. Ulcerative colitis (UC) is a prevalent autoimmune colitis. Since TAK and UC share HLA-B*52:01 and IL12B as genetic determinants, and since there are case reports of the co-occurrence of these diseases, we hypothesized that UC is a common complication of TAK. We undertook this study to perform a large-scale analysis of TAK, both to evaluate the prevalence of concurrent cases of TAK and UC and to identify and estimate susceptibility genes shared between the 2 diseases. METHODS: We analyzed a total of 470 consecutive patients with TAK from 14 institutions. We characterized patients with TAK and UC by analyzing clinical manifestations and genetic components. Genetic overlapping of TAK and UC was evaluated with the use of UC susceptibility single-nucleotide polymorphisms by comparing risk directions and effect sizes between susceptibility to the 2 diseases. RESULTS: Thirty of 470 patients with TAK had UC (6.4% [95% confidence interval 4.3-9.0]). This percentage was strikingly higher than that expected from the prevalence of UC in Japan. Patients with TAK complicated with UC developed TAK at an earlier stage of life (P = 0.0070) and showed significant enrichment of HLA-B*52:01 compared to TAK patients without UC (P = 1.0 × 10(-5) ) (odds ratio 12.14 [95% confidence interval 2.96-107.23]). The 110 non-HLA markers of susceptibility to UC significantly displayed common risk directions with susceptibility to TAK (P = 0.0054) and showed significant departure of permutation P values from expected P values (P < 1.0 × 10(-10) ). CONCLUSION: UC is a major complication of TAK. These 2 diseases share a significant proportion of their genetic background, and HLA-B*52:01 may play a central role in their co-occurrence.

Sustainable Efficacy of Switching From Intravenous to Subcutaneous Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis.

OBJECTIVE: To evaluate the efficacy and safety of switching from intravenous (IV) tocilizumab (TCZ) to subcutaneous (SC) TCZ monotherapy in rheumatoid arthritis patients. METHODS: Patients who had completed 24 weeks of TCZ-SC (162 mg/2 weeks) or TCZ-IV (8 mg/kg/4 weeks) monotherapy in the double-blind period of the MUSASHI study were enrolled in an 84-week open-label extension period. All received TCZ-SC (162 mg/2 weeks) monotherapy. Effects of the IV to SC switch were evaluated at week 36 (12 weeks after switching). RESULTS: Overall, 319 patients received ≥1 dose of TCZ-SC during the open-label extension period; 160 switched from TCZ-IV to TCZ-SC (TCZ IV/SC) and 159 continued TCZ-SC (TCZ SC/SC). Disease Activity Score in 28 joints using the erythrocyte sedimentation rate clinical remission rates were 62.5% (100 of 160) for TCZ IV/SC and 50.0% (79 of 158) for TCZ SC/SC at week 24, and were maintained at 62.5% (100 of 160) and 57.0% (90 of 158), respectively, at week 36. In the TCZ IV/SC group, 9% of patients (9 of 100) who had achieved remission at week 24 could not maintain remission at week 36. In TCZ IV/SC patients weighing ≥70 kg, the percentage with a sufficient serum TCZ concentration (≥1 µg/ml) decreased from 90.9% (10 of 11) at week 24 to 45.5% (5 of 11) at week 36. Overall safety profiles were similar in TCZ IV/SC and TCZ SC/SC except for mild injection site reactions in TCZ IV/SC. CONCLUSION: Efficacy is adequately maintained in most patients switching from TCZ-IV (8 mg/kg/4 weeks) to TCZ-SC (162 mg/2 weeks) monotherapy. Patients receiving TCZ-IV can switch to TCZ-SC without serious safety concerns. Clinical efficacy may be reduced after switching in some patients with high body weight.

Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry.

INTRODUCTION: The objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice. METHODS: This prospective cohort study included RA patients starting TCZ [TCZ group, n=302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n=304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis. RESULTS: Patients in the TCZ group had longer disease duration (P<0.001), higher disease activity (P=0.019) and more frequently used concomitant corticosteroids (P<0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37). CONCLUSIONS: The adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice.